Pharmacokinetic-pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients.

AIM: To characterize ticagrelor exposure-response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using non-linear mixed effects modelling and simulation. METHODS: Platelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR-C1249010XX in a population pharmacokinetic and pharmacodynamic (PK/PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS-TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily. RESULTS: Platelet inhibition by ticagrelor was described by a sigmoidal Emax model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol/L. Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak-to-trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations. CONCLUSIONS: In patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modeled doses below 60mg, the response is overall reduced, more variable between patients, and patients will display greater peak-to-trough variability

Atorvastatin induces associated reductions in platelet P-selectin, oxidized low-density lipoprotein, and interleukin-6 in patients with coronary artery diseases.

The development and progression of atherosclerosis comprises various processes, such as endothelial dysfunction, chronic inflammation, thrombus formation, and lipid profile modification. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that have pleiotropic effects in addition to cholesterol-lowering properties. However, the mechanisms of these effects are not completely understood. Here, we investigated whether atorvastatin affects the levels of malondialdehyde-modified low-density lipoprotein (MDALDL), an oxidized LDL, the proinflammatory cytokine interleukin-6 (IL-6), or platelet P-selectin, a marker of platelet activation, relative to that of LDL cholesterol (LDL-C). Forty-eight patients with coronary artery disease and hyperlipidemia were separated into two groups that were administered with (atorvastatin group) or without (control group) atorvastatin. The baseline MDA-LDL level in all participants significantly correlated with LDL-C (r = 0.71, P < 0.01) and apolipoprotein B levels (r = 0.66, P < 0.01). Atorvastatin (10 mg/day) significantly reduced the LDL-C level within 4 weeks and persisted for a further 8 weeks of administration. Atorvastatin also reduced the MDA-LDL level within 4 weeks and further reduced it over the next 8 weeks. Platelet P-selectin expression did not change until 4 weeks of administration and then significantly decreased at 12 weeks, whereas the IL-6 level was gradually, but not significantly, reduced at 12 weeks. In contrast, none of these parameters significantly changed in the control group within these time frames. The reduction (%) in IL-6 between 4 and 12 weeks after atorvastatin administration significantly correlated with that of MDALDL and of platelet P-selectin (r = 0.65, P < 0.05 and r = 0.70, P < 0.05, respectively). These results suggested that the positive effects of atorvastatin on the LDL-C oxidation, platelet activation and inflammation that are involved in atherosclerotic processes are exerted in concert after lowering LDL-C

Peri-Procedural Platelet Reactivity in Percutaneous Coronary Intervention

Platelet activation and aggregation play a pivotal role in thrombotic complications occurring during percutaneous coronary intervention (PCI), and peri-PCI anti-platelet therapy represents a standard of care. High platelet reactivity prior to PCI has been correlated with an increased incidence of peri-procedural myonecrosis. Pre-PCI platelet reactivity predicts post-PCI platelet reactivity and has a prognostic impact on subsequent ischaemic and bleeding events, so as the platelet inhibition measured post-PCI. Many anti-platelet treatment strategies, including aspirin, glycoprotein IIb/IIIa inhibitors, P2Y 12 receptor blockers and vorapaxar, are being used in the routine clinical practice to modify platelet reactivity at each stage, e.g. pre-, during and post-PCI. Anti-platelet strategies with a &apos;stronger and faster&apos; pharmacodynamic effect than clopidogrel have been mostly adopted in patients with acute coronary syndromes. However, several issues regarding the anti-platelet treatment such as benefits/risks of anti-platelet therapy pre-treatment and duration, and definite association between speed and potency of various anti-platelet agents and clinical outcomes remain controversial. We believe that a better understanding of peri-PCI platelet reactivity and its relations to outcomes may lead to the development of more effective and safe treatment strategies. © 2018 Georg Thieme Verlag KG

What is the optimum adjunctive reperfusion strategy for primary percutaneous coronary intervention?

Acute ST-segment elevation myocardial infarction (STEMI) is a dynamic, thrombus-driven event. As understanding of its pathophysiology has improved, the central role of platelets in initiation and orchestration of this process has become clear. Key components of STEMI include formation of occlusive thrombus, mediation and ultimately amplification of the local vascular inflammatory response resulting in increased vasoreactivity, oedema formation, and microvascular obstruction. Activation, degranulation, and aggregation of platelets are the platforms from which these components develop. Therefore, prompt, potent, and predictable antithrombotic therapy is needed to optimise clinical outcomes after primary percutaneous coronary intervention. We review present pharmacological and mechanical adjunctive therapies for reperfusion and ask what is the optimum combination when primary percutaneous coronary intervention is used as the mode of revascularisation in patients with STEMI

The Rationale for and Clinical Pharmacology of Prasugrel 5 mg

Prasugrel is a third-generation thienopyridine platelet P2Y12 adenosine diphosphate (ADP) receptor antagonist administered with aspirin for the treatment of patients with acute coronary syndrome (ACS) with planned percutaneous coronary intervention. Prasugrel is administered periprocedurally at an oral loading dose of 60 mg followed by daily maintenance doses (MDs) of 10 mg for most patients and 5 mg for patients weighing &amp;lt;60 kg or aged ≥75 years. Data from a prasugrel phase III study, TRITON-TIMI 38, suggested that a lower MD might be more suitable for patients weighing &amp;lt;60 kg or aged ≥75 years; subsequent pharmacokinetic and pharmacodynamic studies have indicated that prasugrel 5 mg reduced platelet reactivity in these populations to an extent similar to that of prasugrel 10 mg in heavier or younger patients. Clinical experience with prasugrel 5 mg is limited, and additional studies are needed to verify the clinical efficacy and safety of this dose in these challenging populations. © 2016, Springer International Publishing Switzerland

Translational platelet research in patients with coronary artery disease: What are the major knowledge gaps?

10.1160/TH12-01-0039Thrombosis and Haemostasis108112-20THHA