Onset offset trial ticagrelor

FDA Resources. Arms and Interventions. After randomization, an initial loading dose of ticagrelor mg was given and maintenance doses ticagrelor 90 mg twice daily was treated for 14 days. After randomization, an initial loading dose of clopidogrel mg was given and maintenance doses clopidogrel 75 mg once daily was treated for 14 days.

Outcome Measures. Primary Outcome Measures : The difference of antiplatelet effects assessed by VerifyNow assay [ Time Frame: 14 days after study drug treatment ] The difference of PRU values achieved following antiplatelet therapy.

Secondary Outcome Measures : the rate of onset and offset of the antiplatelet effects [ Time Frame: 14 days after study drugs treatment ] the difference of slope during onset and offset of study drugs. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials. More Information. National Library of Medicine U. The thienopyridines clopidogrel and ticlopidine, along with aspirin, have been the mainstay of antiplatelet therapy in patients with acute coronary syndromes. However, ticlopidine Ticlid, Roche use has been limited because of its hematologic adverse effects, including neutropenia.

Several limitations are now recognized with clopidogrel Plavix, Sanofi-Aventis , including the need for early discontinuation before surgery and variable efficacy due to genetic abnormalities and drug interactions. However, similar to the other thienopyridines, it requires conversion by the liver to an active moiety. Ticagrelor Brilinta, AstraZeneca , a cyclopentyl-triazolo-pyrimidine, is a new antiplatelet agent with structural similarities to adenosine.

Ticagrelor reversibly inhibits the P2Y12 receptors on platelets, preventing platelet activation and, consequently, aggregation. Unlike the thienopyridines, it does not require metabolic activation. The onset of action is 1. This pharmacokinetic profile may translate into clinical advantages over clopidogrel, including a faster time to steady state and shorter time for reversal.

Besides bleeding, several unique adverse effects were observed in ticagrelor clinical trials. Dyspnea, ventricular pauses of at least 3 seconds, and hyperuricemia are likely attributed to the structural similarity to adenosine. In the DISPERSE-2 trial, ticagrelor 90 mg twice daily, ticagrelor mg twice daily and clopidogrel mg once, followed by 75 mg daily, were compared to assess the safety and tolerability of ticagrelor. Rates of protocol-defined major or minor bleeding at 4 weeks were not significantly different between ticagrelor 90 mg 9.

In RESPOND, ticagrelor was given for 14 days before or after 2 weeks of clopidogrel in patients classified as clopidogrel responders or non-responders. Pharmacokinetics and IPA were evaluated following the loading and last maintenance doses.

Ticagrelor is a cyclopentyltriazolopyrimidine. The chemical structure is shown in Figure 1. Chemical structure of ticagrelor. From Brilinta prescribing information. Ticagrelor inhibits platelet activation and aggregation by reversibly interacting with the platelet P 2 Y 12 adenosine diphosphate ADP receptor to prevent signal transduction.

At all time points, IPA was higher in the ticagrelor group. The maximum IPA effect of ticagrelor was reached at about 2 hours and was maintained for at least 8 hours. After 5 days, IPA in the ticagrelor group was similar to that in the placebo group. It is not known how bleeding risk and thrombotic risk correspond to IPA for either ticagrelor or clopidogrel. Switching patients from clopidogrel to ticagrelor resulted in an absolute IPA increase of Patients can be switched from clopidogrel to ticagrelor without interrupting the antiplatelet effect.

Ticagrelor demonstrates dose—proportional pharmacokinetic characteristics. These features are similar in both patients and healthy volunteers. Oral ticagrelor may be taken with or without food.

The steady-state volume of distribution of ticagrelor is 88 L. This results in the formation of the major active metabolite. Ticagrelor and its active metabolite are weak P-glycoprotein substrates and inhibitors. The primary route of elimination for ticagrelor is hepatic, whereas the primary route of elimination for the major metabolite is most likely biliary excretion. The mean half-life of ticagrelor is approximately 7 hours. The active metabolite has a mean half-life of about 9 hours.

Both medications were given in combination with aspirin and other standard therapy. In the clopidogrel arm, patients received an initial loading dose of clopidogrel mg if previous clopidogrel therapy had not been given before randomization.

In the ticagrelor arm, patients received a loading dose of mg, followed by a maintenance dose of 90 mg twice daily. Concomitant aspirin was recommended at loading doses of to mg. A low daily maintenance dose of aspirin 75— mg was recommended, but higher maintenance doses were allowed.

The patients were treated for 6 to 12 months. The individual components were also assessed as secondary endpoints. The key findings are summarized in Table 2. At 12 months, lower rates of the first occurrence of primary composite endpoint—death from vascular causes, nonfatal MI excluding silent MI , or stroke. Decreased rates of the composite endpoint of death from vascular causes, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic events.

An attenuated benefit in patients weighing less than the median weight for their sex, in those not taking lipid-lowering drugs at randomization, and in those enrolled in North America. More episodes of intracranial bleeding and fatal intracranial bleeding compared with clopidogrel. No differences in rates of stroke; major bleeding per TIMI criteria ; fatal or life-threatening bleeding; CABG-related major bleeding; bleeding requiring transfusion of red blood cells; syncope, pre-syncope, or loss of consciousness; or pacemaker implantation.

Data compiled from Wallentin et al. The primary composite endpoint—cardiovascular death, nonfatal MI excluding silent MI , or stroke—occurred in 9. Figure 2 shows the time to the first occurrence of the primary composite endpoint in the overall study.

In the figure, the ticagrelor and clopidogrel curves separate within 30 days from randomization and continue to diverge throughout the month treatment period.

Ticagrelor patients had a significantly reduced rate of the secondary composite endpoint of death from any cause, MI, or stroke compared with clopidogrel patients Ticagrelor resulted in a significantly reduced rate of the secondary composite endpoint of death from vascular causes, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic events versus clopidogrel Ticagrelor patients had a significantly reduced rate of MI compared with clopidogrel patients 5.

Ticagrelor therapy led to a significantly reduced rate of death resulting from vascular causes versus clopidogrel 4. Ticagrelor resulted in a significantly reduced rate of death from any cause when compared with clopidogrel 4. Consequently, the patterns of aspirin use differed greatly in the U. Overall, the efficacy results favored ticagrelor when the drug was used with lower maintenance doses of aspirin mg or less. Higher doses of aspirin appear to reduce the effectiveness of ticagrelor.