To read Patrono and Rocca’s reply to this letter, click here
In their review of aspirin resistance in the January 2007 issue of Nature Clinical Practice Cardiovascular Medicine,1 authors Patrono and Rocca state that our target for optimal inhibition of serum thromboxane (TX) B2 of 2.2 ng/ml (approximately 99% inhibition)2 in patients with coronary artery disease (CAD) is hard to justify.
The authors reference prior studies suggesting that ex vivo serum TX generation must be reduced by 95% before functional inhibition of platelet COX-1 is attained. Indeed, this value is quoted frequently as a target for inhibition of serum TX.3 However, the study by Reilly and FitzGerald also showed significantly greater inhibition of platelet aggregation and prolongation of the bleeding time in response to further suppression of serum TX to a mean of 99% of control. This figure is consistent with our findings, which suggest that additional platelet inhibition is achieved in patients with CAD with higher than 95% suppression of serum TX.
Patrono and Rocca also state that our results ‘contrast’ with those of Fontana et al. in their study of aspirin response among healthy volunteers.4 They describe that in the Fontana study, only one subject had a serum TX greater than 80 pg/µl. Fontana et al. actually reported that one subject had a serum TX level greater than 80 pg/µl (80 ng/ml) and the median serum TX value for their population was 3.0 ng/ml (IQR 2–5 ng/ml). This figure is similar to our findings in healthy volunteers and in patients with CAD.2,5 Only one of our patients with CAD had a serum TX value greater than 80 ng/ml and the median value in our population was 2 ng/ml.
The more substantial issue here is the appropriate target level for suppression of serum TX in a specific population, rather than so-called ‘aspirin resistance’ in individuals. Our serum TX target of 2.2 ng/ml is derived from a plot of serum TX versus TX generated by platelet rich plasma upon addition of excess arachidonic acid. Any value above this threshold suggests that there is persistent platelet COX-1 activity. Indeed, patients with CAD who had higher serum TX values were seven-times more likely to have platelet aggregation in response to arachidonic acid despite aspirin therapy.2 In addition, patients who exceeded this threshold were more likely to have had prior myocardial infarction and evidence of predisposition to coronary artery thrombosis. Whatever the reason for population variance (weight, age, genetic variation), it is hardly surprising that a ‘one low-dose aspirin fits all’ approach results in some people having a less than optimal response.
References
Patrono C and Rocca B (2007) Drug insight: aspirin resistance–fact or fashion? Nat Clin Pract Cardiovasc Med 4: 42–50
Maree AO et al. (2005) Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease. J Am Coll Cardiol 46: 1258–1263
Reilly IA and FitzGerald GA (1987) Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 69: 180–186
Fontana P et al. (2006) Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers. J Thromb Haemost 4: 813–819
Cox D et al. (2006) Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke 37: 2153–2158
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AO Maree receives research support from Abbott Vascular, Accumetrics and Boehringer-Ingelheim. DJ Fitzgerald has acted as a consultant/advisory board member for Eli Lilly and Company, Sanofi Aventis and Bayer. D Cox receives research support from Boehringer-Ingelheim.
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Maree, A., Cox, D. & Fitzgerald, D. Drug Insight: aspirin resistance—fact or fashion?. Nat Rev Cardiol 4, E1 (2007). https://doi.org/10.1038/ncpcardio0834
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DOI: https://doi.org/10.1038/ncpcardio0834
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