Individualised Antiplatelet Therapy

genetic testing is limited by the fact that results can take at least three hours to obtain, the information yielded provides conclusive data – any information obtained is either a yes or a no. By contrast, the results from point-of-care platelet function tests can be obtained within minutes but may be highly variable from one time of testing to another. In future it may be that platelet genetic and functional testing are combined, but this would depend on a shortened genetic testing time, as well as guidance or recommendations on whether any one test should be performed or both. Thus far, various studies have pointed towards an increased risk of atherothrombotic complications among patients with high on-treatment platelet reactivity, but the relationship between clinical outcomes and the polymorphisms underlying high on-clopidogrel platelet reactivity remains uncertain. However, the high degree of overlap observed between clinical, biochemical and genetic aspects of high on-clopidogrel platelet reactivity indicates the potential need to cross-correlate this information for greater accuracy. Any concordance between these aspects will require appropriately designed studies to evaluate one characteristic for subsequent cross-checking against the other. Aside from the limited but rapidly increasing data to correlate measures of platelet function to clinical outcomes, there is no single assay at the moment that accounts for both platelet biology and function. Moreover, the nature of platelets makes blood sample collection and handling a major challenge for platelet function testing in that results can be influenced by a variety of individual, chemical and mechanical factors during the collection, preparation and handling of blood samples.19

These issues suggest

areas of improvement for many platelet function testing systems, as no point-of-care assay currently exists with sufficient validation to

1. CAPRIE Steering Committee, A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE), Lancet, 1996;348:1329–39.

2. Mehta SR, Yusuf S, Peters RJ, 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;358:527–33.

3. Steinhubl SR, Berger PB, Mann JT, 3rd, et al., Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial, JAMA, 2002;288:2411–20.

4. Smith SC, Jr., Allen J, Blair SN, et al., AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute, Circulation, 2006;113:2363–72.

5. Serebruany VL, Steinhubl SR, Berger PB, et al., Variability in platelet responsiveness to clopidogrel among 544

individuals, J Am Coll Cardiol, 2005;45:246–51.

6. Muller I, Besta F, Schulz C, et al., Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent

placement, Thromb Haemost, 2003;89:783–7.

7. Matetzky S, Shenkman B, Guetta V, et al., Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction, Circulation, 2004;109:3171–5.

8. Cuisset T, Frere C, Quilici J, et al., High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary

syndrome, J Thromb Haemost, 2006;4:542–9.

9. Gurbel PA, Bliden KP, Guyer K, et al., Platelet reactivity in patients and recurrent events post-stenting: results of

the PREPARE POST-STENTING Study, J Am Coll Cardiol,

2005;46:1820–26.

10. Hochholzer W, Trenk D, Bestehorn HP, et al., Impact of the degree of peri-interventional platelet inhibition after

fulfil the necessary criteria for an ideal monitoring system, e.g. using small amounts of whole blood, lack of pipetting or handling of blood, reproducible results and rapidly available results. Nevertheless, it should be noted that of the available point-of-care tests to date, from a theoretical point of view the VerifyNow system addresses many of these criteria with its fully automated technique that allows for rapid assessment of platelet inhibition in whole blood in the absence of specially trained technicians.

There also remains an unresolved issue with bleeding in platelet inhibition therapy. Recent preliminary data suggest that peri-procedural platelet response to clopidogrel can predict the risk of spontaneous major bleeds.114

However, there are currently no indications as to

whether results from platelet function tests can guide antiplatelet treatment in avoiding bleeding events until specifically designed trials are conducted, especially in the area of planned invasive procedures. Although underpowered to asses the risk of bleeding, the recent POpular study found no association between the degree of platelet reactivity and bleeding.64

There is a high risk of major bleeding events

among patients with cardiovascular disease receiving antiplatelet treatment, especially among the elderly; there is a definite urgency to

address this issue, potentially by using reversible P2Y12 inhibitors that are currently under investigation. With this in mind, the ideal scenario concerning antiplatelet therapy is platelet function tests that allow for the identification of poor responders, possibly guiding therapy towards optimal treatment regimens while potentially identifying whether hypo- responsiveness is associated with excessive bleeding. If such circumstances can be achieved, the resulting prospects in antiplatelet therapy could provide greatly improved options. n

loading with clopidogrel on early clinical outcome of

elective coronary stent placement, J Am Coll Cardiol,

2006;48:1742–50.

11. Bonello L, Camoin-Jau L, Armero S, et al., Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent

thrombosis, Am J Cardiol, 2009;103:5–10.

12. Buonamici P, Marcucci R, Migliorini A, et al., Impact of platelet reactivity after clopidogrel administration on

drug-eluting stent thrombosis, J Am Coll Cardiol,

2007;49:2312–17.

13. Marcucci R, Gori AM, Paniccia R, et al., Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up,

Circulation, 2009;119:237–42.

14. Patti G, Nusca A, Mangiacapra F, et al., Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts

Outcome) study, J Am Coll Cardiol, 2008;52:1128–33.

15. Price MJ, Endemann S, Gollapudi RR, et al., Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation, Eur Heart J, 2008;29: 992–1000.

16. Chen WH, Cheng X, Lee PY, et al., Aspirin resistance and adverse clinical events in patients with coronary artery

disease, Am J Med, 2007;120:631–5.

17. Sibbing D, Braun S, Morath T, et al., Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis, J Am Coll

Cardiol, 2009;53:849–56.

18. Siller-Matula JM, Christ G, Lang IM, et al., Multiple Electrode Aggregometry predicts stent thrombosis better than the VASP assay, J Thromb Haemost, 2010;8(2):351–9.

19. van Werkum JW, Hackeng CM, Smit JJ, et al., Monitoring antiplatelet therapy with point-of-care platelet function assays: a review of the evidence, Future Cardiol, 2008;4: 33–55.

20. Yusuf S, Zhao F, Mehta SR, et al., 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.

21. Wiviott SD, Braunwald E, McCabe CH, et al., Prasugrel versus clopidogrel in patients with acute coronary

syndromes, N Engl J Med, 2007;357:2001–15.

22. Krasopoulos G, Brister SJ, Beattie WS, et al., Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis, BMJ, 2008;336: 195–8.

23. Lordkipanidze M, Pharand C, Schampaert E, et al., A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease, Eur Heart J, 2007;28:1702–8.

24. Dalen JE, Aspirin resistance: is it real? Is it clinically

significant?, Am J Med, 2007;120:1–4.

25. Chen WH, Lee PY, Ng W, et al., Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite

clopidogrel pretreatment, J Am Coll Cardiol, 2004;43:

1122–6.

26. Lee PY, Chen WH, Ng W, et al., Low-dose aspirin increases aspirin resistance in patients with coronary

artery disease, Am J Med, 2005;118:723–7.

27. Michelson AD, Platelet function testing in cardiovascular diseases, Circulation, 2004;110:e489–93.

28. Wang TH, Bhatt DL, Topol EJ, Aspirin and clopidogrel resistance: an emerging clinical entity, Eur Heart J, 2006;27:647–4.

29. Goodman T, Sharma P, Ferro A, The genetics of aspirin

resistance, Int J Clin Pract, 2007;61:826–34.

30. Michelson AD, Furman MI, Goldschmidt-Clermont P, et al., Platelet GP IIIa Pl(A) polymorphisms display different

EUROPEAN CARDIOLOGY

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