prasugrel-hydrochloride and Obesity

Increased body weight is independently associated with impaired clopidogrel pharmacodynamic (PD) response. Prasugrel has more potent PD effects compared with clopidogrel, although its PD effects in obese patients are unknown. The aim of this prospective, randomised, study was to compare the PD effects of standard-dose prasugrel [60 mg loading dose (LD)/10 mg daily maintenance dose (MD)] with high-dose clopidogrel (900 mg LD/150 mg daily MD) in non-diabetic obese [body mass index (BMI) ≥30 kg/m²] patients, with coronary artery disease (CAD) on aspirin therapy. PD assessments (baseline, 2 hours post-LD and 6 ± 2 days after MD) were conducted using four platelet function assays, and the platelet reactivity index (PRI) assessed by VASP was used for sample size estimation. A total of 42 patients with a BMI of 36.42 ± 5.6 kg/m² completed the study. There were no differences in baseline PD measures between groups. At 2 hours post-LD, prasugrel was associated with lower PRI compared with clopidogrel (24.3 ± 5.5 vs 58.7 ± 5.7, p≤0.001), with consistent findings for all assays. At one-week, PRI values on prasugrel MD were lower than clopidogrel MD without reaching statistical significance (34.7 ± 5.8 vs 42.9 ± 5.8, p=0.32), with consistent findings for all assays. Accordingly, rates of high on-treatment platelet reactivity were markedly reduced after prasugrel LD, but not after MD. In conclusion, in non-diabetic obese patients with CAD, standard prasugrel dosing achieved more potent PD effects than high-dose clopidogrel in the acute phase of treatment, but this was not sustained during maintenance phase treatment. Whether an intensified prasugrel regimen is required in obese patients warrants investigation.

Topics: Aspirin; Biomarkers; Blood Platelets; Body Mass Index; Cell Adhesion Molecules; Clopidogrel; Coronary Artery Disease; Drug Therapy, Combination; Female; Florida; Humans; Male; Microfilament Proteins; Middle Aged; Obesity; Phosphoproteins; Phosphorylation; Piperazines; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Prospective Studies; Receptors, Purinergic P2Y12; Thiophenes; Ticlopidine; Time Factors; Treatment Outcome

Ticagrelor inhibits the equilibrative-nucleoside-transporter-1 and thereby, adenosine cell re-uptake. Ticagrelor limits infarct size (IS) in non-diabetic rats and the effect is adenosine-dependent. Statins, via ecto-5'-nucleotidase activation, also increase adenosine levels and limit IS.. Ticagrelor and rosuvastatin have additive effects on myocardial adenosine levels, and therefore, on IS and post-reperfusion activation of the NLRP3-inflammasome.. Diabetic ZDF rats received via oral gavage; water (control), ticagrelor (150 mg/kg/d), prasugrel (7.5 mg/kg/d), rosuvastatin (5 mg/kg/d), ticagrelor + rosuvastatin and prasugrel + rosuvastatin for 3d. On day 4, rats underwent 30 min coronary artery occlusion and 24 h of reperfusion. Two additional groups received, ticagrelor + rosuvastatin or water in combination with CGS15943 (CGS, an adenosine receptor antagonist, 10 mg/kg i.p. 1 h before ischemia).. Both ticagrelor and rosuvastatin increased myocardial adenosine levels with an additive effect of the combination whereas prasugrel had no effect. Similarly, both ticagrelor and rosuvastatin significantly reduced IS with an additive effect of the combination whereas prasugrel had no effect. The effect on IS was adenosine dependent as CGS15943 reversed the effect of ticagrelor + rosuvastatin. The ischemia-reperfusion injury increased myocardial mRNA levels of NLRP3, ASC, IL-1β and IL-6. Ticagrelor and rosuvastatin, but not prasugrel, significantly decreased these pro-inflammatory mediators with a trend to an additive effect of the combination. The combination also increased the levels of anti-inflammatory 15-epilipoxin A. Ticagrelor and rosuvastatin when given in combination have an additive effect on local myocardial adenosine levels in the setting of ischemia reperfusion. This translates into an additive cardioprotective effect mediated by adenosine-induced effects including downregulation of pro- but upregulation of anti-inflammatory mediators.

Topics: Adenosine; Animals; Apoptosis Regulatory Proteins; CARD Signaling Adaptor Proteins; Cardiotonic Agents; Cyclooxygenase 2; Diabetes Mellitus, Experimental; Drug Synergism; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-1beta; Interleukin-6; Lipoxins; Male; Myocardial Reperfusion Injury; Myocardium; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Rats, Zucker; RNA, Messenger; Rosuvastatin Calcium; Ticagrelor

This study aimed to analyze the impact of body mass index (BMI) and the metabolic syndrome (MS) on responses to clopidogrel or prasugrel and bleeding risk after acute coronary syndrome. The study included 1,542 consecutive patients who underwent coronary stenting (287 clopidogrel 75 mg, 868 clopidogrel 150 mg, and 387 prasugrel 10 mg). Platelet reactivity was assessed 1 month after discharge using platelet reactivity index vasodilator stimulated phosphoprotein (PRI VASP). Three hundred thirty-six patients (21.8%) were obese (BMI ≥30), and we observed higher platelet reactivity associated with higher BMI across thienopyridine regimens. Incidence of high on-treatment platelet reactivity (PRI VASP >50%) was higher in obese than nonobese patients (p <0.05 for all regimens). Conversely, incidence of low on-treatment platelet reactivity with prasugrel therapy (PRI VASP <20%) was lower in obese than nonobese patients: 13% (12 of 93) versus 33% (97 of 294); odds ratio 0.30, 95% confidence interval 0.16 to 0.58; p <0.001. Accordingly, incidence of Bleeding Academic Research Consortium bleeding complications was higher in nonobese than in obese patients: 10% (119 of 1,206) versus 6% (20 of 336); odds ratio 1.7, 95% confidence interval 1.1 to 2.8; p = 0.03. This impaired response was only observed in obese patients with the MS, and obese with the MS had significantly higher platelet reactivity than other obese patients with all regimens (p <0.01). Obese patients without the MS had no significant difference in platelet reactivity compared with nonobese patients. In conclusion, the present study confirmed that BMI has a strong impact on response to clopidogrel and prasugrel with higher incidence of high on-treatment platelet reactivity, lower incidence of low on-treatment platelet reactivity, and lower bleeding complication in obese patients. However, among obese patients, the presence of the MS strongly affects response to antiplatelet agents, indicating that the metabolic status might be a better predictor of platelet inhibition than BMI.

Topics: Aged; Clopidogrel; Coronary Artery Disease; Female; Humans; Incidence; Male; Metabolic Syndrome; Middle Aged; Obesity; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Retrospective Studies; Stents; Thiophenes; Ticlopidine; United States

Topics: Adolescent; Adolescent Nutritional Physiological Phenomena; American Heart Association; Cardiovascular Diseases; Cholesterol; Congresses as Topic; Coronary Artery Disease; Drug Approval; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Obesity; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Thiophenes; United States