Fast platelet suppression by lysine acetylsalicylate in chronic stable coronary patients. Potential clinical impact over regular aspirin for coronary syndromes (original) (raw)
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Arquivos Brasileiros de Cardiologia, 2019
Cardiovascular diseases (CVD) are the leading cause of death in the world, with coronary heart disease being the main etiology, accounting in 2016 for 31% of global deaths. 1 Myocardial infarction (MI) is usually due to changes in the arterial wall or thrombotic occlusion of a coronary vessel caused by the rupture of a vulnerable plaque. 1,2 Instability in the atherosclerotic plaque is the result of local and systemic oxidative stress, thus leading to platelet activation and formation of aggregates in the circulation. 3 The major function of platelets is as part of the homeostatic mechanism, halting blood loss after tissue trauma, but in oxidative conditions, they are associated with various CVD such as hypertension, heart failure, stroke, diabetes and atherosclerosis. 3
Platelets, 2006
Platelet activation contributes to thrombotic events in cardiovascular disease. Acetylsalicylic acid (ASA) is used in combination with clopidogrel to reduce cardiovascular events. Lysine acetylsalicylate (L-ASA), also inhibits platelet activation with fewer gastrointestinal side effects than ASA. Dual therapy with L-ASA and clopidogrel may result in an antiplatelet effect with fewer side effects. We compared the antiplatelet effect of combined ASA/clopidogrel versus L-ASA/ clopidogrel in healthy subjects. Fourteen volunteers (seven men and seven women, aged 25-45 years) received antiplatelet therapy during 14-day periods in the following sequence: 75 mg ASA; 160 mg L-ASA; 75 mg clopidogrel; 160 mg L-ASA plus 75 mg clopidogrel, and 75 mg ASA plus 75 mg clopidogrel. We evaluated platelet aggregation and glycoprotein IIb/IIIa activation. Our results show that administration of L-ASA/clopidogrel is as effective as ASA/clopidogrel combination.
Journal of Thrombosis and Thrombolysis, 2020
Arachidonic acid (AA)-induced platelet aggregation (PA) and serum thromboxane B 2 (TxB 2) inhibition are widely used to indicate cyclooxygenase-1 activity and the antiplatelet effect of acetylsalicylic acid (ASA). Despite decades of investigations, the relation between these measurements remains unclear. We sought to evaluate the relation between AA-PA and serum TxB 2 inhibition. We serially measured AA-PA (conventional aggregation), serum TxB 2, plasma ASA and salicylic acid (SA) (liquid chromatography-mass spectrometry), and urinary 11-dehydro thromboxane B 2 (u11-dh TxB 2) (enzymelinked immunosorbent assay) levels at 10 times over 24 hours in seventeen healthy volunteers receiving a single dose of 162 mg chewed and swallowed ASA (n = 6), 50 mg inhaled ASA (n = 6), or 100 mg inhaled ASA (n = 5) (ClinicalTrials. gov Identifier: NCT04328883, April 1, 2020). Baseline variability was more pronounced with serum TxB 2 (31-680 ng/mL) as compared to maximal AA-PA (65-81%) and u11-dh TxB 2 (1556-4440 pg/mg creatinine). The relation between serum TxB 2 inhibition and AA-PA was stepwise; after 30-40% inhibition of serum TxB 2 , AA-PA fell to < 5%. By receiver operating characteristic curve analysis using AA-PA < 5% to define aspirin responsiveness, serum TxB2 inhibition > 49% and u11-dh TxB2 < 1520 pg/mg creatinine met the definition. Our study demonstrates a non-linear relation between serum TxB 2 inhibition and AA-PA. Aggregation was nil once TxB 2 inhibition reached > 49%. Moreover, these results suggest that the definition of > 95% inhibition of serum TxB 2 to indicate the level of platelet COX-1 inhibition needed for clinical efficacy may be overestimated and should be reconsidered in future translational research investigations that attempt to link the clinical efficacy of ASA with a laboratory measurement cutoff.
The American Journal of Cardiology, 2011
Aspirin has been shown to decrease cardiovascular (CV) events by ϳ25%. Despite aspirin therapy 10% to 20% of patients with arterial vascular disease develop atherothrombotic events. A meta-analysis of antiplatelet therapy showed a progressive decrease in clinical efficacy of aspirin after 2 years. Whether this is due to a decreased sensitivity to aspirin during long-term therapy remains unclear. A prospective randomized clinical trial with serial monitoring over 5 years was conducted in 100 patients with documented coronary heart disease. We investigated whether long-term treatment with aspirin 50 and 100 mg affects platelet response similarly. Occurrence of CV events was documented. Platelet sensitivity to aspirin, prostacyclin, and adenosine diphosphate-, collagen-, and epinephrine-induced platelet aggregation were evaluated over time. In addition, -thromboglobulin and inflammatory markers were measured. Four patients were lost to follow-up and 10 patients died. Eleven patients developed nonfatal CV events. In the 2 groups platelet response to aspirin and the referenced variables remained unchanged over 5 years. In patients who developed CV events, the last monitoring interval revealed no difference in platelet response to aspirin. However, patients with nonfatal and fatal CV events showed increased inflammatory markers versus patients without CV events independent of aspirin 50 or 100 mg intake. In conclusion, our study revealed no difference in antiplatelet response to aspirin 50 versus 100 mg or CV events over 5 years in patients with coronary heart disease.
Thrombosis Research, 2003
Condensed abstract: Heightened platelet reactivity may affect the occurrence of ischemic events in patients with coronary artery disease on aspirin therapy. However, a definition to stratify platelet reactivity in this group of patients has not been previously reported. We studied platelet reactivity and activation by measuring platelet aggregation and the expression of p-selectin, total GP IIb/IIIa and active GP IIb/IIIa (n = 96). Patients were divided into quartiles by each of the markers; correlations were made between the markers; and a definition of heightened platelet reactivity was proposed. Marked variability in activation and reactivity were observed despite aspirin therapy. Background: Heightened platelet reactivity and activation may affect the occurrence of ischemic events in patients with coronary artery disease on aspirin therapy. However, a definition to stratify platelet reactivity has not been previously reported. Methods and results: Platelet aggregation (5 and 20 Amol/l ADP), total GP IIb/IIIa, active GP IIb/IIIa and the expression of maximally stimulated p-selectin were measured in patients about to undergo elective coronary stenting (n = 96). All patients had received aspirin (325 mg). There was marked variability in platelet reactivity and activation as measured by all markers. The highest quartile was defined by 77 F 1% and 98 F 1% aggregation by 5 and 20 Amol/l ADP, respectively; 65 F 2% p-selectin positivity; 508 F 15 MFI for total GP IIb/IIIa; and 23.0 F 1.8 MFI for active GP IIb/IIIa. Conclusions: There is a wide range in platelet reactivity and activation as measured by multiple markers in stable coronary disease patients on aspirin therapy. From these indices, we can define those patients at the extremes of reactivity and activation and thus, the greatest potential risk of thrombosis and bleeding. These indices will serve as a guide to future studies investigating the relationships of platelet reactivity, activation, drug-induced inhibition and clinical outcomes.
Background-The antiplatelet effect of aspirin is attributed to platelet cyclooxygenase-1 inhibition. Controversy exists on the prevalence of platelet resistance to aspirin in patients with coronary artery disease and effects of aspirin dose on inhibition. Our primary aim was to determine the degree of platelet aspirin responsiveness in patients, as measured by commonly used methods, and to study the relation of aspirin dose to platelet inhibition. Methods and Results-We prospectively studied the effect of aspirin dosing on platelet function in 125 stable outpatients with coronary artery disease randomized in a double-blind, double-crossover investigation (81, 162, and 325 mg/d for 4 weeks each over a 12-week period). At all doses of aspirin, platelet function was low as indicated by arachidonic acid (AA)-induced light transmittance aggregation, thrombelastography, and VerifyNow. At any 1 dose, resistance to aspirin was 0% to 6% in the overall group when AA was used as the agonist, whereas it was 1% to 27% by other methods [collagen and ADP-induced light transmittance aggregation, platelet function analyzer (PFA-100)]. Platelet response to aspirin as measured by collagen-induced light transmittance aggregation, ADP-induced light transmittance aggregation, PFA-100 (81 mg versus 162 mg, PՅ0.05), and urinary 11-dehydrothromboxane B 2 was dose-related (81 mg versus 325 mg, Pϭ0.003). No carryover effects were observed. Conclusions-The assessment of aspirin resistance is highly assay-dependent; aspirin is an effective blocker of AA-induced platelet function at all doses, whereas higher estimates of resistance were observed with methods that do not use AA as the stimulus. The observation of dose-dependent effects despite nearly complete inhibition of AA-induced aggregation suggests that aspirin may exert antiplatelet properties through non-cyclooxygenase-1 pathways and deserves further investigation. (Circulation. 2007;115:3156-3164.)