Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome

Abstract

Interindividual variation in the ability of aspirin to inhibit platelet cyclooxygenase-1 (COX-1) could account for some on-treatment cardiovascular events. Here, we sought to determine whether there are clinical phenotypes that are associated with a suboptimal pharmacological effect of aspirin. In a prospective, 2-week study, we evaluated the effect of aspirin (81 mg) on platelet COX-1 in 135 patients with stable coronary artery disease by measuring serum thromboxane B(2) (sTxB(2)) as an indicator of inhibition of platelet COX-1. A nested randomized study compared enteric-coated with immediate-release formulations of aspirin. We found that sTxB(2) was systematically higher among the 83 patients with metabolic syndrome than among the 52 patients without (median: 4.0 versus 3.02 ng/mL; P=0.013). Twelve patients (14%) with metabolic syndrome, but none without metabolic syndrome, had sTxB(2) levels consistent with inadequate inhibition of COX (sTxB(2) ≥13 ng/mL). In linear regression models, metabolic syndrome (but none of its individual components) significantly associated with higher levels of log-transformed sTxB(2) (P=0.006). Higher levels of sTxB(2) associated with greater residual platelet function measured by aggregometry-based methods. Among the randomized subset, sTxB(2) levels were systematically higher among patients receiving enteric-coated aspirin. Last, urinary 11-dehydro thromboxane B(2) did not correlate with sTxB(2), suggesting that the former should not be used to quantitate aspirin's pharmacological effect on platelets. In conclusion, metabolic syndrome, which places patients at high risk for thrombotic cardiovascular events, strongly and uniquely associates with less effective inhibition of platelet COX-1 by aspirin.

Trial registration: ClinicalTrials.gov NCT00753935.

Figures

Figure 1

Comparison of serum TxB2 levels between patients with and without metabolic syndrome (P=0.013), all of whom had known coronary artery disease. The dashed line (13 ng/mL) represents an estimate of 95% inhibition of cyclooxygenase.

Figure 2

Serum TxB2 levels by body mass index (BMI) across metabolic syndrome (MetSyn) status. Solid lines indicate medians. No significant differences were detected between BMI categories among patients with or without metabolic syndrome (P=0.08 and P=0.11, respectively).

Figure 3

Positive values of “without SQ – with SQ” suggest greater residual thromboxane receptor-mediated platelet aggregability. The bounds of the boxes indicate the 1st and 3rd quartiles; the line within the box indicates the median.

Figure 4

Serum TxB2 did not correlate with urinary 11-dehydrothromboxane B2 among patients with coronary artery disease taking aspirin 81mg daily (Spearman’s ρ=0.04, P=0.63).