European Heart Journal Advance Access published online on April 15, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn159
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How to react to high platelet reactivity? Reply
Division of Cardiovascular Diseases
Scripps Clinic
1066 North Torrey Pines Road
Maildrop S1056
La Jolla, CA 92037
USA
Email: price.matthew{at}scrippshealth.org
We thank Dr Clappers and colleagues for their thoughtful comments and interest in our work.1 We strongly agree that the appropriate threshold that is chosen to define anti-platelet ‘non-responsiveness’ by a particular platelet function test must not be arbitrary but determined through prospective, clinical studies of thrombotic events. Dr Clapper is concerned about our use of the term ‘prognostic significance’ when describing the univariate association we observed between high platelet reactivity measured by the VerifyNow P2Y12 assay and thrombotic events after drug-eluting stent implantation. However, ‘prognostic’ means ‘to be predictive of something in the future’, and we demonstrated the predictive value of platelet reactivity upon thrombotic outcomes using the area under-the-curve by receiver-operating characteristic curve analysis. Post-clopidogrel platelet reactivity will always have a low positive predictive value for stent thrombosis outside of very selected high-risk populations, since the incidence of stent thrombosis is very low and the inter-individual variability in post-clopidogrel reactivity is very wide. This does not undermine the prognostic significance of platelet reactivity—indeed, as we note, post-clopidogrel platelet reactivity has an excellent negative predictive value.
Dr Clappers raises the important question of whether increased platelet reactivity is independently associated with clinical outcomes. We were unable to perform a multivariable analysis because of the relatively small size of our study. Interestingly, as Dr Clappers notes, a large number of the clinical risk factors that have been associated with post-PCI outcomes, including stent thrombosis, have also been associated with high post-clopidogrel platelet reactivity. The relative independence of these clinical risk factors from platelet reactivity (or vice versa) is speculative since none of the large studies that identified these clinical risk factors measured platelet reactivity in a prospective fashion. We agree that future large studies should account for clinical, angiographic, and procedural variables that may be associated with thrombotic events, but such studies will be challenging to perform given the large sample size required (assuming that at least 10 thrombotic events are required for each candidate predictor2) and the need for additional blood tests around the time of the index procedure.
A unique aspect of platelet reactivity, however, is that it is modifiable; this enables studies to provide indirect support of its independent role in patient outcome. Prasugrel results in more potent and uniform P2Y12-inhibition than clopidogrel (even among individuals who have high post-clopidogrel reactivity3). Compared with clopidogrel, prasugrel markedly reduces ischaemic outcomes, including stent thrombosis, with a greater effect in diabetics and regardless of the presence of chronic renal insufficiency.4 However, the downside of very potent P2Y12-inhibition in unselected patients is increased bleeding. Although large but difficult-to-implement cohort studies may definitively answer whether the association between high platelet reactivity and outcome is independent from immutable clinical, angiographic, and procedural characteristics, a randomized trial of tailored anti-platelet therapy in patients with high post-clopidogrel platelet reactivity may not only provide insight into this scientifically important question, but also teach us how to react to platelet reactivity—hopefully to our patients' benefit.
References
- Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, Ernst A, Sawhney NS, Schatz RA, Teirstein PS. 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.
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[Abstract/Free Full Text] - Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J (2006) 27:1166–1173.
[Abstract/Free Full Text] - Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med (2007) 357:2001–2015.
[Abstract/Free Full Text]
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