for the PLATO Investigators Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a. terney.info Page 1 of 3. PLATO: Ticagrelor. BRILINTA vs Clopidogrel. PLAVIX in Acute . days and persisted throughout study. . DAPT RxFiles Trial Summary : terney.info which lead clinicians to withhold ticagrelor from COPD patients. Methods and The PLATO study showed superior efficacy of the non- thienopyridine.
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PLATelet inhibition and patient Outcomes (PLATO) investigators. Summary . of masked ticagrelor study drug (active to those in the ticagrelor. PDF | BACKGROUND: Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine the Study of Platelet Inhibition and Patient Out-. PDF | The PLATO trial revealed a remarkable advantage of ticagrelor over Unless the regulatory authorities discover serious flaws with the study, which is.
Higher IPA for ticagrelor was also observed in the maintenance therapy phase.
A faster offset rate for IPA was observed after the last dose of ticagrelor than for clopidogrel from 4 to 72 h. In addition, ticagrelor was shown to be associated with low prevalence of high platelet reactivity at 2, 8 and 24 h, and 6 weeks compared with clopidogrel according to multiple established platelet function assays. The RESPOND study 12 was a randomized, double-blind, double-dummy, crossover trial that examined the use of ticagrelor in 98 patients with stable coronary artery disease as a function of responsiveness to clopidogrel.
In a two-way crossover design, non-responders and responders were randomly assigned to receive clopidogrel mg loading dose, then 75 mg once daily or ticagrelor mg loading dose, then 90 mg twice daily for 14 days period 1. Thereafter, all non-responders switched treatment, with half of the responders continuing the previous treatment, and half switching treatment. The use of ticagrelor among non-responders resulted in a 0. These results indicated that the anti-platelet effect of ticagrelor is consistent regardless of responsiveness to clopidogrel, that ticagrelor may represent a logical substitute for clopidogrel non-responders, and that platelet inhibition in patients responsive to clopidogrel may be significantly augmented by switching to ticagrelor without reduction in anti-platelet effect.
The study included over 18 patients who were admitted to hospital for an ACS, with or without ST-segment elevation. Patients in the ticagrelor group were given a loading dose of mg, followed by a dose of 90 mg twice daily.
Patients in the clopidogrel group received a mg loading dose followed by 75 mg daily. Both cohorts required endpoint-free survival for 10 days post-randomization to determine revascularization status. Endpoints The primary efficacy endpoint of the present study was the composite of cardiovascular death, myocardial infarction, excluding silent infarctions and stroke.
Each component alone and all-cause death were secondary efficacy endpoints.
Secondary safety endpoints were CABG-related major bleeding, non-CABG-related major bleeding, minor bleeding, intracranial bleeding, and fatal bleeding. An independent central adjudication committee, unaware of treatment assignments, assessed all endpoints. Statistical analyses Patient characteristics and medical history, in-hospital procedures and medications, discharge ACS status, and post-discharge medications are presented by treatment in the NSTE-ACS patient cohort as well as by revascularization status subgroup.
Continuous variables are presented as median and 25th—75th percentiles; categorical variables are presented as number and percentage. The treatment effect of ticagrelor vs.
Kaplan—Meier estimated event rates at days and total number of observed events during the study were presented for each endpoint. Hazard ratios HR , confidence intervals CI , and P-values from unadjusted Cox proportional hazards regression models were presented.
Kaplan—Meier estimated event rates were plotted by treatment for the primary efficacy endpoint, all-cause death, major bleeding, and non-CABG related major bleeding. Both ticagrelor and rosuvastatin were shown to increase the concentration of adenosine in animal models, which may further contribute to the beneficial effect of their co-administration.
Because ticagrelor is a weak inhibitor of P-glycoprotein, which is involved in the metabolism of digoxin, the concentration of digoxin may increase once ticagrelor is initiated.
Hence, in patients treated with ticagrelor the concentration of digoxin should be monitored. Importantly, the modest genetic impact on plasma levels of ticagrelor and the active metabolite of ticagrelor AR-CXX [ARC] did not translate into effect on any efficacy ie, CV death, MI, and stroke or safety endpoints ie, non-CABG-related bleeds or investigator-reported dyspnea.
The study showed that the SNP can decrease the ex vivo antiplatelet activity of ticagrelor, especially at low concentration, though the baseline platelet activity was not affected by the polymorphism.
However, the ITGB3 rs or rs polymorphisms had no effect on either the baseline platelet activity or the ex vivo antiplatelet effect of ticagrelor.
T, rs A. G, rs G. A, rs T.
C, rs C. T, and rs G.
T polymorphism. It was found that PEAR1 rs polymorphism is associated with in vitro antiplatelet activity of ticagrelor but no significant difference in ticagrelor pharmacokinetics with the rs genotype was observed. Minor homozygotes of two SNPs rs, rs exhibited statistically significant lower maximal platelet activation and minor allele carriers of rs polymorphism exhibited statistically significant higher maximal platelet activation.
However, the mechanisms by which rs polymorphism influences ticagrelor response remain unknown. Mechanism underlying the pleiotropic effects of ticagrelor The results of the PLATO trial were embraced with growing interest in the extra-platelet effects of ticagrelor. Ticagrelor administration was shown to be associated with the increased concentration of adenosine caused by 1 inhibition of adenosine reuptake by blocking human equilibrative nucleoside transporter 1, 45 and 2 increased release of ATP, subsequently transformed into adenosine.
Effects induced by an increased concentration of adenosine and stimulation of adenosine receptors A1—A3 are summarized in Table 3.
Figure 2 Mechanisms underlying the probable adenosine-dependent and non-adenosine-dependent pleiotropic effects of ticagrelor.
The first described pleiotropic effect was decreased death rate in patients with ACS receiving ticagrelor PLATO subgroup who presented with sepsis or pulmonary infection. Table 4 summarizes the most frequent adverse effects of ticagrelor in patients with ACS, coronary artery disease, and pulmonary disease asthma, chronic obstructive pulmonary disease [COPD].
Dyspnea during ticagrelor administration and during simultaneous adenosine infusion was confirmed in numerous studies.