Aspirin is a mainstay in the prevention of atherosclerotic events. Research indicates that there are patients who are resistant to aspirin. There are alternate drugs available to replace or supplement aspirin. The primary alternate drug available is clopidogrel (Plavix®).
Both aspirin and clopidogrel inhibit the ability of blood platelets to aggregate, or clump. Clumping is one of the early steps in producing a blood clot, which is, under ordinary circumstances, a beneficial effect. Inappropriate clot formation in the arteries supplying blood to the heart or brain impairs blood flow, which can lead to damage or death of tissue.
Aspirin is an antiplatelet drug that works to prevent heart attacks and strokes by reducing the production of thromboxane, the chemical that makes platelets sticky. Although thromboxane cannot be measured directly, its chemical biomarker, 11-dehydro-thromboxane B², can. A low level of this biomarker in the urine means that aspirin is working as it should to reduce thromboxane production. High levels of the biomarker in the patient's urine may mean that the dosage of aspirin is not effective for decreasing the risk of a heart attack or stroke for that particular patient.
Aspirin's ability to suppress the production of prostaglandins and thromboxanes (both of which are produced during the metabolism of aspirin or clopidogrel) is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A² in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks. A dose of 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A² release provoked acutely, with the prostacyclin synthesis being little affected. However, higher doses of aspirin are required to attain further inhibition.
Approximately 10-20 percent of aspirin-treated patients will have a cardiovascular event wthin five years of initiating therapy. This led to the concept that there is a subset of "aspirin resistant" patients who do not respond to aspirin clumping therapy and are, therefore, at persistent risk of future cardiovascular events. True biochemical aspirin resistance must be differentiated from non-compliance, a more common reason for therapy failure.
It is difficult to assess the clinical importance of aspirin resistance, since there is currently no consensus on how to define, measure and treat aspirin or clopidogrel resistance. Laboratory tests are becoming available. Test results vary related to the laboratory performing the test and the test being performed. As a result, the incidence of "resistance" has been estimated to be as low as 5 percent and as high as 60 percent in different studies. This variation may also indicate differences in treatment dosage, duration and compliance. Other medications that are being taken may also influence the drug action.
The lack of standardized measures of platelet function makes estimation of the prevalence of aspirin resistance challenging. Evidence suggests that aspirin resistance is associated with adverse clinical outcomes in patients with coronary artery disease, cerebrovascular disease, peripheral vascular disease and myocardial infarction. Patients with aspirin resistance have significantly more adverse vascular events than patients without such resistance. There are no guidelines, however, for the treatment of aspirin resistance.
The measurement of thromboxane metabolites in urine (e.g., AspirinWorks) to evaluate aspirin resistance is considered INVESTIGATIONAL for all indications.
Measurement of Thromboxane Metabolites in Urine
The U.S. Preventive Services Task Force (USPSTF, 2009) has developed guidelines for chronic aspirin therapy based upon a person's age and Framingham risk score. Long-term aspirin administration has clear benefits for the secondary prevention of cardiovascular diseases, with a significant 21 percent reduction in the risk of cardiovascular events over two years (Berger et al., 2008). However, this indicates that not all individuals respond equally to aspirin therapy, and cardiovascular events may occur during aspirin therapy. This is often described as "clinical aspirin resistance." A systematic review and meta-analysis on aspirin resistance indicated that patients who are resistant to aspirin are at a greater risk (odds ratio [OR]: 3.85) of clinically important cardiovascular morbidity than patients who are sensitive to aspirin(Krasopoulos et al., 2008). The effect of aspirin administration varies considerably among patients at high risk for cardiovascular events. Gum and coworkers (2001) found insufficient inhibition of platelet aggregation by aspirin in 6 to 24 percent of patients with stable coronary artery disease, while other estimates range from 5 to 60 percent (Martin and Talbert, 2005).
Many authors believe that aspirin resistance can be detected by biochemical tests, and several commercially available products are being marketed for this purpose. Tests used in research laboratories are aggregometry (turbidometric and impedance) tests, based on activation-dependent changes in platelet surface, and tests based on activation-dependent release from platelets. Point-of-care tests include PFA-100, IMPACT and VerifyNow, which can detect platelet dysfunction that may be due to aspirin effect.
It has been proposed that aspirin resistance can also be detected by thromboxane metabolites in urine. Aspirin inhibits platelet activation through the permanent inactivation of the cyclooxygenase (COX) activity of prostaglandin H synthase-1 (referred to as COX-1), and consequently inhibits the biosynthesis of thromboxane A2(TXA2), a platelet agonist. The urinary concentrations of the metabolite 11-dehydrothromboxane B2(11 dhTxB2) indicate the level of TXA2 generation.
Eikelboom et al. (2002) studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population. Baseline urine samples were obtained from 5,529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, the investigators measured urinary 11 dhTxB2 levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke or cardiovascular death during five years of follow-up and in 488 sex- and age-matched control subjects also receiving aspirin who did not have an event. After adjustment for baseline differences, the odds for the composite outcome of myocardial infarction, stroke or cardiovascular death increased with each increasing quartile of 11 dhTxB2, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95 percent CI: 1.2 to 2.7; p = 0.009). Those in the upper quartile had a 2-times-higher risk of myocardial infarction (OR, 2.0; 95 percent CI: 1.2 to 3.4; p = 0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95 percent CI: 1.7 to 7.4; p < 0.001) than those in the lower quartile. The authors concluded that in aspirin-treated patients, urinary concentrations of 11 dhTxB2 predict the future risk of myocardial infarction or cardiovascular death and that these findings raise the possibility that elevated urinary 11 dhTxB2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional anti-platelet therapies or treatments that more effectively block in vivo thromboxane production or activity. However, Altman et al. (2004) reviewed this study and stated that the authors support the view that failure to suppress thromboxane generation defines aspirin resistance and that this hypothesis assumes a direct association between the rise of urinary 11 dhTxB2 levels and increment of vascular events (e.g., myocardial infarction, stroke and cardiovascular death). Altman and colleagues explained that failure of aspirin to produce the expected inhibition of platelet function might be attributed to several mechanisms and that it cannot be defined by the level of serum thromboxane or its urinary metabolites because these measurements do not correlate with the reduction of inhibition of platelet aggregation in response to multiple stimuli, and also because (i) although most of the thromboxane is believed to come from the platelets, there are additional cellular origins (e.g., monocytes/macrophages are also a rich source of TXA2), (ii) unlike the platelet, the macrophage is capable of synthesizing new COX-2 after aspirin has inhibited it; COX-2 is the enzyme responsible for most of the metabolism of arachidonic acid in the macrophage, and low dose aspirin is not sufficient to inhibit COX-2 maximally, (iii) macrophages in atheromata may contribute significantly to the pool of TXA2 and (iv) aspirin only inhibits monocyte PGHS-2, which is inducible by inflammatory stimuli, transiently at very high concentrations.
The AspirinWorks Test Kit (Corgenix Medical Corp; Broomfield, CO) is an enzyme-linked immunoassay test that can be used to determine levels of 11 dhTxB2 in human urine. AspirinWorks received 510(k) marketing clearance from the FDA in May 2007 and is intended to aid in the qualitative detection of aspirin in apparently healthy individuals post ingestion.
The AspirinWorks Test Kit was compared to the Accurnetrics VerifyNow Aspirin Assay as the predicate device. The manual AspirinWorks Test Kit measures urinary 11 dhTxB2, while the automated Accumetrics VerifyNow Aspirin Assay is a turbidimetric-based optical detection system, which measures platelet-induced aggregation in whole blood. The two devices have similar intended uses, in that they both measure aspirin effect. The AspirinWorks kit detects a metabolite of TxA2, a direct inducer of platelet aggregation, while the Accumetrics kit measures ex vivo platelet aggregation caused by TxA2 by artificially inducing aggregation and measuring an optical signal. Ultimately, both are analyzing aspirin's effect through the reduction of TxA2 production or the resulting inhibition of platelet aggregation.
According to the FDA, 2 different clinical studies were employed for the evaluation of the AspirinWorks Test Kit. Results from these studies established a cutoff for aspirin effect at less than 1,500 pg 11d hTxB2/mg creatinine. Further analysis revealed that 180/204 (88.2 percent) of samples from individuals not taking aspirin were above the cutoff value. Analysis of samples from individuals taking various doses of aspirin revealed that 7/163 (4.3 percent) of 81 mg/day aspirin users indicated a lack of aspirin effect (greater than 1,500 pg 1 ldhTxB2/mg creatinine) and 4/38 (10.5 percent) of the 325 mg/day aspirin users indicated a lack of aspirin effect. In total, 11/201 (5.5 percent) of all aspirin users tested indicated a lack of aspirin effect. These percentages are consistent with those in published literature for aspirin non-responsiveness or lack of aspirin effect.
Lordkipanidze et al. (2007) compared the results obtained from six major platelet function tests in the assessment of the prevalence of aspirin resistance in patients with stable coronary artery disease. Patients with stable coronary artery disease (n = 201) receiving daily aspirin therapy (80 mg or more) were recruited. Platelet aggregation was measured by: (i) light transmission aggregometry (LTA) after stimulation with 1.6 mM of arachidonic acid (AA), (ii) LTA after adenosine diphosphate (ADP) (5, 10 and 20 microM) stimulation, (iii) whole blood aggregometry, (iv) PFA-100 and (v) VerifyNow Aspirin; urinary 11 dhTxB2 concentrations were also measured. Eight patients (4 percent, 95 percent CI: 0.01 to 0.07) were deemed resistant to aspirin by LTA and AA. The prevalence of aspirin resistance varied according to the assay used: 10.3 to 51.7 percent for LTA using ADP as the agonist, 18.0 percent for whole blood aggregometry, 59.5 percent for PFA-100, 6.7 percent for VerifyNow Aspirin and, finally, 22.9 percent by measuring urinary 11 dhTxB2 concentrations. Results from these tests showed poor correlation and agreement between themselves. The authors concluded that platelet function tests are not equally effective in measuring aspirin's anti-platelet effect and correlate poorly amongst themselves and that the clinical usefulness of the different assays to classify correctly patients as aspirin resistant remains undetermined.
Hedegaard et al. (2009) assessed the use of optical platelet aggregation versus thromboxane metabolites in healthy individuals and patients with stable coronary artery disease after low-dose aspirin administration. The authors investigated whether 75 mg of daily non-enteric coated aspirin would completely inhibit the platelet cyclooxygenase-1 activity to a comparable extent in healthy individuals and stable coronary artery disease (CAD) patients. Serum thromboxane B2 (S-TxB2), urinary 11 dhTxB2 (U-TxM) and arachidonic acid-induced optical platelet aggregometry (OPA) were compared in 44 coronary artery disease (CAD) patients on aspirin and in 22 healthy individuals before and after aspirin. Optical platelet aggregometry was performed in duplicate for four consecutive days during aspirin treatment after one week of treatment. Compliance was optimized by face-to-face interviews and pill counting and confirmed by S-TxB2 measurements. The authors found that aspirin inhibited S-TxB2 in healthy individuals (greater than 99 percent; median 1.1 ng/mL, inter-quartile range [IQR] = 0.8;1.9 after aspirin) and in patients, S-TxB2 was reduced to a similar level (0.9 ng/mL (0.7;1.5)). Healthy individuals had a median U-TxM of 278.5 pg/mg creatinine (229.5;380.0) before aspirin and 68.5 pg/mg creatinine (59.0;99.7) on aspirin, corresponding to an average 74 percent inhibition of the endogenous TxA2 biosynthesis. In patients, median U-TxM was 67.5 pg/mg creatinine (54.0;85.5). Seven study participants (11 percent) were aspirin low-responders according to OPA, but none had S-TxB2 in the highest quartile. The authors concluded that low-dose aspirin suppressed S-TxB2 to comparable levels in CAD patients and healthy individuals. The authors found that despite an almost complete inhibition of S-TxB2, some participants were low-responders, according to OPA. The authors concluded that thorough compliance control and use of thromboxane-specific assays are important when measuring platelet response to aspirin.
While some investigators believe that aspirin resistance can be detected by thromboxane metabolites in urine, other investigators support the view that aspirin resistance cannot be defined by the level of serum thromboxane or its urinary metabolites because these measurements do not correlate with the reduction of inhibition of platelet aggregation in response to multiple stimuli as well as various other factors. Investigators have found a number of variables that may impact an individual's response to aspirin, including patient's compliance, dose, smoking, hyperlipidemia, hyperglycemia, acute coronary syndrome, percutaneous revascularization, recent stroke, extracorporeal circulation, heart failure, exercise, circadian rhythm, absorption, concomitant medications and polymorphisms.
Many issues are yet to be resolved in order to apply the concept of "aspirin resistance" to actual clinical practice. The clinical usefulness of a test that measures thromboxane metabolites in urine has yet to be determined. The relevance of the various ex vivo functional indexes of platelet capacity to in vivo platelet activation and the precise mechanisms underlying aspirin resistance are still largely unknown. Further investigation is needed regarding strategies to identify and treat patients resistant to aspirin.
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THROMBOXANE METABOLITE(S), INCLUDING THROMBOXANE IF PERFORMED, URINE
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