Skip to main content
SpringerLink
Log in

Cigarette Smoking and Antiplatelet Effects of Aspirin Monotherapy Versus Clopidogrel Monotherapy in Patients with Atherosclerotic Disease: Results of a Prospective Pharmacodynamic Study

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Smokers have a greater relative benefit of clopidogrel therapy compared with nonsmokers, likely attributed to its enhanced pharmacodynamic (PD) effects. However, to date, all PD studies have been conducted in patients on dual antiplatelet therapy with aspirin and clopidogrel, and it is unknown whether clopidogrel monotherapy can offer more effective antithrombotic effects compared with aspirin alone among smoking patients. Sixty aspirin-treated (81 mg/day) patients with vascular disease, classified as nonsmokers, light smokers, and heavy smokers according to cotinine serum levels, were enrolled. Patients were switched to clopidogrel (75 mg/day) monotherapy for 7–10 days. PD assessments were performed before and after switch by multiple electrode aggregometry (MEA) and kaolin-activated thromboelastography (TEG). Complete PD data were obtained in 57 patients (nonsmokers, n = 27; light smokers, n = 13; heavy smokers, n = 17). On treatment platelet reactivity following MEA, adenosine diphosphate (ADP) + prostaglandin E1 (PGE1) and thrombin receptor-activating peptide (TRAP) stimuli were significantly lower among heavy smokers following switch to clopidogrel. A significant inverse effect was observed with MEA arachidonic acid (ASPI), while neutral findings were shown with MEA collagen (COLL) stimulus. Thrombin and fibrin activity assessed by clot generation parameters were all nonsignificantly different but showed trends towards enhanced antithrombotic activity with clopidogrel among heavy smokers. In heavy smokers with vascular disease manifestations, clopidogrel is associated with enhanced platelet inhibitory effects, affecting purinergic and non-purinergic pathways, compared with aspirin as measured by MEA. Moreover, among smokers, clopidogrel offers trends towards enhanced effects on parameters of clot generation measured by TEG.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Cigarette smoking among adults: United States, 2006. (2007). MMWR Morb Mortal Wkly Rep, 56, 1157–1161.

    Google Scholar 

  2. Ockene, I. S., & Miller, N. H. (1997). Cigarette smoking, cardiovascular disease, and stroke: a statement for healthcare professionals from the American Heart Association: American Heart Association Task Force on Risk Reduction. Circulation, 96, 3243–3247.

    Article  CAS  PubMed  Google Scholar 

  3. Ambrose, J. A., & Barua, R. S. (2004). The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol, 43, 1731–1737.

    Article  CAS  PubMed  Google Scholar 

  4. Mangiacapra, F., & Barbato, E. (2013). Clinical implications of platelet-vessel interaction. J Cardiovasc Transl Res, 6, 310–315.

    Article  PubMed  Google Scholar 

  5. Zhao, Z. G., Chen, M., Peng, Y., Chai, H., Liu, W., Li, Q., Ren, X., Wang, X. Q., Luo, X. L., Zhang, C., Huang, D. J. (2013). The impact of smoking on clinical efficacy and pharmacodynamic effects of clopidogrel: a systematic review and meta-analysis. Heart Jun 8. [Epub ahead of print].

  6. Gagne, J. J., Bykov, K., Choudhry, N. K., Toomey, T. J., Connolly, J. G., & Avorn, J. (2013). Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison. BMJ, 347, f5307.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Gurbel, P. A., Nolin, T. D., & Tantry, U. S. (2012). Clopidogrel efficacy and cigarette smoking status. JAMA, 307, 2495–2496.

    Article  CAS  PubMed  Google Scholar 

  8. Desai, N. R., Mega, J. L., Jiang, S., Cannon, C. P., & Sabatine, M. S. (2009). Interaction between cigarette smoking and clinical benefit of clopidogrel. J Am Coll Cardiol, 53, 1273–1278.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Berger, J. S., Bhatt, D. L., Steinhubl, S. R., Shao, M., Steg, P. G., Montalescot, G., Hacke, W., Fox, K. A., Lincoff, A. M., Topol, E. J., Berger, P. B., & CHARISMA Investigators. (2009). Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation, 120, 2337–2344.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Mehta, S. R., Tanguay, J. F., Eikelboom, J. W., Jolly, S. S., Joyner, C. D., Granger, C. B., Faxon, D. P., Rupprecht, H. J., Budaj, A., Avezum, A., Widimsky, P., Steg, P. G., Bassand, J. P., Montalescot, G., Macaya, C., Di Pasquale, G., Niemela, K., Ajani, A. E., White, H. D., Chrolavicius, S., Gao, P., Fox, K. A., Yusuf, S., & CURRENT-OASIS 7 trial investigators. (2010). Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet, 376, 1233–1243.

    Article  CAS  PubMed  Google Scholar 

  11. Saraff, K. Y., Steinhubl, S. R., Hsu, A. P., & Topol, E. J. (2006). Smoking influences the effectiveness of dual antiplatelet therapy on long-term outcomes following percutaneous coronary intervention. J Am Coll Cardiol, 47, p36B [Abstract].

    Google Scholar 

  12. Ferreiro, J. L., Bhatt, D., Ueno, M., Bauer, D., & Angiolillo, D. J. (2013). Impact of smoking on long-term outcomes in patients with atherosclerotic vascular disease treated with aspirin or clopidogrel: insights from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. J Am Coll Cardiol. doi:10.1016/j.jacc.2013.10.043.

    Google Scholar 

  13. Salek, F. S. (2010). Relationship between clopidogrel and cigarette smoking status in patients with acute coronary syndromes without ST-segment elevation myocardial infarction. Pharmacotherapy, 30, 154e [Abstract].

    Google Scholar 

  14. Hochholzer, W., Trenk, D., Mega, J. L., Morath, T., Stratz, C., Valina, C. M., O'Donoghue, M. L., Bernlochner, I., Contant, C. F., Gou, J., Sabatine, M. S., Schömig, A., Neumann, F. J., Kastrati, A., Wiviott, S. D., & Sibbing, D. (2011). Impact of smoking on antiplatelet effect of clopidogrel and prasugrel after loading dose and on maintenance therapy. Am Heart J, 162, 518–526.

    Article  CAS  PubMed  Google Scholar 

  15. Bliden, K. P., Dichiara, J., Lawal, L., Singla, A., Antonino, M. J., Baker, B. A., Bailey, W. L., Tantry, U. S., & Gurbel, P. A. (2008). The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol, 52, 531–533.

    Article  CAS  PubMed  Google Scholar 

  16. Ueno, M., Ferreiro, J. L., Desai, B., Tomasello, S. D., Tello-Montoliu, A., Capodanno, D., Capranzano, P., Kodali, M., Dharmashanker, K., Charlton, R. K., Bass, T. A., & Angiolillo, D. J. (2012). Cigarette smoking is associated with a dose-response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study. JACC Cardiovasc Interv, 5, 293–300.

    Article  PubMed  Google Scholar 

  17. Gurbel, P. A., Bliden, K. P., Logan, D. K., Kereiakes, D. J., Lasseter, K. C., White, A., Angiolillo, D. J., Nolin, T. D., Maa, J. F., Bailey, W. L., Jakubowski, J. A., Ojeh, C. K., Jeong, Y. H., Tantry, U. S., & Baker, B. A. (2013). The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study. J Am Coll Cardiol, 62, 505–512.

    Article  CAS  PubMed  Google Scholar 

  18. Gremmel, T., Steiner, S., Seidinger, D., Koppensteiner, R., Panzer, S., & Kopp, C. W. (2009). Smoking promotes clopidogrel-mediated platelet inhibition in patients receiving dual antiplatelet therapy. Thromb Res, 124, 588–591.

    Article  CAS  PubMed  Google Scholar 

  19. Faber, M. S., & Fuhr, U. (2004). Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther, 76, 178–184.

    Article  CAS  PubMed  Google Scholar 

  20. Washio, I., Maeda, M., Sugiura, C., Shiga, R., Yoshida, M., Nonen, S., Fujio, Y., & Azuma, J. (2011). Cigarette smoke extract induces CYP2B6 through constitutive androstane receptor in hepatocytes. Drug Metab Dispos, 39, 1–3.

    Article  CAS  PubMed  Google Scholar 

  21. CAPRIE Steering Committee. (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet, 348, 1329–1339.

    Article  Google Scholar 

  22. Shanker, G., Kontos, J. L., Eckman, D. M., Wesley-Farrington, D., & Sane, D. C. (2006). Nicotine upregulates the expression of P2Y12 on vascular cells and megakaryoblasts. J Thromb Thrombolysis, 22, 213–220.

    Article  CAS  PubMed  Google Scholar 

  23. Wall, M. A., Johnson, J., Jacob, P., & Benowitz, N. L. (1988). Cotinine in the serum, saliva, and urine of nonsmokers, passive smokers, and active smokers. Am J Public Health, 78, 699–701.

    Article  CAS  PubMed  Google Scholar 

  24. Ueno, M., Ferreiro, J. L., Tomasello, S. D., Tello-Montoliu, A., Capodanno, D., Seecheran, N., Kodali, M., Dharmashankar, K., Desai, B., Charlton, R. K., Bass, T. A., & Angiolillo, D. J. (2011). Impact of pentoxifylline on platelet function profiles in patients with type 2 diabetes mellitus and coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. JACC Cardiovasc Interv, 4, 905–912.

    Article  PubMed  Google Scholar 

  25. Tello-Montoliu, A., Thano, E., Rollini, F., Patel, R., Wilson, R. E., Muñiz-Lozano, A., Franchi, F., Darlington, A., Desai, B., Guzman, L. A., Bass, T. A., & Angiolillo, D. J. (2013). Impact of aspirin dose on adenosine diphosphate-mediated platelet activities. Results of an in vitro pilot investigation. Thromb Haemost, 110, 777–784.

    Article  CAS  PubMed  Google Scholar 

  26. Gurbel, P. A., Bliden, K. P., Guyer, K., Aggarwal, N., & Tantry, U. S. (2007). 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, 119, 563–570.

    Article  CAS  PubMed  Google Scholar 

  27. Barua, R. S., Sy, F., Srikanth, S., Huang, G., Javed, U., Buhari, C., Margosan, D., & Ambrose, J. A. (2010). Effects of cigarette smoke exposure on clot dynamics and fibrin structure: an ex vivo investigation. Arterioscler Thromb Vasc Biol, 30, 75–79.

    Article  CAS  PubMed  Google Scholar 

  28. Angiolillo, D. J., Capranzano, P., Desai, B., Shoemaker, S. B., Charlton, R., Zenni, M. M., Guzman, L. A., & Bass, T. A. (2009). Impact of P2Y(12) inhibitory effects induced by clopidogrel on platelet procoagulant activity in type 2 diabetes mellitus patients. Thromb Res, 124, 318–322.

    Article  CAS  PubMed  Google Scholar 

  29. Lancaster, G. A., Dodd, S., & Williamson, P. R. (2004). Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract, 10, 307–312.

    Article  PubMed  Google Scholar 

  30. Prodan, C. I., Joseph, P. M., Vincent, A. S., & Dale, G. L. (2007). Coated-platelet levels are influenced by smoking, aspirin, and selective serotonin reuptake inhibitors. J Thromb Haemost, 5, 2149–2151.

    Article  CAS  PubMed  Google Scholar 

  31. Willi, C., Bodenmann, P., Ghali, W. A., Faris, P. D., & Cornuz, J. (2007). Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. JAMA, 298, 2654–2664.

    Article  CAS  PubMed  Google Scholar 

  32. Smith, S. C., Jr., Benjamin, E. J., Bonow, R. O., Braun, L. T., Creager, M. A., Franklin, B. A., Gibbons, R. J., Grundy, S. M., Hiratzka, L. F., Jones, D. W., Lloyd-Jones, D. M., Minissian, M., Mosca, L., Peterson, E. D., Sacco, R. L., Spertus, J., Stein, J. H., & Taubert, K. A. (2011). AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol, 58, 2432–2446.

    Article  PubMed  Google Scholar 

  33. Tantcheva-Poór, I., Zaigler, M., Rietbrock, S., & Fuhr, U. (1999). Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasian using saliva-based caffeine test. Pharmacogenetics, 9, 131–144.

    PubMed  Google Scholar 

  34. Park, K. W., Kang, S. H., Kang, J., Jeon, K. H., Park, J. J., Han, J. K., Koh, J. S., Lee, S. E., Yang, H. M., Lee, H. Y., Kang, H. J., Koo, B. K., Oh, B. H., Park, Y. B., & Kim, H. S. (2012). Enhanced clopidogrel response in smokers is reversed after discontinuation as assessed by VerifyNow assay: additional evidence for the concept of ‘smokers' paradox’. Heart, 98, 1000–1006.

    Article  CAS  PubMed  Google Scholar 

  35. Wennmalm, A., Benthin, G., Granström, E. F., Persson, L., Petersson, A. S., & Winell, S. (1991). Relation between tobacco use and urinary excretion of thromboxane A2 and prostacyclin metabolites in young men. Circulation, 83, 1698–1704.

    Article  CAS  PubMed  Google Scholar 

  36. Pamukcu, B., Oflaz, H., Onur, I., Cimen, A., & Nisanci, Y. (2011). Effects of cigarette smoking on platelet aggregation. Clin Appl Thromb Hemost, 17, E175–E180.

    Article  PubMed  Google Scholar 

  37. Loke, W. M., Lam Mok Sing K., Lee, C. Y., Chong, W. L., Chew, S. E., Huang, H., Looi, W. F., Quek, A. M., Lim, E. C., Seet, R. C. (2012). Cyclooxygenase-1-mediated platelet reactivity in young male smokers. Clin Appl Thromb Hemost Dec 14. [Epub ahead of print]

  38. Henry, P., Vermillet, A., Boval, B., Guyetand, C., Petroni, T., Dillinger, J. G., Sideris, G., Sollier, C. B., & Drouet, L. (2011). 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost, 105, 336–344.

    Article  CAS  PubMed  Google Scholar 

  39. Eikelboom, J. W., Hankey, G. J., Thom, J., Bhatt, D. L., Steg, P. G., Montalescot, G., Johnston, S. C., Steinhubl, S. R., Mak, K. H., Easton, J. D., Hamm, C., Hu, T., Fox, K. A., & Topol, E. J. (2008). Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization. Management and Avoidance (CHARISMA) Investigators. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation, 118, 1705–1712.

    Article  CAS  PubMed  Google Scholar 

  40. Angiolillo, D. J., Ueno, M., & Goto, S. (2010). Basic principles of platelet biology and clinical implications. Circ J, 74, 597–607.

    Article  CAS  PubMed  Google Scholar 

  41. Cimmino, G., & Golino, P. (2013). Platelet biology and receptor pathways. J Cardiovasc Transl Res, 6, 299–309.

    Article  PubMed  Google Scholar 

  42. Monroe, D. M., Hoffman, M., & Roberts, H. R. (2002). Platelets and thrombin generation. Arterioscler Thromb Vasc Biol, 22, 1381–1389.

    Article  CAS  PubMed  Google Scholar 

  43. Leon, C., Ravanat, C., Freund, M., Cazenave, J. P., & Gachet, C. (2003). Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity. Arterioscler Thromb Vasc Biol, 23, 1941–1947.

    Article  CAS  PubMed  Google Scholar 

  44. Norgard, N. B., Saya, S., Hann, C. L., Hennebry, T. A., Schechter, E., & Dale, G. L. (2008). Clopidogrel attenuates coated-platelet production in patients undergoing elective coronary catheterization. J Cardiovasc Pharmacol, 52, 536–539.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The present study was funded by an institutional grant of the University of Florida College of Medicine-Jacksonville and by a grant provided by the James and Esther King Biomedical Research Program (1KN01-33989).

Conflict of Interest

Conflict of interest forms will be submitted offline.

Fabiana Rollini has no conflict of interest to report.

Francesco Franchi has no conflict of interest to report.

Jung Rae Cho has no conflict of interest to report.

Christopher DeGroat has no conflict of interest to report.

Mona Bhatti has no conflict of interest to report.

Elisabetta Ferrante has no conflict of interest to report.

Ronakkumar Patel has no conflict of interest to report.

Andrew Darlington has no conflict of interest to report.

Antonio Tello-Montoliu has no conflict of interest to report.

Bhaloo Desai has no conflict of interest to report.

José Luis Ferreiro received payment as an individual for (a) honoraria for lectures from Eli Lilly Co; Daiichi Sankyo, Inc.; and Astra Zeneca and (b) consulting fees from Astra Zeneca and Eli Lilly Co.

Ana Muniz-Lozano has no conflict of interest to report.

Martin M. Zenni has no conflict of interest to report.

Luis A. Guzman has no conflict of interest to report.

Theodore A. Bass has no conflict of interest to report.

Dominick J. Angiolillo received payment as an individual for (a) consulting fee or honorarium from Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular, and PLx Pharma; (b) Participation in review activities from Johnson & Johnson, St. Jude, and Sunovion; and (c) institutional payments for grants from Bristol Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Evolva, and Gilead and has other financial relationships with Esther and King Biomedical Research Grant.

Author information

Authors and Affiliations

  1. University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA

    Fabiana Rollini, Francesco Franchi, Jung Rae Cho, Christopher DeGroat, Mona Bhatti, Elisabetta Ferrante, Ronakkumar Patel, Andrew Darlington, Antonio Tello-Montoliu, Bhaloo Desai, JoséLuis Ferreiro, Ana Muniz-Lozano, Martin M. Zenni, Luis A. Guzman, Theodore A. Bass & Dominick J. Angiolillo

Authors
  1. Fabiana Rollini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesco Franchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jung Rae Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher DeGroat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mona Bhatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisabetta Ferrante
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ronakkumar Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrew Darlington
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Antonio Tello-Montoliu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bhaloo Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. JoséLuis Ferreiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ana Muniz-Lozano
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Martin M. Zenni
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Luis A. Guzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Theodore A. Bass
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Dominick J. Angiolillo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dominick J. Angiolillo.

Additional information

Associate Editor Emanuele Barbato oversaw the review of this article

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rollini, F., Franchi, F., Cho, J.R. et al. Cigarette Smoking and Antiplatelet Effects of Aspirin Monotherapy Versus Clopidogrel Monotherapy in Patients with Atherosclerotic Disease: Results of a Prospective Pharmacodynamic Study. J. of Cardiovasc. Trans. Res. 7, 53–63 (2014). https://doi.org/10.1007/s12265-013-9535-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-013-9535-3

Keywords

Search

Navigation