11-dehydrothromboxane B2 Levels Research Articles

11-dehydrothromboxane B2 as a marker of acetylsalicylic acid resistance in patients with stable coronary artery disease

Introduction. Acetylsalicylic acid (ASA, aspirin) resistance is the inability to reduce thromboxane A2 synthesis in platelets and inhibit platelets activation and aggregation while taking ASA. Assessment of urinary 11-dehydrothromboxane B2 (11-dhTxB2) levels is one of the methods to identify aspirin resistance. Our research aimed to investigate whether urinary 11-dhTxB2 levels and other clinical and laboratory parameters are associated with a history of major adverse cardiovascular events (MACE) including myocardial infarction and ischaemic stroke in aspirin-treated patients with stable coronary artery disease. Patients and methods. In a cross-­sectional study we investigated 82 patients with stable coronary artery disease who took ASA at doses of 75–150 mg/day. We used the evaluation of the urinary 11-dhTxB2 levels standardized by creatinine as a method to identify aspirin resistance. Statistical analysis was performed using Mann-­Whitney U-test, ROC-analysis and multivariable logistic regression. Results. The medians of urinary 11-dehydrothromboxane B2 level in patients with and without MACE were 587.8 (Q1-Q3 512.8–800.3) pg/mg creatinine and 438.3 (Q1–Q3 337.6–577.9) pg/mg creatinine, respectively (p=0.001). The threshold level of urinary 11-dhTxB2, which predicted a high risk of aspirin resistance, was 521.1 pg/mg creatinine, and in 36 (43.9 %) patients the concentration of the 11-dhTxB2 exceeded this level. The regression model characterising the dependence of the presence of a history of MACE was constructed. It included platelet count, urinary levels of 11-dhTxB2 and the presence of type 2 diabetes. Sensitivity and specificity of the model were 55 % and 88.9 %, respectively. Conclusions. The results of the study demonstrate that the antiplatelet effect of aspirin is weaker in stable coronary artery disease patients with a history of MACE than in those without a history of MACE.

MO403: The Association Between Urinary 11-Dehydrothromboxane B2 and Laboratory Parameters in Aspirin-Treated Patients With Cardiorenal Syndrome

Abstract BACKGROUND AND AIMS Evaluation of urinary levels of the 11-dehydrothromboxane B2 is one of the methods for assessing platelet reactivity while taking aspirin. High levels of 11-dehydrothromboxane B2 in urine indicate continued thromboxane generation which is associated with an increased risk of atherothrombotic cardiovascular events. The present study aimed to evaluate the association between 11-dehydrothromboxane B2 in urine and laboratory parameters in aspirin-treated patients with the cardiorenal syndrome in subgroups from quartile with the highest and the lowest levels of thromboxane metabolite. METHOD A total of 82 patients with stable coronary artery disease (CAD) and CKD (stages 2–4) were included in the study. Urinary levels of 11-dehydrothromboxane B2 (a stable metabolite of thromboxane A2) were assessed using ELISA kit by Enzo Life Sciences (Switzerland). Statistical analysis was performed using the chi-squared test and Spearman's rank correlation coefficient. RESULTS In the subgroup of patients from the quartile with the highest levels of urinary 11-dehydrothromboxane B2, a history of ischemic stroke (P = 0.032) and a history of myocardial infarction (P = 0.048) were more common. There were significant correlations between urinary 11-dehydrothromboxane B2 and platelet count (rs = 0.457, P = 0.043), platelet crit (rs = 0.481, P = 0.037), pulmonary artery systolic pressure (rs = 0.847, P = 0.016) and left ventricular ejection fraction (rs = −0.719, P = 0.045) in the same subgroup of patients. In the subgroup of patients from the quartile with the lowest levels of 11-dehydrothromboxane B2 in urine statistically significant correlations between thromboxane metabolite and fasting plasma glucose (rs = 0.581, P = 0.007) and hematocrit (rs = 0.441, P = 0.003) were found. CONCLUSION Our study identified the relationships between the urinary concentration of 11-dehydrothromboxane B2 and laboratory and echocardiography parameters in aspirin-treated patients with cardiorenal syndrome. Accordingly, the received results represent the varying response to aspirin in patients with stable CAD and CKD. Additional research is needed to clarify the impact of platelet indices and the association between platelet reactivity while taking aspirin and pulmonary hypertension on behalf of the possibility of personalization of antiplatelet therapy.

Long Non-Coding RNA H19 Positively Associates With Aspirin Resistance in the Patients of Cerebral Ischemic Stroke.

Background and purposeAspirin is a novel anti-platelet drug that is intensively recommended for the prevention and treatment of cerebral ischemic stroke. However, the existence of aspirin resistance weakens the effects of aspirin and usually induces the recurrence of ischemic stroke. While the mechanism underlying aspirin resistance is still unclear. Long non-coding RNA H19 (H19) is closely associated with the onset and prognosis of cerebral ischemic stroke. Since the relationship between H19 and aspirin resistance have never been reported, herein, we aimed to evaluate the H19 expression in aspirin-resistant ischemic stroke patients and subsequently, ascertain the ability of H19 to diagnose aspirin resistance.MethodsWe included 150 patients with acute cerebral ischemic stroke who were followed up for one year to determine stroke recurrence. Levels of 11-dehydro thromboxane B2 (11dhTXB2) in urine were tested to evaluate the status of aspirin resistance, and those of H19 and 8-iso-prostaglandin-2α in plasma were assessed. The relationship between 11dhTXB2 or and 8-iso-prostaglandin-2α and H19, and the receiver operating characteristic curve of H19, the association of H19 and aspirin resistance with the recurrence of stoke were statistically analyzed.ResultsPlasma H19 was significantly up-regulated in patients with aspirin resistance (p=0.0203), and the H19 levels were positively associated with urine 11dhTXB2/creatinine (R=0.04364, p=0.0106) and positively associated with the level of 8-iso-PGF2α (R=0.04561, p=0.0089). The ROC curves indicated that H19 can sensitively and specifically diagnose aspirin resistance (area under the curve, 0.8005; 95% CI, 0.7301–0.8710; p < 0.0001; specificity, 75.86207%; sensitivity, 73.84615%.). H19 is an independent risk factor for aspirin resistance (OR=1.129, p=0.0321), and aspirin resistance and H19 are closely related with ischemic stroke recurrence.ConclusionsH19 is closely associated with aspirin resistance, and H19 probably induces aspirin resistance through increasing the production of 8-iso-prostaglandin-2α. Besides which, H19 may serve as a serological marker for diagnosing aspirin resistance with high specificity and sensitivity, and the test of H19 could give clues to the recurrence of ischemic stroke.

Evaluation of the efficacy and safety of text messages targeting adherence to cardiovascular medications in secondary prevention: the txt2heart Colombia randomised controlled trial protocol

IntroductionAnti-platelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta-blockers and statins are cost-effective in patients with atherosclerotic cardiovascular diseases (ASCVD) for reducing the risk of ASCVD events. Unfortunately, there is...

Immature platelets and antiplatelet therapy response to aspirin in Kawasaki disease.

IntroductionKawasaki disease is a kind of systemic vasculitis that mainly damages moderate and small-sized blood vessels, and is a leading cause of coronary artery lesions (CAL). Antiplatelet therapy is a routine component of Kawasaki disease treatment strategies. So it is important to evaluate the antiplatelet effect of aspirin because of the individual biological variability of antiplatelet effect of aspirin. The immature platelet fraction (IPF) has attracted particular attention as it may influence the antiplatelet effect of aspirin. This study investigated the prognostic factors for evaluating the degree of vasculitis and the effect of antiplatelet therapy in children with Kawasaki disease.Materials and methodsBlood samples were collected from 44 patients with Kawasaki disease before aspirin treatment and 7 to 10 days after treatment. The IPF counts, percentage of the IPF, and highly fluorescent IPF were detected by a Sysmex XE-5000 instrument. The levels of 11-dehydrothromboxane B2 (11-DH-TXB2), soluble CD40 ligand (sCD40L), and soluble P-selectin (sP-selectin) were measured by ELISA. The correlation between the measured factors and the degree of coronary artery damage in Kawasaki disease was analyzed.ResultsWe found that 11-DH-TXB2, sP-selectin, and sCD40L levels were much more elevated in the CAL group than in the non-coronary artery lesions (NCAL) group before aspirin treatment. The concentrations of 11-DH-TXB2, sCD40L, sP-selectin, and IPF were reduced after aspirin treatment in the NCAL group but not the CAL group. This is related to the degree of coronary artery damage in Kawasaki disease patients. Additionally, 11-DH-TXB2, sCD40L, sP-selectin, and IPF were positively correlated with the degree of coronary artery damage in Kawasaki disease patients.ConclusionThe current study suggests that the presence of high plasma concentrations of 11-DH-TXB2, sCD40L, sP-selectin, and IPF can be considered a risk factor and experimental biomarker for CAL in Kawasaki disease patients.

(677) - Elevated Levels of 11-dehydrothromboxane B2 in Urine Is Associated with an Increased Risk of Bleeding in Patients Supported with a Continuous Flow-Left Ventricular Assist Device

(677) - Elevated Levels of 11-dehydrothromboxane B2 in Urine Is Associated with an Increased Risk of Bleeding in Patients Supported with a Continuous Flow-Left Ventricular Assist Device

Overcoming aspirin resistance with loading clopidogrel earlier in elective percutaneous coronary intervention.

We aimed to analyze the clinical effect of clopidogrel loading time on adverse cardiovascular events among patients with aspirin resistance. Recurrent adverse events may still occur despite dual antiplatelet therapy after coronary stenting. Aspirin resistance is one of the possible reasons of this trouble. Optimal antiplatelet strategy for coronary stenting is unknown among patients with aspirin resistance. A total of 980 patients scheduled for elective coronary stenting were enrolled and allocated into two groups according to the loading time of clopidogrel more or less than 6 hours before coronary intervention (early- or late-loaded groups, respectively). Aspirin resistance was determined according to the urinary levels of 11-dehydrothromboxane B2. Overall 240 patients who were allocated to early- and late-loaded groups were identified as aspirin resistant according to the urinary levels of 11-dehydrothromboxane B2. After a follow-up period of 12 months major adverse cardiac events were observed among 16 patients (13.9%) in the early-loaded group and 30 patients (25.8%) in the late-loaded group (p = 0.02). Early loading of clopidogrel was an independent predictor of lower rate of cardiac events (hazard ratio = 0.46 [0.32-0.76, 95% confidence interval], p = 0.001). The rates of bleeding events and periprocedural myocardial infarction were similar in early- and late-loaded groups. The current study demonstrated that loading of clopidogrel earlier than 6 hours before elective coronary stenting among aspirin-resistant patients was associated with increased benefits for ischemic events with similar bleeding rates.

Relation of Fish Oil Supplementation to Markers of Atherothrombotic Risk in Patients With Cardiovascular Disease Not Receiving Lipid-Lowering Therapy

Fish oil supplementation (FOS) is known to have cardiovascular benefits. However, the effects of FOS on thrombosis are incompletely understood. We sought to determine if the use of FOS is associated with lower indices of atherothrombotic risk in patients with suspected coronary artery disease (sCAD). This is a subgroup analysis of consecutive patients with sCAD (n=600) enrolled in the Multi-Analyte, Thrombogenic, and Genetic Markers of Atherosclerosis study. Patients on FOS were compared with patients not on FOS. Lipid profile was determined by vertical density gradient ultracentrifugation (n=520), eicosapentaenoic acid+docosahexaenoic acid was measured by gas chromatography (n=437), and AtherOx testing was performed by immunoassay (n=343). Thromboelastography (n=419), ADP- and collagen-induced platelet aggregation (n=137), and urinary 11-dehydrothromboxane B2 levels (n=259) were performed immediately before elective coronary angiography. In the total population, FOS was associated with higher eicosapentaenoic acid+docosahexaenoic acid content (p<0.001), lower triglycerides (p=0.04), total very low-density lipoprotein cholesterol (p=0.002), intermediate-density lipoprotein cholesterol (p=0.02), and AtherOx levels (p=0.02) but not in patients on lipid-lowering therapy. Patients not on lipid-lowering therapy taking FOS had lower very low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, remnant lipoproteins, triglycerides, low-density lipoprotein cholesterol, AtherOx levels, collagen-induced platelet aggregation, thrombin-induced platelet-fibrin clot strength, and shear elasticity (p<0.03 for all). In clopidogrel-treated patients, there was no difference in ADP-induced aggregation between FOS groups. Patients on FOS had lower urinary 11-dehydrothromboxane B2 levels regardless of lipid-lowering therapy (p<0.04). In conclusion, the findings of this study support the potential benefit of FOS for atherothrombotic risk reduction in sCAD with the greatest benefit in patients not receiving lipid-lowering therapy. Future prospective studies to compare FOS with lipid-lowering therapy and to assess the independent effects of FOS on thrombogenicity are needed.

Age-related differences in urinary 11-dehydroxythromboxane B2 between infants, children, and adolescents: another example of developmental hemostasis?

Our study was developed to ascertain reference ranges of 11-dehydrothromboxane B2 (11-dhTXB2) in the urine of healthy pediatric subjects. Urine samples were analyzed using the AspirinWorks™ assay that measures levels of 11-dehydrothromboxane B2. 128 individuals (2 months to 18 years) were identified as healthy and not receiving aspirin. When adjusted as picograms/milligrams urine creatinine, there was a negative correlation between age and level of 11-dehydrothromboxane B2 (P = 0.0001). This study confirms a negative correlation between age and level of urinary 11-dehydrothromboxane B2 and provides a set of age-specific reference ranges.

TCT-715 First Demonstration of dose Dependent Effect of Statin Therapy on Urinary 11-dehydrothromboxane B2 levels in Patients Undergoing Coronary Angiography

Background: Aspirin and statin therapy are primary treatment strategies in patients with cardiovascular disease. Heightened urinary 11-dehydrothromboxane B2(11-dTxB2) levels have been associated with an increased risk of adverse cardiovascular events. The aim of the study was to determine the effect of statin therapy on 11-dTxB2 levels in patients undergoing coronary angiography on 325 mg aspirin. Methods: Urinary 11-dTxB2 was measured in patients prior to coronary angiography with (n 155) and without (n 95) statin therapy. Lipoproteins by vertical density gradient ultracentrifugation technique and thrombin-induced platelet-fibrin clot strength(TIP-FCS), a marker for cardiovascular events by thrombelastography, were also measured. The dose dependent effect of statin therapy was analyzed according to atorvastatin equivalent dose, categorized as: 5-10mg, 20-40mg, 80mg. Results: Baseline demographics and cardiac risk factors were similar between groups. Statins significantly reduced urinary 11-dTxB2 levels in a dose dependent manner (Figure). There was a significant relation between quartiles of 11-dTxB2 and TIPFCS,(p 0.05 for ANOVA). Patients on statin therapy had significantly lower levels of LDL, triglycerides, VLDL, atherox and apo B100 (p 0.005 for all). However, Urinary 11-dTxB2 did not correlate with lipids and lipoproteins measurements. Conclusions: This is the first study to demonstrate the dose dependent response of statin therapy on urinary 11-dTxB2 levels, independent of lipid lowering effects.Clinical outcome studies are required to determine the utility of this novel marker for optimizing statin therapy. TCT-716

Urinary 11-dehydro thromboxane B2 levels in type 2 diabetic patients before and during aspirin intake

BackgroundDiabetic patients commonly present an increased risk for cardiovascular events, for which aspirin is the most frequently used medication for primary prevention. Urinary 11-dehydro thromboxane (11-dhTXB2) concentrations assess the effect of aspirin on platelets and identify patients who are at risk of cardiovascular events. The present study investigated whether or not type 2 diabetic patients who took a daily dose of 100mg of aspirin had a significant reduction in urinary 11-dhTXB2 concentrations and whether these results were associated with clinical and laboratory variables. MethodsEighty-one type 2 diabetic patients were enrolled in the study. Laboratory tests included the determination of lipidic profile, glycated hemoglobin, platelets count, molecular analysis for both GPIIbIIIa and COX-1 polymorphisms, and urinary 11-dhTXB2. ResultsPatients' median value for urinary 11-dhTXB2 before aspirin intake was 179pg/mg of creatinine. After 15days taking aspirin, the patients presented median of 51pg/mg of creatinine, thus revealing a significant difference between medians (p=0.00). A reduction of 95% in urinary 11-dhTXB2 concentrations could only be identified in 4 patients (5%). A BMI of ≥26 presented a significant association with a reduction of urinary 11-dhTXB2 concentrations (p=0.010), as shown by the multiple logistic regression model. Other clinical and laboratory variables showed no association. ConclusionsRegardless of the mechanisms related to aspirin non-responsiveness, most patients enrolled in the present study also presented a reduced or minimal response to low-dose aspirin therapy, thereby indicating a clear variability related to aspirin effectiveness. Moreover, BMI appears to be independently associated to the reduction of urinary 11-dhTXB2 concentrations in type 2 diabetic patients taking aspirin.

Post interventional cardiology urinary thromboxane correlates with PlateletMapping® detected aspirin resistance

Introduction We have previously defined aspirin resistance detected by TEG PlateletMapping using arachidonic acid (AA). This aspirin resistance is observed as platelet activation (> 20%) by AA in whole blood, even though the isolated platelets are inhibited by aspirin. This platelet activation in whole blood is due to a transcellular pathway mediated by platelets and leukocytes. Methods To determine if this PlateletMapping assay of aspirin resistance on pre-procedure blood samples correlated with an in vivo response we assayed the first voided urine samples collected 2-8 hours post interventional cardiology procedures for 11-dehydro thromboxane B2. Results and Conclusions We detected 27 aspirin resistant patients out of a total of 81 (33%), in agreement with our previous study. All of these patients were on aspirin therapy, confirmed by a < 20% aggregation response to AA by light transmission platelet aggregometry using isolated platelet rich plasma. Aspirin resistant patients urine samples (14 out of a total of 60 patients analyzed) contained significantly (P = 0.008) higher 11-dehydro thromboxane B2 levels than the other 46 aspirin sensitive patients urine samples. Since our previous study implicated 12- and 15-lipoxygenases in this pathway, we also assayed for polymorphisms to determine any correlation with aspirin resistance. A correlation was found in a polymorphism affecting the lipoxygenase domain of platelet 12-lipoxygenase. This result indicates that aspirin resistance detected in whole blood by the TEG PlateletMapping assay correlates with a physiological consequence in terms of thromboxane formation. This is the first report of such a correlation.

Aspirin resistance in Indian patients with coronary artery disease and cardiovascular events

Aspirin resistance is a major problem and its incidence and clinical significance in Indian patients with documented coronary artery disease are not known. We sought to study the incidence of aspirin resistance and its clinical significance in a cohort of Indian patients with coronary heart disease on therapy with aspirin using urinary 11-Dehydrothromboxane B2 levels as a surrogate marker for antiplatelet efficacy. Non randomized single center prospective study in cohort of patients with stable cardiovascular disease on chronic aspirin therapy attending the cardiology outpatient clinic of a tertiary care hospital. Urinary dehydrothromboxane levels were analyzed in a cohort of 63 patients with stable documented coronary artery disease and in 21 healthy volunteers. The cases were followed up prospectively for a median period of 36 (1-53) months. The clinical endpoint was a composite of acute coronary syndrome, stroke, revascularization and death. Comparison of urinary dehydrothromboxane concentration values between various risk factors was done using Mann Whitney U test, a non parametric alternative of independent t test. All statistical analyses were done using SPSS 11.0 (Chicago, USA) software. The median (range) absolute values of urinary11- dehydrothromboxane B2 levels for the healthy volunteers and cases were 440 (286-2050) pg/ml and 320 (72-2600) pg/ml (P=0.007). The corresponding normalized values were 87.3 (43-143) and 60.8 (16.7-943) ng/mmol of creatinine (P=0.131). Among the various vascular risk factors, patients who were overweight had higher absolute levels of 11- urinary dehydrothomboxane B2 levels (P=0.016). There were significantly more clinical events in patients with absolute urinary 11-dehydrothromboxane B2 levels in the upper two quartiles compared to the lower two quartiles (P=0.04). The incidence of aspirin resistance in the cohort of patients with documented heart disease was 38.1%. Patients with elevated absolute urinary dehydrothomboxane levels (>320 pg/ml) on chronic aspirin therapy constitute a high risk subset for recurrent vascular events.

Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid

Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B(2) concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B(2) concentrations that could thereby reduce cardiovascular risk. Urinary 11-dehydro thromboxane B(2) concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B(2) concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P=0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B(2), whereas aspirin dose > or =150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B(2) levels. In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B(2) are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.

Phenotypic predictors of increased urinary 11-dehydrothromboxane B2 levels in patients treated with aspirin

Inhibition of thromboxane A2 by aspirin can be estimated by urinary levels of a metabolite 11-dehydrothromboxane B2 (TXB2). Our objective was to compare TXB2 levels in relation to cardiovascular risk factors that may affect resistance to aspirin.

Urinary 11-Dehydrothromboxane B2 Levels in Healthy Individuals Following a Single Dose Response to Two Concentrations of Aspirin.

Introduction: The purpose of this protocol was to determine the effect of aspirin on urinary 11-dehydrothromboxane B2 (11-DHT) levels in normal healthy adults who had ingested a single dose of aspirin (ASA).Methods: We enrolled 50 normal healthy volunteers 18–58 years of age who had not ingested ASA or other NSAIDs for the previous 14 days. A baseline urine specimen was obtained followed by ingestion of a single 81 mg enteric-coated ASA. Twenty-four hours later a post-ASA urine specimen was obtained. Two weeks later another baseline urine specimen was obtained followed by a single 325 mg ASA enteric-coated tablet. Twenty-four hours later another post-ASA urine specimen was obtained. Urines were stored at -70°C until testing. Platelet response to aspirin was assessed using the 11-DHT immunoassay (Cayman Biochemical, Ann Arbor, MI). Aspirin Works® controls (Creative Clinical Concepts, Denver, CO) were utilized to control for lot to lot and run to run variability. Testing was completed by Hemostasis Reference Laboratories (Hamilton, ON). In 2002, HOPE study investigators computed quartiles by comparing clinical outcomes to urinary 11-DHT levels from subjects who were taking ASA to prevent a second adverse cardiovascular event. A level of 298 pg 11-DHT/mg urinary creatinine was the limit for determining platelet response to ASA and for projecting cardiovascular risk While 298 pg/mg was the lower limit of the fourth quartile, this limit may not apply to the 11-DHT effect of a single dose of ASA. Our limit for ASA response was established by determining the 50% difference between baseline and outcome. This approach was applied to both ASA concentration arms.Results: Twenty-two of 48 subjects in the 81 mg ASA group showed an ASA response (46%). Forty of the 46 subjects (85%) in the 325 mg dosage group responded. The 325 mg ASA dose showed a significantly greater platelet response, based on mean 11-DHT levels.Discussion: Previous studies have shown that non-responders to ASA have a greater risk of cardio-vascular problems using the quartile distribution. The current study may be used to extend these findings by applying them to single-dose ASA in normal healthy subjects. Further studies may apply these data to primary cardiovascular risk.

The antithrombotic profile of aspirin. Aspirin resistance, or simply failure?

The antithrombotic profile of aspirin. Aspirin resistance, or simply failure?

Vascular viewpoint

Question: Among high-risk patients with vascular disease treated with aspirin, is incomplete suppression of thromboxane generation associated with an increased risk of recurrent cardiovascular events? Population: Men and women 55 years of age who had a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes plus at least one other CV risk factor who participated in the HOPE trial which was a 2 2 factorial randomized controlled trial of ramipril and vitamin E.1 Design and methods: Nested case-control study of the 5529 patients from the HOPE trial participants from Canada in whom a urine sample was collected at baseline. All samples were sent to a central laboratory and stored at -80°C. Only those patients who were taking aspirin were included. Cases were defined as individuals who had a confirmed MI, stroke, or CV death after randomization. Control subjects were randomly selected from aspirin-treated patients who provided adequate urine samples but did not suffer MI, stroke or CV death after randomization. Cases and controls were matched according to sex and age (5 years) in a ratio of 1:1. Urine was thawed and assayed for 11-dehydro thromboxane B2 levels using the Caymann Chemical immunoassay. Results: Among 488 cases and 488 matched controls, the odds of an MI, stroke or CV death increased with each increasing quartile of 11-dehydro thromboxane B2, with patients in the upper quartile having a 1.8 times higher risk than those in the lower quartile (OR = 1.8; 95% CI: 1.2-2.7, p = 0.009). Conclusion: Among aspirin-treated patents who have established vascular disease, urinary 11- dehydro thromboxane B2 predicts the future risk of MI and CV death, and may reflect ‘aspirin resistance’.

Why Are Some Individuals Resistant to the Cardioprotective Effects of Aspirin?

It has been slightly more than 100 years since the synthesis, development, and commercialization of acetylsalicylic acid, the most widely consumed drug in the world. It is estimated that 35 000 kg are consumed daily in the United States and 6000 kg in the UK.1 Who would have ever thought that this widely consumed drug would achieve significant uses other than as an analgesic, antipyretic, and anti-inflammatory. The first report of a possible antithrombotic effect of aspirin appeared in 1953 in the Mississippi Valley Medical Journal .2 Dr Craven noticed that the patients who took Aspergum had a tendency to bleed more easily. He concluded that aspirin must be thinning the blood and because thrombosis of the coronary arteries led to myocardial infarction, if his patients took aspirin, they might be less prone to experiencing a myocardial infarction. See p 1650 These prescient observations were succeeded by the discovery by numerous investigators that aspirin could significantly decrease platelet function. In 1971, the mechanism by which aspirin inhibited platelet function began to unfold when Smith and Willis3 demonstrated that aspirin inhibited platelet prostaglandin synthesis. It was subsequently shown that aspirin irreversibly acetylated serine-529 close to the active site of the fatty acid cyclooxygenase (COX).4 In the case of the anucleate platelet, the enzyme is rendered inactive for its lifetime. Samuelsson and co-workers5 demonstrated that thromboxane A2 along with prostaglandin H2 were the arachidonic acid metabolites responsible for activation of the platelet. Thromboxane A2 is also a very effective vasoconstrictor and mitogenic substance. After the discovery of thromboxane A2, numerous studies followed that investigated its potential role in thrombotic cardiovascular diseases. Platelet thromboxane A2 synthesis is increased in acute myocardial infarction, unstable angina, thrombolysis therapy, percutaneous transluminal coronary artery angioplasty, and …

Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events.

We 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 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, we measured urinary 11-dehydro thromboxane B2 levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke, or cardiovascular death during 5 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-dehydro thromboxane B2, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95% 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% CI, 1.2 to 3.4; P=0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95% CI, 1.7 to 7.4; P<0.001) than those in the lower quartile. In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 predict the future risk of myocardial infarction or cardiovascular death. These findings raise the possibility that elevated urinary 11-dehydro thromboxane B2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity.