Skip Navigation

This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Bode, C.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Bode, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Introduction

E-mail address: christoph.bode{at}uniklinik-freiburg.de

Atherothrombotic disease is the leading cause of cardiovascular disorders and related deaths worldwide; its prevalence is increasing in society primarily because of the aging demographic. Humans have evolved a highly efficient coagulation system to prevent unwanted bleeding, but this system is also reactive with damaged endothelium and atherosclerotic plaque. These can lead to platelet activation, and ultimately clot formation, resulting in thrombotic events. Antiplatelet therapies have therefore become a cornerstone of treatment for atherothrombotic disease, and the benefits of currently available antiplatelet agents (including aspirin, irreversible thienopyridine ADP receptor antagonists, and glycoprotein IIb/IIIa receptor antagonists) in improving ischaemic outcomes have been well established in numerous clinical studies.1–4 Despite the benefits observed, current antiplatelet therapies have limitations with regard to efficacy, reversibility, patient variability in response to treatment, and bleeding complications, resulting in residual cardiovascular risk.

The global burden of atherothrombotic disorders means that there is a need to identify optimal treatment strategies. This supplement, entitled ‘Antiplatelet therapy: current issues and new developments’, discusses current issues surrounding available antiplatelet agents, with a particular focus on those patients who are considered high risk for a thrombotic event, and new developments within the field which could ultimately improve the management of patients at risk for atherothrombotic complications.

Our first article is entitled ‘Dual antiplatelet therapy in high-risk patients’. Antiplatelet therapy has been shown to reduce the rate of ischaemic events in high-risk patients (those with acute/previous vascular disease or another predisposing condition) significantly. Aspirin monotherapy is the most commonly used antiplatelet treatment, although patients receiving this regimen still retain a significant cardiovascular risk. Numerous studies have suggested that this risk can further be reduced using aspirin in combination with other antiplatelet drugs. The STent Anticoagulation Restenosis Study (STARS)5 established the benefit of antiplatelet combination therapy (ticlopidine with aspirin) after coronary stent implantation. Other studies, including the well-documented Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial,3 have found similar benefits using aspirin and clopidogrel in patients with non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina. Key findings from these studies and others discussing the use of dual antiplatelet therapy for patients with STEMI or undergoing percutaneous coronary intervention are detailed. The evidence for triple therapy in the high-risk patient is also examined. In addition, the article explores the finding that despite the evidence supporting the use of combined antiplatelet therapy and its inclusion in treatment guidelines, such therapies remain underutilized in clinical practice throughout Europe. Possible reasons for this underuse are highlighted, together with potential solutions including educational programmes which engage physicians. Limitations of dual antiplatelet therapy, as assessed in the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management, and Avoidance (CHARISMA) trial,6 are also discussed.

‘The use of antiplatelet agents following percutaneous coronary intervention: focus on late stent thrombosis’, our second article, examines the use of antiplatelet agents for patients receiving intracoronary stents. The purpose of stent implantation is the prevention of vessel recoil following balloon angioplasty. However, early bare-metal devices are associated with vessel restenosis in 20–30% of patients.7,8 Drug-eluting stents that slowly release agents that inhibit cell proliferation were introduced in an attempt to reduce restenosis rates. There has been considerable uptake of these devices, with approximately 6 million patients receiving them worldwide.9 There are several drugs used in these stents, with key elutants being sirolimus, paclitaxel, and zotarolimus, which trials have shown significantly reduce the need for revascularization. However, a possible increased risk of late stent thrombosis (more than 30 days after implantation) has been identified, which could be linked to the inhibition of re-endothelialization by the anti-proliferative agents used in drug-eluting stents.10 The main risk factor for late stent thrombosis is discontinuation of antiplatelet therapy, highlighting the importance of maintaining effective antiplatelet activity in patients who have drug-eluting stents. Guidelines have been published that recommend oral antiplatelet therapy for up to 12 months with drug-eluting stents, and with the currently widespread use of these stents, correct application of antiplatelet therapy is imperative.11–14 In addition, some patients show variability in response to current antiplatelet agents and may be inadequately protected from thrombotic events.15,16 The article discusses how new devices and antiplatelet drug options may therefore be needed to ensure individuals receiving intracoronary stents benefit from treatment.

Our final article, entitled ‘New developments in oral antiplatelet therapy’, explores new antiplatelet agents in clinical development that seek to address the limitations of existing agents, offering the potential for improved efficacy and safety. Oral antiplatelet drug classes discussed include thromboxane A2/prostaglandin H2 receptor antagonists and thrombin protease-activated receptor antagonists, which are both currently being evaluated in phase I–III clinical trials. New additions to the P2Y12 receptor antagonist class are also assessed. The benefits of clopidogrel have been well documented, but limitations have also been observed. Considerable interpatient variability, suboptimal onset of action, and a relatively modest inhibition of the ex vivo platelet aggregation response to ADP have all been reported with current regimens of clopidogrel.17,18 These limitations also include the irreversible binding of clopidogrel to the P2Y12 receptor, resulting in the inhibition of platelet aggregation and potentially increasing the risk of bleeding in an individual following invasive procedures or surgery if performed prior to the formation of new platelets. Novel oral P2Y12 receptor antagonist agents that are in phase III clinical development and which aim to address some of these issues are the irreversible thienopyridine prasugrel and AZD6140, a CPTP (cyclo-pentyl-triazolo-pyrimidine) agent that represents the first reversible oral P2Y12 receptor antagonist. Only the ongoing clinical trials will be able to tell us whether a favourable balance exists between antithrombotic efficacy and bleeding by new regimens and/or innovative drugs.

Acknowledgements

This work was supported by an unrestricted educational grant from AstraZeneca. Editorial assistance was provided by MediTech Media Ltd.

Conflict of interest: The author has received a lecture honoraria from Cordis, Medtronik, AstraZeneca, Sanofi-Aventis, and Essex-Pharma.

Christoph Bode

University Hospital
Freiburg
Germany

References

  1. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci (1996) 143:1–13.[CrossRef][ISI][Medline]
  2. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet (2006) 367:1665–1673.[CrossRef][ISI][Medline]
  3. The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med (2001) 345:494–502.[Abstract/Free Full Text]
  4. Schulman SP, Goldschmidt-Clermont PJ, Topol EJ, Califf RM, Navetta FI, Willerson JT, Chandra NC, Guerci AD, Ferguson JJ, Harrington RA, Lincoff AM, Yakubov SJ, Bray PF, Bahr RD, Wolfe CL, Yock PG, Anderson HV, Nygaard TW, Mason SJ, Effron MB, Fatterpacker A, Raskin S, Smith J, Brashears L, Gottdiener P, du Mee C, Kitt MM, Gerstenblith G. Effects of integrelin, a platelet glycoprotein IIb/IIIa receptor antagonist, in unstable angina: a randomized multicenter trial. Circulation (1996) 94:2083–2089.[Abstract/Free Full Text]
  5. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE, Stent Anticoagulation Restenosis Study Investigators. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med (1998) 339:1665–1671.[Abstract/Free Full Text]
  6. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med (2006) 354:1706–1717.[Abstract/Free Full Text]
  7. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy JJ, van den Heuvel P, Delcan J, Morel M-A, for The Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med (1994) 331:489–495.[Abstract/Free Full Text]
  8. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, Cleman R, Heuser R, Almond D, Teirstein P, Fish RD, Colombo A, Brinker J, Moses J, Shaknovich A, Hirshfeld J, Bailey S, Ellis S, Rake R, Goldberg S, for the Stent Restenosis Study Investigators. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med (1994) 331:496–501.[Abstract/Free Full Text]
  9. Shuchman M. Trading restenosis for thrombosis? New questions about drug-eluting stents. N Engl J Med (2006) 355:1949–1952.[Free Full Text]
  10. Eisenberg MJ. Drug-eluting stents: some bare facts. Lancet (2004) 364:1466–1467.[CrossRef][ISI][Medline]
  11. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB III, Morrison DA, O'Neill WW, Schaff HV, Whitlow PL, Williams DO, Antman EM, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA/SCAI 2005 Guideline update for percutaneous coronary intervention—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation (2006) 113:156–175.[Free Full Text]
  12. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J (2005) 26:804–847.[Free Full Text]
  13. Hodgson JM, Stone GW, Michael LA, Klein L, Walpole H, Bottner R, Weiner BH, Leon MB, Feldman T, Babb J, Dehmer GJ. Late stent thrombosis: considerations and practical advice for the use of drug-eluting stents: a report from the Society for Cardiovascular Angiography and Interventions drug-eluting stent task force. Catheter Cardiovasc Interv (2007) 69:327–333.[CrossRef][ISI][Medline]
  14. Love MP, Schampaert E, Cohen EA, Webb JG, Anderson TJ, Labinaz M, Tanguay JF, Dzavik V. The Canadian Association of Interventional Cardiology and the Canadian Cardiovascular Society joint statement on drug-eluting stents. Can J Cardiol (2007) 23:121–123.[ISI][Medline]
  15. Pamukcu B. A review of aspirin resistance; definition, possible mechanisms, detection with platelet function tests, and its clinical outcomes. J Thromb Thrombolysis (2007) 23:213–222.[CrossRef][ISI][Medline]
  16. Gurbel PA, Tantry US. Drug Insight: clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med (2006) 3:387–395.[CrossRef][ISI][Medline]
  17. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost (2003) 89:783–787.[ISI][Medline]
  18. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol (2005) 45:246–251.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Bode, C.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Bode, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?