European Heart Journal Advance Access originally published online on June 2, 2006
European Heart Journal 2006 27(14):1754; doi:10.1093/eurheartj/ehl056
Aspirin and clopidogrel resistance: an emerging clinical entity
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E-mail address: tony.johns.b{at}bayer.com
Bayer HealthCare
36 Columbia Road
PO Box 1910
Morristown
NJ 07962-1910
USA
Bayer HealthCare
36 Columbia Road
PO Box 1910
Morristown
NJ 07962-1910
USA
We read with interest the recent article which reviewed the issue of aspirin and clopidogrel resistance.1 The authors review the aspirin and clopidogrel clinical trial data and conclude that both therapies have emerged as efficacious in both the primary and secondary prevention settings. The referenced data for a beneficial effect of clopidogrel on the primary prevention of cardiovascular (CV) disease events is not quoted. In fact, the recent results from the CHARISMA trial suggest that the long-term addition of clopidogrel to aspirin is inappropriate for broad populations and may indeed be harmful in primary prevention patients.2 Aspirin is the only antiplatelet agent with incontrovertible data proving it valuable in the prevention of first CV events.
The discussion of aspirin and clopidogrel resistance that follows admittedly provides no clear definition of the two terms. Although a definition of aspirin or clopidogrel resistance has not been universally accepted, a reasonable approach would be to limit the definitions to the known pharmacological pathways exhibited by the two drugs, respectively. In the case of aspirin, resistance should be confined to the failure of aspirin to block arachidonic acid-induced platelet aggregation, as this is the most precise mechanism to identify its effect on the COX-1 pathway. Similarly, clopidogrel resistance should be limited to its efficacy in inhibiting ADP-induced platelet aggregation through blockade of the P2Y12 purinergic receptor. The authors identify these as the key mechanisms of action by which both agents exert their clinical effects. Despite this admission, the authors continue to suggest that there is an unpredictable response and variability to aspirin therapy. Recent data demonstrate that resistance under its pharmacological definition is extremely rare,3 whereas clopidogrel response to ADP-induced aggregation is broad, as seen in Figure 2 of the authors' article. This more exact definition would then essentially rule out the results of the non-specific assays (i.e. VerifyNow Rapid Platelet Function Assay, PFA-100) and their associated reports of prevalent aspirin resistance. We agree that non-specific measurements may be important if future studies reveal their relationship to clinical events, but to characterize these as adequate tests for assessing the response to aspirin therapy is invalid.
Finally, the authors ask, how many (of the millions of patients taking low dose aspirin) are taking the wrong drug? We suggest that the answer to this question is likely none, as aspirin is the justifiable cornerstone of any pharmacological strategy for the prevention both primary and secondary CV events.
References
- Wang TH, Bhatt DL, Topol EJ. (2006) Aspirin and clopidogrel resistance: an emerging clinical entity. Eur Heart J 27:647–654.
[Abstract/Free Full Text] - Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen PEA, 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 LJ, Topol EJ. (2006) Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354:1706–1717.
[Abstract/Free Full Text] - Tantry US, Bliden KP, Gurbel PA. (2005) Overestimation of platelet aspirin resistance detection by thromboelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol 46:1705–1709.
[Abstract/Free Full Text]
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