The clinical benefits of acetylsalicylic acid (ASA) in the primary or secondary prevention of cardiovascular disease are attributed to its ability to inhibit the generation of platelet-derived thromboxane A2, a potent vasoconstrictor and promoter of platelet aggregation [1]. Low doses of ASA irreversibly acetylate the platelet cyclooxygenase-1 (COX-1) pathway and are capable of blocking over 95% of subsequent thromboxane production for the entire life cycle of platelets [2]. Despite its wide use, ASA fails to prevent atherothrombotic events because 10–25% of patients with arterial thrombotic disease suffer a recurrent vascular event while on aspirin therapy [3]. The failure to prevent thrombotic events with therapeutic doses of ASA has been referred to as aspirin resistance [4]. The precise mechanism(s) for the inadequate or poor response to ASA therapy remain controversial, and may include genetic variations, increased platelet turnover, activation by additional platelet pathway(s), alternative sources of thromboxane production, and/or drug bioavailability [5]. High thromboxane levels in cardiovascular patients on aspirin therapy have been associated with increased risk of adverse events, suggesting a causative role of thromboxane. The HOPE [6] and CHARISMA [7] studies demonstrated that elevated levels of the urinary thromboxane metabolite 11-dehydrothromboxane B2 (11dhTxB2) in ASA-treated patients predict future risk of stroke, myocardial infarction and cardiovascular death. However, the significance of baseline (aspirin-free) thromboxane B2 levels for cardiovascular risk was not evaluated.

We studied 287 consecutive aspirin-free acute coronary syndrome (ACS) patients admitted to Kurashiki Central Hospital (Kurashiki, Japan) for percutaneous coronary intervention (PCI) from December 2007 to November 2010 to evaluate a possible association of urinary thromboxane B2 levels pre- and post-ASA ingestion with adverse events. Inclusion criteria included ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI) or early onset (within 24 h) invasive revascularization procedure. Upon enrollment and prior to PCI, a baseline (aspirin-free) urine sample was obtained, followed by a daily regimen of 100 mg of ASA. Urine samples from aspirin-treated patients were collected at hospital discharge (7–14 days) and upon 6 and 12 months follow-up. Adverse cardiovascular events (AEs) were recorded during a 12-month patient follow-up. Primary endpoints included stent thrombosis, Q wave myocardial infarction (QMI), non-Q wave myocardial infarction (NQMI) and death (cardiac and non-cardiac). Secondary endpoints included stroke, transient ischemic attack (TIA), target lesion revascularization of PCI or CABG, or other vascular event. Primary and secondary endpoints were used in the analysis of results. Urinary 11dhTxB2 was measured by ELISA and results were expressed as pg 11dhTxB2 mg−1 creatinine.

The mean age of the ACS patients was 68.9 ± 11.9 years. Age did not influence baseline 11dhTxB2 levels (r = 0.060, P = 0.310), but female patients had significantly higher mean baseline 11dhTxB2 (7675 ± 8180 pg mg−1) compared with male patients (6949 ± 14 076 pg mg−1, P = 0.0171). The mean baseline aspirin-free 11dhTxB2 (7082 pg mg−1) for this cohort of ACS patients was two to three times higher than that of various healthy populations we have previously studied (range 2450–3337 pg mg−1). ASA significantly suppressed (81%, P > 0.0001) baseline 11dhTxB2 levels to 1402 ± 1178 pg mg−1 at discharge and beyond (Table 1). The overall rate of AEs was 17.1%. The rate of AEs according to baseline aspirin-free 11dhTxB2 decreased slightly from 19.4% in quartile 1 to 15.5% in quartile 4 (Table 2). In contrast, the rate of AEs in aspirin treatment quartiles increased from 9.1% in quartile 1 to 24.2% in quartile 3 and 20% in quartile 4. The relative risk for AEs of quartile 3 was 2.7 (1.112–6.391, P = 0.019). When upper quartiles (3 and 4) were compared with lower quartiles (1 and 2), the relative risk was 2.1 (1.156–3.766, P = 0.011). The correlation between AEs and discharge 11dhTxB2 was not observed at 6- or 12-month measurements.

Table 1.   Thromboxane B2 levels before (baseline) and after ASA treatment in patients with ACS
Time n Urinary 11dhTxB2 (pg mg−1 creatinine)
Mean ± SD95% CI* P value** (vrs baseline)
  1. *95% confidence interval; **Wilcoxon/Kruskal-Wallis Rank Sum.

Baseline2877082 ± 12 8135598–8565 
7–14 days ASA2671402 ± 11781259–1544< 0.0001
6 months ASA2421354 ± 8861241–1466< 0.0001
12 months ASA1321395 ± 9471232–1558< 0.0001
Table 2.   Prevalence and relative risk for adverse events according to baseline and post-ASA 11dhTxB2 quartiles in patients with ACS
11dhTxB2 quartilesBaseline*Post-ASA**
n % adverse eventsRelative risk (95% CI)# P value^ (versus Q1) n % adverse eventsRelative risk (95% CI)# P value^ (versus Q1)
  1. *Baseline quartiles: Q1 = 0–1826; Q2 = 1827–4235; Q3 = 4236–7171; Q4 = 7172–142 691 pg mg−1. **Post-ASA (discharge) quartiles: Q1 = 0–772; Q2 = 773–1054; Q3 = 1055–1604; Q4 = 1605–12 796 pg mg−1. #95% confidence interval. ^Pearson’s chi-square.

Q17219.4  669.1  
Q27216.70.9 (0.829–1.127)0.6656612.11.3 (0.489–3.631)0.572
Q37216.71.1 (0.580–2.345)0.6656624.22.7 (1.112–6.391)0.019
Q47115.51.2 (0.612–2.574)0.5346520.02.2 (0.890–5.436)0.076
Q1 + 2 versus Q3 + 4144 / 14318.1 / 16.11.1 (0.673–1.871)0.657132 / 13110.6 / 22.12.1 (1.156–3.766)0.011

High baseline 11dhTxB2 levels were associated with poor ASA response (data not shown), a finding consistent with a possible underlying platelet hyperactivity that may contribute to the development of atherothrombosis. To determine whether higher doses of ASA reduce the rate of poor responders and improve outcomes will require additional studies. However, baseline aspirin-free 11dhTxB2 levels did not predict 1-year AEs. The degree to which platelet COX-1 or COX-2 pathways contribute to high baseline 11dhTxB2 levels in ACS requires further investigation. In spite of a significant inhibition (81%) of urinary 11dhTxB2 generation by ASA, 29% of ACS patients were classified as poor ASA responders. This rate was over three times the rate of poor responders we have seen in previous studies of healthy volunteers (7.0–8.5%), and two times that of type 2 diabetic patients (14.8%). Thus, high levels of 11dhTxB2 after ASA ingestion are likely to represent extra-platelet (i.e. monocyte/macrophage-derived) COX-2 production of thromboxane. The increased relative risk (2.7) for AEs associated with high post-ASA 11dhTxB2 levels (upper quartiles) suggests that COX-2 production of thromboxane may be a factor associated with a cardiovascular inflammatory process. Healthy subjects with poor aspirin response manifest an incomplete inhibition of COX-1 in a proinflammatory milieu with enhanced oxidative stress [8]. Aspirin-insensitive thromboxane generation has been associated with oxidative stress in diabetes. Amongst several biomarkers tested, only baseline urinary 8-isoPGF2α discriminated between normal and poor thromboxane responders, suggesting that oxidative stress may maintain platelet function irrespective of COX-1 inhibition and/or increased systemic generation of thromboxane from non-platelet sources [9]. Thromboxane alone may not be directly implicated in atherothrombosis. Nonetheless, our results confirm previous reports that post-ASA urinary 11dhTxB2 may be useful in predicting adverse outcomes in ACS patients [6,7].


  1. Top of page
  2. Acknowledgements
  3. Disclosure of Conflict of Interests
  4. References

We thank Medical and Biological Laboratories Co. Ltd, Japan, for testing the urine samples.

Disclosure of Conflict of Interests

  1. Top of page
  2. Acknowledgements
  3. Disclosure of Conflict of Interests
  4. References

LRL is an employee of Corgenix. KG has received consulting fees from Corgenix.


  1. Top of page
  2. Acknowledgements
  3. Disclosure of Conflict of Interests
  4. References
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