Authors’ response to “Drug Insight: aspirin resistance—fact or fashion?”

Response to: Maree AO et al. (2007) Drug insight: aspirin resistance–fact or fashion? Nat Clin Pract Cardiovasc Med [doi:10.1038/ncpcardio0834]

To read Patrono and Rocca’s original review, click here

The point we made in our review¹ is that it is hard to justify a serum TXB₂ target of 2.2 ng/ml, as the defined border between ‘complete’ and ‘incomplete’ or ‘suboptimal’ aspirin response. In the paper by Maree et al.,² the evaluation of ‘completeness’ of aspirin response associated with serum TXB2 concentrations lower than 2.2 ng/ml was based on an additional in vitro test, which measured TXB₂ released by platelets loaded in vitro with arachidonic acid, defined by the authors as ‘Platelet TX’. The relationship between this additional capacity index and the actual rate of production of TXA₂ in vivo, as reflected by urinary TX metabolite (TXM) excretion is presently unknown.

Moreover, according to Maree et al., “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”. Unfortunately, neither platelet aggregation nor bleeding time was measured in the study of Reilly and FitzGerald.³ We suspect that Maree et al. refer to data represented in Figure 3 of that paper, where the strikingly non-linear relationship between inhibition of serum TXB₂ ex vivo (an index of platelet biosynthetic capacity) and TXM excretion (an index of the actual rate of whole body thromboxane biosynthesis in vivo) is depicted. As indicated in the figure legend, “data indicating complete inhibition of both serum TXB₂ (99%) and TXM excretion (97%), were obtained after administration of aspirin 2,600 mg/d⁴”. Because such a high dose has inhibitory effects on both platelet and extra-platelet sources of TXA₂ biosynthesis, it is unclear how these findings are relevant to the present discussion. Furthermore, in the study by Reilly and FitzGerald,³ the absolute values of serum TXB₂ corresponding to 99% inhibition ranged between 3.5 and 3.8 ng/ml. The absolute threshold defined by Maree et al.,² corresponding to an unspecified percentage inhibition of serum TXB₂, is inconsistent with this previous study. There is also substantial inconsistency, rather than similarity, between the data of Fontana et al.⁵ and the data of Maree et al.² Fontana et al.⁵ identified as ‘non-responsive’ a residual value of 113 ng/ml of serum TXB₂ after 1 week of aspirin, corresponding to 68% inhibition. Furthermore, in the study of Fontana et al.,⁵ the median serum TXB₂ in the platelet-responders was 3 ng/ml. This value is closer to the value reported by Reilly and FitzGerald³ while, by applying the threshold of <2.2 ng/ml would have meant that >50% of the population was ‘incompletely’ responsive to aspirin.

It should also be emphasized that data published by Maree et al.² were derived from a study of patients with stable cardiovascular disease who were taking 75 mg enteric-coated aspirin. As emphasized by the same authors in a successive publication⁶ equivalent doses of enteric-coated aspirin were not as effective as plain aspirin. Lower bioavailability of these preparations and poor absorption from the higher pH environment of the small intestine could result in inadequate platelet inhibition.⁶

Finally, putting a decimal figure (i.e. 2.2), for a biochemical index that has at least 20% intrasubject coefficient of variation is perhaps over-interpreting biological consistency.