Polymorphisms associated with in vitro aspirin resistance are not associated with clinical outcomes in patients with coronary artery disease who report regular aspirin use

doi:10.1016/j.ahj.2011.03.026

American Heart Journal

Volume 162, Issue 1, July 2011, Pages 166-172.e1

https://doi.org/10.1016/j.ahj.2011.03.026 Get rights and content

Background

We hypothesized that single-nucleotide polymorphisms (SNPs) associated with heightened in vitro platelet function during aspirin exposure (which we define as “laboratory aspirin resistance”) would be associated with greater risk for death, myocardial infarction (MI) or stroke among patients with coronary artery disease regularly using aspirin.

Methods

Duke Databank for Cardiovascular Disease patients with (n = 3,449, CATHeterization GENetics cohort) or without (n = 11,754, nongenetic cohort) banked DNA with ≥1 coronary stenosis >75% were followed up at 6 months, then annually for death, MI, or stroke occurring during periods of reported aspirin use. We evaluated associations of candidate SNPs from GNB3, PEAR1, ITGB3, VAV3, ITGA2, GPVI, PTGS1, F2R, THBS1, A2AR, and GP1BA with events during follow-up using Cox proportional hazards modeling adjusted for clinical characteristics associated with outcomes in the nongenetic cohort.

Results

Over a median of 3.5 years, 2,762 (24%) nongenetic cohort patients and 648 (19%) CATHeterization GENetics cohort patients had the composite outcome during reported aspirin use. No candidate SNPs were significantly associated with death, MI, or stroke in either univariable or multivariable analyses. A prospective analysis demonstrated 80% to 88% power to detect a hazard ratio of ≥1.3 for minor allele carriers.

Conclusion

Patients with angiographically significant coronary artery disease regularly using aspirin and carrying SNPs associated with laboratory aspirin resistance were not at higher risk for death, MI, or stroke. Using these SNPs to guide more aggressive antiplatelet therapy is not justified by these results. Direct extrapolation from in vitro findings to the clinical setting should be avoided.

Section snippets

Patient population

Using the DDCD, an ongoing longitudinal clinical registry of patients undergoing cardiac procedures at Duke University Medical Center (DUMC) since 1969 and its associated CATHGEN biorepository (http://cathgen.duhs.duke.edu), which has collected and stored blood samples (for DNA, RNA, and plasma) from consenting patients at the time of cardiac catheterization since 2001, we studied potential clinical and genetic factors associated with death, MI, or stroke during regular aspirin use in patients

Patient population

We identified 11,754 eligible patients in the DDCD who were not enrolled in CATHGEN and who had available follow-up for the development of the clinical model and 3,449 who had DNA samples available in CATHGEN. Baseline characteristics, concomitant medication use, and outcomes of these cohorts are displayed in Table I. Median (interquartile range) follow-up was 3.5 years (1.4-5.0 years) in the nongenetic cohort and 4.0 years (1.7-5.0 years) in the CATHGEN cohort. Baseline characteristics were

Discussion

Numerous genetic associations with in vitro aspirin resistance have been reported, although their ability to predict future events in patients reporting aspirin use is not known. We examined the association of SNPs that have been associated with aspirin resistance in the laboratory with clinical events during follow-up while using aspirin in 3,449 patients with CAD. Despite adequate statistical power, we found no evidence for significantly increased risk for clinical events associated with any

Limitations

Despite methodological strengths, there are limitations that require consideration. First, we did not measure laboratory aspirin response in our study. Second, although we selected variants of interest from the literature, because of differences in population admixture and linkage disequilibrium, we may not have captured the causal variant, thus diminishing any potential association of the SNP of interest with clinical outcome. Therefore, we cannot know with confidence whether the selected

Conclusions

The present study failed to find an association between genetic variants associated with heightened in vitro platelet function during aspirin exposure and death, MI, or stroke during aspirin treatment in long-term follow-up in patients with significant CAD. The use of these genetic variants for risk stratifying patients with CAD or for guiding more aggressive antiplatelet therapy in this population is not justified.

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Citation Excerpt :
The surface of platelets contains lots of transmembrane Glucose Protein (GP) receptors, which are highly polymorphic and are encoded by two or more allelic isoforms. Single nucleotide polymorphisms (SNPs), which occur within a gene or in the regulatory regions near a gene, are the important contributors to residual platelet reactivity in patients with aspirin resistance [15]. The difference in amino acid sequences resulted from these SNPs might affect the secondary or tertiary structure of the GP receptors, and ultimately lead to corresponding changes in their biological function.
Aspirin is the most widely prescribed drug for the primary and secondary prevention of cardiovascular and cerebrovascular diseases. However, a large number of patients continue to experience thromboembolic events despite aspirin therapy, a phenomenon referred to as aspirin resistance or treatment failure. Aspirin resistance is often observed along with a high incidence of unstable plaque, cardiovascular events and cerebrovascular accident. Studies have shown that aspirin reduces the production of TXA2, but not totally inhibits the activation of platelets. In this review, we analyze current and past research on aspirin resistance, presenting important summaries of results regarding the potential contributive roles of single nucleotide polymorphisms, inflammation, metabolic syndrome and miRNAs. The aim of this article is to provide a brief review on aspirin resistance and platelet function, which will provide important insights into the research of aspirin resistance.

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: Philip F. Binkley, MD, MPH served as guest editor for this article.

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Clinical InvestigationGeneticsPolymorphisms associated with in vitro aspirin resistance are not associated with clinical outcomes in patients with coronary artery disease who report regular aspirin use

Background

Methods

Results

Conclusion

Section snippets

Patient population

Patient population

Discussion

Limitations

Conclusions

Am Heart J

J Biol Chem

J Thromb Haemost

J Thromb Haemost

Am J Hypertens

Atherosclerosis

Atherosclerosis

J Am Coll Cardiol

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials

The Lancet

Residual arachidonic acid–induced platelet activation via an adenosine diphosphate–dependent but cyclooxygenase-1– and cyclooxygenase-2–independent pathway: a 700-patient study of aspirin resistance

Circulation

Association of cyclooxygenase-1–dependent and –independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization

Circulation

Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxygenase-1

Circulation

The C50T polymorphism of the cyclooxygenase-1 gene and the risk of thrombotic events during low-dose therapy with acetyl salicylic acid

Thromb Haemost

Role of PLA2 polymorphism on clinical events after percutaneous coronary intervention

Acute Card Care

The BC genotype of the VNTR polymorphism of platelet glycoprotein Ibalpha is overrepresented in patients with recurrent stroke regardless of aspirin therapy

Cerebrovasc Dis

Clinical Investigation
Genetics
Polymorphisms associated with in vitro aspirin resistance are not associated with clinical outcomes in patients with coronary artery disease who report regular aspirin use