Relation Between Atherosclerosis Risk Factors and Aspirin Resistance in a Primary Prevention Population

doi:10.1016/j.amjcard.2006.04.015

The American Journal of Cardiology

Volume 98, Issue 6, 15 September 2006, Pages 774-779

https://doi.org/10.1016/j.amjcard.2006.04.015 Get rights and content

Resistance to inhibition of platelet function by aspirin may contribute to future myocardial infarction and stroke. Adverse cardiovascular outcomes have been associated with aspirin resistance on several different platelet function assays, including the level of urinary 11-dehydro thromboxane B2 (Tx-M), platelet aggregation to arachidonic acid and adenosine diphosphate, and closure time on the platelet function analyzer-100. We examined the concordance of these aspirin-resistance assays and their relation to cardiovascular risk factors in a primary prevention population. Asymptomatic patients (n = 1,311) at increased risk for coronary heart disease were evaluated before and after 2 weeks of aspirin (81 mg/day). Aspirin resistance was defined according to published criteria for these 3 assays of platelet function. Subjects were characterized for the presence of atherosclerosis risk factors. Agreement among the 3 assays was poor. Only 5 patients met aggregation criteria for aspirin resistance. Attenuated suppression of urinary Tx-M by aspirin was associated with a greater atherosclerotic risk profile and Framingham risk score in multivariable regression analysis. Aspirin resistance by platelet function analyzer-100 was associated only with increased von Willebrand factor levels and not with atherosclerotic risk profile. In conclusion, in a primary prevention population, different published criteria for aspirin resistance classify distinct groups of patients as aspirin resistant with very little overlap. Higher Tx-M, which reflects decreased suppression of thromboxane production in vivo, is the only criterion associated with atherosclerosis risk factors, suggesting that this measurement may represent the most relevant approach for identifying asymptomatic subjects whose aspirin treatment will “fail.”

Section snippets

Participants and study design

The study was approved by the institutional review board of Johns Hopkins Medical Center (Baltimore, Maryland) and all subjects provided written informed consent. Asymptomatic siblings of patients with documented coronary artery disease at <60 years of age and the sibling’s adult offspring and the offspring’s co-parent were recruited for this study. Subjects were eligible if they were free of coronary artery disease, any bleeding disorder, or previous hemorrhagic event and had no serious

Results

In total, 1,311 patients were evaluated before and after aspirin. The average age of study subjects was 45 ± 13 years; 57% were women and 39% were African-American. Eighty-seven percent of subjects took 100% of the expected 14 aspirin tablets, and >94% took ≥12 tablets. After 14 days of aspirin, urinary Tx-M was markedly decreased (272 ± 1,259 at baseline to 50 ± 221 ng/mmol of creatinine at follow-up, p <0.0001) and PFA closure time was markedly prolonged (124 ± 30 seconds at baseline to 259 ±

Discussion

Three different published criteria for aspirin resistance identified 3 distinct groups of patients who met resistance criteria with very little overlap. In our primary prevention population, only 0.4% met published aggregation criteria for resistance, which is probably too infrequent to be clinically useful. Cardiovascular disease risk profiles for subjects who met the Tx-M and PFA criteria for aspirin resistance were significantly different and distinct. Aspirin resistance defined by urinary

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Cited by (62)

Association of Thromboxane Generation With Survival in Aspirin Users and Nonusers
2022, Journal of the American College of Cardiology
Persistent systemic thromboxane generation, predominantly from nonplatelet sources, in aspirin (ASA) users with cardiovascular disease (CVD) is a mortality risk factor.
This study sought to determine the mortality risk associated with systemic thromboxane generation in an unselected population irrespective of ASA use.
Stable thromboxane B₂ metabolites (TXB₂-M) were measured by enzyme-linked immunosorbent assay in banked urine from 3,044 participants (mean age 66 ± 9 years, 53.8% women) in the Framingham Heart Study. The association of TXB₂-M to survival over a median observation period of 11.9 years (IQR: 10.6-12.7 years) was determined by multivariable modeling.
In 1,363 (44.8%) participants taking ASA at the index examination, median TXB₂-M were lower than in ASA nonusers (1,147 pg/mg creatinine vs 4,179 pg/mg creatinine; P < 0.0001). TXB₂-M were significantly associated with all-cause and cardiovascular mortality irrespective of ASA use (HR: 1.96 and 2.41, respectively; P < 0.0001 for both) for TXB₂-M in the highest quartile based on ASA use compared with lower quartiles, and remained significant after adjustment for mortality risk factors for similarly aged individuals (HR: 1.49 and 1.82, respectively; P ≤ 0.005 for both). In 2,353 participants without CVD, TXB₂-M were associated with cardiovascular mortality in ASA nonusers (adjusted HR: 3.04; 95% CI: 1.29-7.16) but not in ASA users, while ASA use was associated with all-cause mortality in those with low (adjusted HR: 1.46; 95% CI: 1.14-1.87) but not elevated TXB₂-M.
Systemic thromboxane generation is an independent risk factor for all-cause and cardiovascular mortality irrespective of ASA use, and its measurement may be useful for therapy modification, particularly in those without CVD.
Significance of urinary 11-dehydro-thromboxane B<inf>2</inf> in age-related diseases: Focus on atherothrombosis
2018, Ageing Research Reviews
Citation Excerpt :
In a fraction of patients, even after optimal disease control and appropriate antiplatelet treatment with low-dose aspirin, a residual TX biosynthesis is detected, suggesting that this measurement may identify asymptomatic subjects whose ASA treatment will "fail." ( Faraday et al., 2006). As a paradigm, patients with T2DM are characterized by persistently increased TX-dependent platelet activation (Davi et al., 2003) and higher CV risk, and their urinary 11-dehydro-TXB2 levels after ASA administration are comparable to those of non-aspirinated, healthy controls (Santilli et al., 2015c).
Platelet activation plays a key role in atherogenesis and atherothrombosis. Biochemical evidence of increased platelet activation in vivo can be reliably obtained through non-invasive measurement of thromboxane metabolite (TXM) excretion.
Persistent biosynthesis of TXA₂ has been associated with several ageing-related diseases, including acute and chronic cardio-cerebrovascular diseases and cardiovascular risk factors, such as cigarette smoking, type 1 and type 2 diabetes mellitus, obesity, hypercholesterolemia, hyperhomocysteinemia, hypertension, chronic kidney disease, chronic inflammatory diseases.
Given the systemic nature of TX excretion, involving predominantly platelet but also extraplatelet sources, urinary TXM may reflect either platelet cyclooxygenase-1 (COX-1)–dependent TX generation or COX-2–dependent biosynthesis by inflammatory cells and/or platelets, or a combination of the two, especially in clinical settings characterized by low-grade inflammation or enhanced platelet turnover.
Although urinary 11-dehydro-TXB₂ levels are largely suppressed with low-dose aspirin, incomplete TXM suppression by aspirin predicts the future risk of vascular events and death in high-risk patients and may identify individuals who might benefit from treatments that more effectively block in vivo TX production or activity. Several disease-modifying agents, including lifestyle intervention, antidiabetic drugs and antiplatelet agents besides aspirin have been shown to reduce TX biosynthesis. Taken together, these aspects may contribute to the development of promising mechanism-based therapeutic strategies to reduce the progression of atherothrombosis.
We intended to critically review current knowledge on both the pathophysiological significance of urinary TXM excretion in clinical settings related to ageing and atherothrombosis, as well as its prognostic value as a biomarker of vascular events.
Comparison between urinary 11-dehydrothromboxane B2 detection and platelet Light Transmission Aggregometry (LTA) assays for evaluating aspirin response in elderly patients with coronary artery disease
2015, Gene
Citation Excerpt :
Thus, the 32.2% prevalence of HAPR found in the current study is generally in agreement with earlier studies by others. However, the weak agreement among different platelet function tests and poor correlation with clinical outcomes raise questions about which method is reliable in assessing aspirin responses (Faraday et al., 2006; Dharmasaroja and Sae-Lim, 2014; Lordkipanidze et al., 2007). Lordkipanize et al. compared six methods to assess platelet function and found poor correlations and low agreements among the various assays (Lordkipanidze et al., 2007).
Aspirin is widely used in the primary and secondary prevention of cardiovascular diseases. The aim of our study was to compare between two established methods of aspirin response, urinary 11-dehydrothromboxane B2 (11dhTXB2) and platelet Light Transmission Aggregometry (LTA) assays in elderly Chinese patients with coronary artery disease (CAD), and to investigate the clinical significance of both methods in predicting cardiovascular events. Urinary 11dhTxB2 assay and arachidonic acid-induced (AA, 0.5 mg/ml) platelet aggregation by Light Transmission Aggregometry (LTA_AA) assay were measured to evaluate aspirin responses. High-on aspirin platelet reactivity (HAPR) was defined as urinary 11dhTxB2 > 1500 pg/mg or AA-induced platelet aggregation ≥ 15.22%—the upper quartile of our enrolled population. The two tests showed a poor correlation for aspirin inhibition (r = 0.063) and a poor agreement in classifying HAPR (kappa = 0.053). With a mean follow-up time of 12 months, cardiovascular events occurred more frequently in HAPR patients who were diagnosed by LTA assay as compared with no-HAPR patients (22.5% versus 10.6%, P = 0.039, OR = 2.45, 95% CI = 1.06–5.63). However, the HAPR status, as determined by urinary 11dTXB2 measurement, did not show a significant correlation with outcomes.
Dual antiplatelet response during PCI: VerifyNow P2Y12 predicts myocardial necrosis and thromboxane B2 generation confirms wide variation in aspirin response
2015, Thrombosis Research
There remains concern that the antiplatelet effects of aspirin and clopidogrel vary between patients and poor responders may be at increased risk of adverse events. However, the optimal method of measuring aspirin and/or clopidogrel response remains unresolved. We compared three methods of measuring clopidogrel response recommended by a recent consensus statement for the European Society of Cardiology, and investigated a novel approach to measuring aspirin response in patients established on both aspirin and clopidogrel. In addition, we investigated whether any of these assays predict peri-procedural myocardial necrosis following percutaneous coronary intervention (PCI).
A cross-section of 323 patients attending for PCI was tested for clopidogrel response using VerifyNow P2Y12, VASP Platelet Reactivity Index (VASP-PRI) and whole blood impedance aggregometry (WBPA). Aspirin response was assessed by measuring the residual ability of platelets to generate thromboxane, calculated as the difference between thromboxane B2 levels in serum and plasma, [TxB2]_S-P. Peri-procedural myocardial necrosis was determined by a change in troponin I > 0.2 μmol/l.
Patients demonstrated wide variation in response to both aspirin and clopidogrel. Correlation between VerifyNow P2Y12 and VASP-PRI was good (r = 0.702, p < 0.001). Correlation was moderate between WBPA and VerifyNow P2Y12 (r = 0.639, p < 0.001) and weak for WBPA and VASP-PRI (r = 0.353, p < 0.001). Only VerifyNow P2Y12 predicted peri-procedural myocardial necrosis.
The three methods of measuring response to clopidogrel identify different patients as poor responders. Poor response to clopidogrel assessed by VerifyNow P2Y12 predicts myocardial necrosis. Measurement of [TxB2]_S-P demonstrates a wide variation in aspirin response in patients taking dual antiplatelet therapy.
Monitoring of Antiplatelet Therapy
2013, Platelets
Relationship between acute stroke outcome, aspirin resistance, and humoral factors
2012, Journal of the Chinese Medical Association
The relationship between biochemical aspirin resistance (AR) and functional outcome of acute ischemic stroke is uncertain.
Prospectively, 269 patients with acute ischemic stroke were recruited. Their responsiveness to aspirin was evaluated by platelet function analyzer (PFA-100). All patients received blood tests for fibrinogen, high-sensitivity C-reactive protein (hs-CRP), CD40-ligand, P-selectin, intercellular adhesion molecule -1, von Willebrand factor (vWF), and D–dimer. The patients' National Institutes of Health Stroke Scale and modified Rankin Scale scores were recorded on admission, at 30 days, and at 90 days after stroke.
Closure-time measured by PFA-100 equipped with epinephrine/collagen cartridge (Epi-CT) was <193 seconds (defined as AR) in 83 patients (30.9%). Patients with AR were less likely to have favorable outcome at 30 days (47.0%, p = 0.047; odds ratio: 0.69, 0.48–0.99) and 90 days (57.8%, p = 0.037; odds ratio: 0.69, 0.47–0.97) after stroke compared with those of patients without AR (60.2% and 71.0%, respectively). The Epi-CT correlated with closure-time measured by adenosine diphosphate/collagen cartridge (r = 0.241, p < 0.001), blood white cell count (r = −0.125, p = 0.041), low density lipoprotein cholesterol (r = 0.120, p = 0.050), hs-CRP (r = −0.150, p = 0.015), vWF (r = −0.134, p = 0.028), and body mass index (r = 0.143, p = 0.019). Multivariate logistic regression analysis showed that higher National Institutes of Health Stroke Scale at admission, atrial fibrillation, increased plasma levels of hs-CRP, and D–dimer were independent predictors for unfavorable stroke outcome at 90 days.
Aspirin resistance evaluated by PFA-100 test was associated with unfavorable 90-day outcome. However, AR determined by PFA-100 dose not predict 90-day functional outcome. The results of PFA-100 testing represented a complex interaction between drug effect, inflammatory reaction, and prothrombotic activity.

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: This work was supported by grants from the National Institutes of Health (NIH)/National Heart, Lung and Blood Institute (U01 HL72518 and HL65229), the NIH/National Institute of Environmental Health Sciences (K23 ES013166-01), and the NIH/National Center for Research Resources (M01-RR000052), Bethesda, Maryland, to The Johns Hopkins General Clinical Research Center. Aspirin tablets were provided by McNeil Consumer and Specialty Pharmaceuticals, Fort Washington, Pennsylvania. Additional support was provided by AspirinWorks (discounts on Tx-M assays), Broomfield, Colorado.

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Preventive cardiologyRelation Between Atherosclerosis Risk Factors and Aspirin Resistance in a Primary Prevention Population

Section snippets

Participants and study design

Results

Discussion

J Am Coll Cardiol

J Thromb Haemost

Am J Cardiol

Thromb Res

Blood

J Biol Chem

Blood

Am J Med

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

Circulation

Aspirin non-responder status in patients with recurrent cerebral ischemic attacks

J Neurol