Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis

Krasopoulos, George; Brister, Stephanie J.; Beattie, W. Scott; Buchanan, Michael R.

doi:10.1136/bmj.39430.529549.be

Cited by 647 publications

(582 citation statements)

References 25 publications

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“…13 In a recent meta-analysis of 20 studies investigating aspirin resistance, a total of 6 different platelet function assays were used, including studies reflecting both in vivo and ex vivo platelet activity. 14 Commonly used platelet function assays, including their strength and limitations, are summarized below (Table 1).…”

Section: Diagnostic Testing Of Platelet Functionmentioning

confidence: 99%

Aspirin Resistance: Current Status and Role of Tailored Therapy

Grinstein

Cannon

2012

Clinical Cardiology

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Aspirin is integral in the primary and secondary prevention of coronary artery disease and acute coronary syndrome. Given the high clinical importance of aspirin in the management of coronary artery disease, much attention has been directed towards the concept of “aspirin resistance.” Unfortunately, the term aspirin resistance is ill‐defined in the literature, leading to a large variance in the reported prevalence of this phenomenon. In this review, the current understanding of aspirin resistance is discussed. Commonly used functional and diagnostic tests of platelet function, including their strengths and weakness, are reviewed. We next discuss several proposed mechanisms of aspirin resistance and special high‐risk groups at risk for aspirin treatment failure. We then discuss optimal dosing and diagnostic strategies for those populations at risk for aspirin resistance with a focus on tailored aspirin therapy for high‐risk groups. Finally, future topics of interest in the field of aspirin resistance are considered. Clin. Cardiol. 2012 doi: 10.1002/clc.22031Jonathan Grinstein has no funding, financial relationships, or conflicts of interest to disclose. Christopher P. Cannon receives research grants/support from the following companies: Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda. He is also on the advisory board (but funds donated to charity) for Alnylam, Bristol‐Myers Squibb, and Pfizer. He is a Clinical Advisor, equity in Automedics Medical Systems.

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Section: Diagnostic Testing Of Platelet Functionmentioning

confidence: 99%

Aspirin Resistance: Current Status and Role of Tailored Therapy

Grinstein

Cannon

2012

Clinical Cardiology

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“…The latter is a stable metabolite excreted in urine, and its measurement provides a reliable estimate of the total in vivo production of TXA 2 including the extraplatelet sources 7, 8. 11‐Dehydro‐TXB 2 has been found to be elevated in several atherothrombotic diseases and to correlate with major adverse clinical events 9, 10, 11, 12, 13, 14. However, none of the studies have evaluated the association of 11‐dehydro‐TXB 2 with patients’ long‐term outcomes in AMI.…”

Section: Introductionmentioning

confidence: 99%

Urinary 11‐Dehydro‐Thromboxane B ₂ as a Predictor of Acute Myocardial Infarction Outcomes: Results of Leukotrienes and Thromboxane In Myocardial Infarction (LTIMI) Study

Szczeklik

Stodółkiewicz

Rzeszutko

et al. 2016

JAHA

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BackgroundUrinary 11‐dehydro‐thromboxane (TX)B2 has been described as a potential predictive biomarker of major adverse cardiovascular events (MACEs) in high cardiac risk patients. This part of LTIMI (Leukotrienes and Thromboxane In Myocardial Infarction) study aimed to evaluate the relationship between 11‐dehydro‐TXB 2 and MACEs in patients with acute myocardial infarction (AMI).Methods and Results LTIMI was an observational, prospective study in 180 consecutive patients with AMI type 1 referred for primary percutaneous coronary intervention. On admission and at follow‐up visits (1 month, 1 year), 11‐dehydro‐TXB 2 was measured in urinary samples by using high‐performance liquid chromatography–tandem mass spectrometry. The primary outcome was occurrence of composite MACEs during 1‐year after AMI. Left ventricular ejection fraction was assessed in echocardiography on admission and at 1‐year follow‐up. Analyses of 11‐dehydro‐TXB 2 (pg/mg creatinine) were performed on log‐transformed data and expressed as median with IQR (Q1–Q3). 11‐Dehydro‐TXB 2 level on admission was 7.39 (6.85–8.01) and decreased at 1 month (6.73, 6.27–7.12; P<0.001) and 1‐year follow‐up (6.37, 5.91–6.94; P<0.001). In univariate analysis, baseline 11‐dehydro‐TXB 2 was higher in patients with MACEs (n=60; 7.73, 7.07–8.60) compared with those without MACEs (n=119; 7.28, 6.68–7.79; P=0.002). In multivariate regression model, 11‐dehydro‐TXB 2 and 3 other variables (diabetes, multivessel disease, and left ventricular ejection fraction) were found to be best 1‐year cumulative MACE predictors with odds ratio for 11‐dehydro‐TXB 2 of 1.58 (95% CI 1.095–2.33; P=0.017) and area under the curve (in receiver operating characteristic analysis of 0.8). Baseline 11‐dehydro‐TXB 2 negatively correlated with both left ventricular ejection fraction on admission (R=−0.21; P=0.006) and after 1 year (R=−0.346; P<0.001).Conclusions11‐Dehydro‐TXB 2 predicts 1‐year cumulative MACEs in AMI patients and provides prognostic information on the left ventricular performance.

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“…We also showed that this antibody does not interfere with physiological hemostasis 19. Aspirin remains the only clinically approved agent for therapeutic interventions that target this pathway, but its use is associated with many limitations, including severe adverse effects (eg, bleeding) and resistance, among others 25, 26, 28, 29, 58. Based on these considerations, there remains interest in developing more selective and new/novel means for targeting the TXA 2 /TPR pathway (namely, agents with TPR antagonistic activity, because they would be expected to exhibit a better/safer pharmacological profile and perhaps be more effective in managing thrombosis‐based diseases).…”

Section: Discussionmentioning

confidence: 77%

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

Alshbool

Karim

Espinosa

et al. 2018

JAHA

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BackgroundDespite the well‐established role for the thromboxane A2 receptor (TPR) in the development of thrombotic disorders, none of the antagonists developed to date has been approved for clinical use. To this end, we have previously shown that an antibody targeted against TPR's ligand‐binding domain inhibits platelet activation and thrombus formation, without exerting any effects on hemostasis. Thus, the goal of the present studies is to design a novel TPR‐based vaccine, demonstrate its ability to trigger an immune response, and characterize its antiplatelet and antithrombotic activity.Methods and ResultsWe used a mouse keyhole limpet hemocyanin/peptide‐based vaccination approach rationalized over the TPR ligand‐binding domain (ie, the C‐terminus of the second extracellular loop). The biological activity of this vaccine was assessed in the context of platelets and thrombotic diseases, and using a host of in vitro and in vivo platelet function experiments. Our results revealed that the TPR C‐terminus of the second extracellular loop vaccine, in mice: (1) triggered an immune response, which resulted in the development of a C‐terminus of the second extracellular loop antibody; (2) did not affect expression of major platelet integrins (eg, glycoprotein IIb‐IIIa); (3) selectively inhibited TPR‐mediated platelet aggregation, platelet‐leukocyte aggregation, integrin glycoprotein IIb‐IIIa activation, as well as dense and α granule release; (4) significantly prolonged thrombus formation; and (5) did so without impairing physiological hemostasis.ConclusionsCollectively, our findings shed light on TPR's structural biological features, and demonstrate that the C‐terminus of the second extracellular loop domain may define a new therapeutic target and a TPR vaccine‐based approach that should have therapeutic applications.

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Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis

Cited by 647 publications

References 25 publications

Aspirin Resistance: Current Status and Role of Tailored Therapy

Aspirin Resistance: Current Status and Role of Tailored Therapy

Urinary 11‐Dehydro‐Thromboxane B ₂ as a Predictor of Acute Myocardial Infarction Outcomes: Results of Leukotrienes and Thromboxane In Myocardial Infarction (LTIMI) Study

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

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Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis

Cited by 647 publications

References 25 publications

Aspirin Resistance: Current Status and Role of Tailored Therapy

Aspirin Resistance: Current Status and Role of Tailored Therapy

Urinary 11‐Dehydro‐Thromboxane B 2 as a Predictor of Acute Myocardial Infarction Outcomes: Results of Leukotrienes and Thromboxane In Myocardial Infarction (LTIMI) Study

Investigation of a Thromboxane A 2 Receptor–Based Vaccine for Managing Thrombogenesis

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Urinary 11‐Dehydro‐Thromboxane B ₂ as a Predictor of Acute Myocardial Infarction Outcomes: Results of Leukotrienes and Thromboxane In Myocardial Infarction (LTIMI) Study

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis