Pending Policies - Medicine

Measurement of Thromboxane Metabolites in Urine


Effective Date:05-15-2018



Measurement of thromboxane metabolites in urine to evaluate aspirin resistance is considered experimental, investigational and/or unproven.


In addition to analgesic and antipyretic indications, aspirin (acetylsalicylic acid) is used for its antiplatelet properties to reduce the risk of serious vascular events in patients with myocardial infarction (MI), ischemic stroke, angina, peripheral vascular disease (PVD), and atrial fibrillation (AF). Despite the efficacy of aspirin for antiplatelet indications, some patients receiving aspirin still experience vascular events; aspirin resistance has been proposed as a possible explanation. The term “aspirin resistance” has been used to describe the inability of aspirin to inhibit platelet aggregation, as demonstrated by platelet function tests, and also to describe the occurrence of cardiovascular (CV) events despite therapeutic aspirin intake. (1) There is no consensus on whether the definition should be based on laboratory evidence, clinical evidence, or both. Although there are several theories, the mechanism of aspirin resistance is unknown, poorly understood, and likely to be multifactorial. There is no consensus on the frequency of aspirin resistance; estimates range from 5-60%. Evidence indicates aspirin resistance is a dynamic state, with significant intrapatient variability in aspirin sensitivity with time. (1)

Aspirin exerts antiplatelet action through irreversible acetylation of platelet cyclooxygenase-1 (COX-1), which is an enzyme responsible for conversion of arachidonic acid to various eicosanoids, including thromboxane A2 (TXA2). This leads to the inhibition of TXA2 synthesis, which then leads to impaired platelet aggregation. One approach to measuring the activity of aspirin is to measure the levels of products of COX-1 enzyme action, which would be reduced as a result of aspirin administration. TXA2 is an unstable compound with a short half-life making it unsuitable for measurement, but TXA2 is quickly hydrated into TXB2, which is then converted by the liver into two metabolites: 2,3-dinor TXB2 and 11-dehydro-TXB2. TXB2, 2,3-dinor TXB2 and 11-dehydro-TXB2 are excreted unchanged in the urine. Of these three, 11-dehydro-TXB2 is a stable metabolite that can be measured in urine and can serve as an indirect measurement of TXA2. (2)

Regulatory Status

AspirinWorks™ by Corgenix is an example of a test that can be used to measure urinary 11-dehydro-TXB2. AspirinWorks received U.S. Food and Drug Administration (FDA) 510(k) approval in April 2007. The FDA approval states that the “AspirinWorks Test Kit is an enzyme-linked immunoassay (ELISA) to determine levels of 11-dehydro-TXB2 in human urine, which aids in the qualitative detection of aspirin effect in apparently healthy individuals post ingestion.” AspirinWorks was substantially equivalent to the predicate device, VerifyNow™ Aspirin Assay by Accumetrics. (3)


This policy was created in 2010 and has been updated periodically with searches of the MEDLINE database. The most recent literature update was performed through March 21, 2018. Following is a summary of the key literature to date.

Identifying aspirin nonresponders and achieving appropriate levels of platelet inhibition with alternative or additive platelet therapy are the basis of ongoing clinical investigation. In their review of aspirin and clopidogrel resistance, Michos et al. stated that no consensus exists regarding the reference standard for measuring platelet activation, and definitions of aspirin and clopidogrel resistance differ, depending on which test is used. (1) They concluded that “many issues remain unresolved regarding the definition, identification, and clinical importance of resistance to aspirin and clopidogrel. Given these limitations, no established consensus exists of whether aspirin- or clopidogrel-resistant patients should discontinue their antiplatelet regimen or whether additional therapy should be added. Future studies will establish whether patients receiving antiplatelet agents should undergo platelet function studies to assess the adequacy of therapy and determine which antiplatelet drug, or combination thereof, is most efficacious.”

Krasopoulos et al. conducted a meta-analysis and systematic review to determine if there is a relationship between aspirin resistance and clinical outcomes in patients with cardiovascular disease (CVD). (4) They reviewed 20 studies totaling 2930 patients with CVD. Most studies used aspirin regimens ranging from 75-325 mg daily, and six studies included adjunct antiplatelet therapy. Overall, 810 patients were classified as aspirin resistant. Aspirin resistant patients did not benefit from other antiplatelet treatment. The study concluded that patients who are resistant to aspirin are at a greater risk of clinically important cardiovascular morbidity long term than patients who are sensitive to aspirin. In a reported interview about the study, Buchanan acknowledged that while proof of the link between aspirin nonresponsiveness and clinical events is growing, no one knows what to do about it—aspirin sensitivity can be tested for, but there are no data suggesting a course of action.

Eikelboom et al. studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of CV events in a high-risk population. (5) Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-controlled design, urinary 11-dehydro-TXB2 was measured as a marker of in vivo thromboxane generation in 488 patients treated with aspirin who had myocardial infarction (MI), stroke, or CV death during five years of follow up, and in 488 sex- and age-matched control subjects who were also receiving aspirin but did not have an event. After adjustment for baseline differences, the odds for the composite outcome of MI, stroke or CV death increased with each increasing quartile of 11-dehydro-TXB2, with patients in the upper quartile having 1.8 times-higher risk than those in the lower quartile. The study concluded that in aspirin treated patients, urinary concentrations of 11-dehydro-TXB2 predict the future risk of MI or CV death, and that these findings raise the possibility that elevated urinary 11-dehydro-TXB2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block thromboxane production or activity. However, Martin et al. reviewed this study and stated that this was a retrospective case-controlled study in which the frequencies of significant risk factors for CVD (obesity, coronary artery disease, peripheral artery disease, hypertension, diabetes, and smoking) were higher in the case group than in the controls and, as such, the reported event risk may be inflated and should be used cautiously as a basis for therapeutic decision-making. (2)

Eikelboom et al. published a later study in which they aimed to determine the external validity of the association of elevated urinary 11-dehydro-TXB2 with increased risk of CV events in aspirin-treated patients enrolled in the Clopidogrel for High Atherosclerotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial, and to determine whether there are any modifiable factors or interventions that lower 11-dehydro-TXB2 concentrations and could thereby reduce risk. (6) They concluded that in aspirin-treated patients, urinary concentrations of 11-dehydro-TXB2 are an externally valid and potentially modifiable determinant of stroke, MI, or CV death in patients at risk for atherothrombotic events, and that “the effectiveness and safety of high-dose aspirin (300-325 mg/day) compared with lower doses (75-100 mg/day) is currently undergoing evaluation in a prospective trial. The potential for statins to mediate some of their favorable effect on vascular events by lowering urinary 11-dehydro-TXB2 is intriguing and worthy of further study.”

McGlasson and Fritsma conducted a study to compare the ability of four commercial platelet function assays (including VerifyNow and urinary 11-dehydro-TXB2 tests) to detect aspirin response in 50 normal individuals taking 81 or 325 mg aspirin in a single-dose response and then in a 7-day dosing regimen. (7) The individuals were not consistently identified as aspirin responsive across all platforms; all assays discriminated between platelet response and nonresponse to aspirin at both dosages. They concluded that it may be necessary to employ multiple assays to detect individual platelet response.

The U.S. National Institutes of Health is funding the PLARAS study (Platelet Hyperreactivity to Aspirin and Stroke), which is currently recruiting participants. VerifyNow and AspirinWorks (11-dehydro-TXB2) are two of the platelet tests being used in the study. (8) Study questions include:

What is the real prevalence of platelet “resistance” to aspirin during the acute phase of stroke and after one year, as measured using different platelet function tests?

Do all methods measure similar levels of resistance, or are some methods more sensitive than others?

Does this resistance result in a worse clinical prognosis? Is this result independent of other variables?

In 2009, Muir et al. published a study they conducted to characterize the prevalence of aspirin resistance in patients with ischemic heart disease, and to investigate the concordance and repeatability of these tests. (9) Consecutive outpatients (n = 172) with stable ischemic heart disease were enrolled. They were started on 150 mg of aspirin daily (day 0), and had platelet function assessment and quantitative analysis at day ≥ 7 and then at a second visit about two weeks later. The tests used were optical platelet aggregometry (OPA), platelet function analyzer (PFA-100), and TXB2 metabolites. The study found poor association between PFA-100 and OPA, and between TXB2 metabolites and platelet function tests, and concluded that the prevalence of aspirin resistance is dependent on the method of testing. Response varies on a temporal basis, indicating that testing on a single occasion is inadequate to diagnose resistance or guide therapy in a clinical setting.

In their review of aspirin resistance, Gurbel and Tantry of the Sinai Center for Thrombosis Research in Baltimore, Maryland, acknowledge that laboratory evaluation of platelet response has identified response variability, nonresponsiveness or resistance in selected patients, and that some studies have correlated this resistance to the occurrence of thrombotic events. (10) However, at this time specific treatment recommendations are not established for patients exhibiting resistance during aspirin therapy.

In 2014, Pagliaccia et al. reported that thromboxane (TX) A2 is a pro-thrombotic prostanoid synthesized by activated platelets, biotransformed into 11-dehydro-TXB2, measurable in urine. (11) Eleven-dehydro-TXB2 excretion is increased in high risk cardiovascular diseases; however, this cardiovascular biomarker awaits validation in large trials. The need of large urine volume (8 - 10 mL) and the unknown stability of 11-dehydro-TXB2 in urine after collection might limit its implementation. In their study, they scaled the original method for urine extraction and 11-dehydro-TXB2 measurement down to 1 mL, and assessed its stability at 4 degrees celsius (C) or 25 degrees C up to 6 days after collection. The sensitivity of the 1 ml procedure was also tested in aspirin-treated patients with low 11-dehydro-TXB2 excretion. The authors concluded that eleven-dehydro-TXB2 can be measured in small urine volumes and is relatively stable for a few days after collection, even at 25 degrees C, and that these data allow the validation of this non-invasive cardiovascular biomarker in large studies.

In 2014, Dharmasaroja et al. prospectively enrolled 101 patients with ischemic stroke. (12) Response to aspirin was assessed by urinary 11-dehydro-TXB2 measurement and VerifyNow Aspirin assay. The measure outcome was the occurrence of cardiovascular events and death. Incidence of aspirin nonresponders was 40% and 6% if they were measured by urinary 11-dehydro-TXB2 and Verify Now Aspirin assay, respectively. Poor correlation in the results between the two tests was found. Although it was noted that with a mean follow-up time of 17 months that the outcomes occurred significantly higher in aspirin nonresponders who were diagnosed by urinary 11-dehydro-TXB2 measurement as compared with patients with aspirin response, the authors include in their conclusions that further research is still needed to identify the best method of diagnosis of aspirin nonresponders.

Summary of Evidence

Although it has been the subject of study, the clinical importance of aspirin resistance remains difficult to assess, as there is no true consensus as to how it should be defined, measured and treated. Currently there is insufficient data to evaluate the effects that the measurement of thromboxane metabolites in urine to evaluate aspirin resistance has on health outcomes. Therefore, it is considered experimental, investigational and/or unproven.


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1. Michos ED, Ardehali R, Blumenthal RS, et al. Aspirin and clopidogrel resistance. Mayo Clin Proc. 2006 Apr; 81(4):518-26. PMID 16610572

2. Martin CP, Talbert RL. Aspirin resistance: an evaluation of current evidence and measurement methods. Pharmacotherapy. 2005 Jul; 25(7):942-53. PMID 16006273

3. FDA-AspirinWorks-510(k) Substantial Equivalence Determination Decision Summary. 510(k) Summary Number K062025. Food and Drug Administration – Center for Devices and Radiologic Health (2007). Available at <> (accessed October 26, 2009).

4. Krasopoulos G, Brister SJ, Beattie WS, et al. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ. 2008 January 26; 336(7637):195–8. PMID 18202034

5. Eikelboom JW, Hirsh J, Weitz JI, et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002 Apr; 105(14):1650-5. PMID 11940542

6. Eikelboom JW, Hankey GJ, Thom J, et al. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation. 2008 Oct 21; 118(17):1705-12. PMID 18838564

7. McGlasson DL, Fritsma GA. Comparison of four laboratory methods to assess aspirin sensitivity. Blood Coagul Fibrinolysis. 2008 Mar; 19(2):120-3. PMID 18277132

8. Platelet hyperreactivity to aspirin and stroke (PLARAS). NCT00766896. (2008 September) Available at <> (accessed October 26, 2009).

9. Muir AR, McMullin MF, Patterson C, et al. Assessment of aspirin resistance varies on a temporal basis in patients with ischaemic heart disease. Heart. 2009 Aug; 95(15):1225-9. PMID 18697805

10. Gurbel PA, Tantry US. Aspirin and clopidogrel resistance: consideration and management. J Interv Cardiol. 2006 Oct; 19(5):439-48. PMID 17020569

11. Pagliaccia F, Habib A, Pitocco D, et al. Stability of urinary thromboxane A2 metabolites and adaptation of the extraction method to small urine volume. Clin Lab. 2014; 60(1):105-11. PMID 24600983

12. Dharmasaroja PA, Sae-Lim S. Comparison of aspirin response measured by urinary 11-dehydrothromboxane B2 and VerifyNow aspirin assay in patients with ischemic stroke. J Stroke Cerebrovasc Dis. 2014 May-Jun; 23(5):953-7. PMID 24126290

Policy History:

Date Reason
5/15/2018 Document updated with literature review. Coverage unchanged.
4/15/2017 Reviewed. No changes.
7/15/2016 Document updated with literature review. Coverage unchanged.
8/15/2015 Reviewed. No changes.
9/15/2014 Document updated with literature review. Coverage unchanged.
3/15/2012 Document updated with literature review. Coverage unchanged.
1/1/2010 New Medical Policy. New CPT code. Measurement of thromboxane metabolites in urine is considered experimental, investigational and unproven to evaluate aspirin resistance.

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