Safety and Efficacy of Low-Dose Ticagrelor in Chinese Patients With NSTE-ACS

April 9, 2015 updated by: First Affiliated Hospital of Harbin Medical University

Safety and Efficacy of Low-Dose Ticagrelor in Chinese Patients With Non-ST-Elevation Acute Coronary Syndrome: A Randomized Clinical Trial

Ticagrelor is an oral, reversibly-binding, direct-acting P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Guideline recommendations on the use of dual antiplatelet therapy (DAPT) have been formulated that ticagrelor 90 mg twice daily plus aspirin in preference to clopidogrel 75mg daily plus aspirin for patients who have an ACS with or without ST-segment elevation. These recommendations are primarily based on large, randomized, Phase III clinical trials. However, few East Asian patients (or those of East Asian descent) have been included in these trials to assess the use of these drugs. In addition, a growing body of data supported that East Asian might have different adverse event profiles (thrombophilia and bleeding) and "therapeutic window" compared with white subjects. Furthermore, "East Asian paradox" phenomenon has been described that East Asian patients have a higher prevalence of platelet reactivity during DAPT, but an ischaemic event rate following PCI or ACS is similar or even lower than white patients. Therefore, the antiplatelet treatment strategy that is most appropriate for East Asian patients is increasingly urgent. Therefore, we performed the current study to observe the different effects of low-dose ticagrelor (45 mg twice daily), conventional-dose ticagrelor (90 mg twice daily) and clopidogrel (75mg once daily) on high platelet reactivity (HPR) and IPA, and investigated the safety and efficacy of low-dose ticagrelor further in Chinese patients with non-ST-elevation ACS (NSTE-ACS).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Ticagrelor is an oral, reversibly-binding, direct-acting P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Guideline recommendations on the use of dual antiplatelet therapy (DAPT) have been formulated that ticagrelor 90 mg twice daily plus aspirin in preference to clopidogrel 75mg daily plus aspirin for patients who have an ACS with or without ST-segment elevation. These recommendations are primarily based on large, randomized, Phase III clinical trials. However, few East Asian patients (or those of East Asian descent) have been included in these trials to assess the use of these drugs. In addition, a growing body of data supported that East Asian might have different adverse event profiles (thrombophilia and bleeding) and "therapeutic window" compared with white subjects. Furthermore, "East Asian paradox" phenomenon has been described that East Asian patients have a higher prevalence of platelet reactivity during DAPT, but an ischaemic event rate following PCI or ACS is similar or even lower than white patients. Therefore, the antiplatelet treatment strategy that is most appropriate for East Asian patients is increasingly urgent. In Korea and Japan, it has been reported that low doses of ticagrelor had a more potent inhibition of platelet aggregation (IPA) than clopidogrel (75 mg once daily) in healthy subjects and patients with stable coronary artery disease, respectively. But it is still not clear whether a low dose of ticagrelor is superior to clopidogrel in a large population of Chinese ACS patients. A recent study on pharmacokinetics and tolerability of ticagrelor has found that maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of ticagrelor (90 mg twice daily) and its active metabolite (AR-C124910XX) tended to be approximately 40% higher in healthy Chinese volunteers compared with Caucasian subjects. This data also suggested that a low dose of ticagrelor might be more appropriate for Chinese ACS patients. In view of a large diurnal variation with a single daily dose, a lower dose twice daily may be a better choice for Chinese patients. Therefore, we performed the current study to observe the different effects of low-dose ticagrelor (45 mg twice daily), conventional-dose ticagrelor (90 mg twice daily) and clopidogrel (75mg once daily) on high platelet reactivity (HPR) and IPA, and investigated the safety and efficacy of low-dose ticagrelor further in Chinese patients with non-ST-elevation ACS (NSTE-ACS).

Study Type

Interventional

Enrollment (Anticipated)

75

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • hospitalized for NSTE-ACS within the preceding 48 h

  • have one of the following additional criteria:

    1. ischemic symptoms at rest, lasting ≥10 minutes;
    2. horizontal or down-sloping ST segment depression ≥0.1 mV;
    3. cardiac troponin I (cTnI), marker associated with NSTE-ACS, local laboratory upper limit of normal values;
    4. underwent percutaneous coronary intervention (PCI); (5) a history of myocardial infarction.

Exclusion Criteria:

  • ST-elevation ACS;
  • planned use of glycoprotein IIb/IIIa receptor inhibitors, adenosine diphosphate (ADP) receptor antagonists, or anticoagulant therapy during the study period;
  • platelet count <100g/L;
  • creatinine clearance rate < 30ml/min;
  • diagnosed as respiratory or circulatory instability (cardiac shock, severe congestive heart failure NYHA II-IV or left ventricular ejection fraction < 40%);
  • a history of bleeding tendency;
  • aspirin, ticagrelor or clopidogrel allergies;
  • diabetes.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: low-dose ticagrelor
To observe the safety and efficacy of low-dose ticagrelor in Chinese patients with non-ST-elevation acute coronary syndrome
Drug: low-dose ticagrelor
90 mg loading dose, then 45 mg twice daily for 5 days
Active Comparator: conventional-dose ticagrelor
To observe the different safety and efficacy between low-dose ticagrelor and conventional-dose ticagrelor.
Drug: conventional-dose ticagrelor
180 mg loading dose, then 90 mg twice daily for 5 days
Active Comparator: clopidogrel
To observe the different safety and efficacy between low-dose ticagrelor and conventional-dose clopidogrel.
Drug: Clopidogrel
300 mg loading dose, then 75 mg once daily for 5 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
the differences in mean inhibition of platelet aggregation or inhibition ratio (%)
Time Frame: before dosing (baseline) and up to 12 hours after the last dose
After overnight fasting, venous blood samples of all subjects were taken for pharmacodynamic measurements before dosing (baseline) and 12 hours after the last dose. VerifyNow P2Y12 (Accumetrics, SanDiego, CA), a whole-blood, cartridge-based and point-of-care turbidometric assay, was performed to test platelet aggregation at baseline and 12 hours after the last dose, and the results were reported in P2Y12 reaction units (PRU). With this assay, a higher PRU reflects greater adenosine-diphosphate-mediated platelet reactivity (PR). High-platelet reactivity (HPR) was defined as a PRU>208. Blood samples were placed in 3.2% sodium citrate (Greiner Bio-One Vacuette North America, Inc, Monroe, NC) for this assay. Additionally, inhibition of platelet aggregation (IPA) calculated by VerifyNow assays was similar to light transmittance aggregometry.
before dosing (baseline) and up to 12 hours after the last dose

Secondary Outcome Measures

Outcome Measure
Time Frame
Number of bleeding events
Time Frame: throughout the study (from baseline to 12 hours after the last dose)
throughout the study (from baseline to 12 hours after the last dose)
Number of difficulty breathing events
Time Frame: throughout the study (from baseline to 12 hours after the last dose)
throughout the study (from baseline to 12 hours after the last dose)
number of ventricular pauses
Time Frame: throughout the study (from baseline to 12 hours after the last dose)
throughout the study (from baseline to 12 hours after the last dose)
number of myocardial infarction events
Time Frame: throughout the study (from baseline to 12 hours after the last dose)
throughout the study (from baseline to 12 hours after the last dose)
number of death events
Time Frame: throughout the study (from baseline to 12 hours after the last dose)
throughout the study (from baseline to 12 hours after the last dose)
number of stroke events
Time Frame: throughout the study (from baseline to 12 hours after the last dose)
throughout the study (from baseline to 12 hours after the last dose)
number of severe recurrent ischemia events
Time Frame: throughout the study (from baseline to 12 hours after the last dose)
throughout the study (from baseline to 12 hours after the last dose)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

First Affiliated Hospital of Harbin Medical University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2014

Primary Completion (Anticipated)

December 1, 2016

Study Registration Dates

First Submitted

March 26, 2015

First Submitted That Met QC Criteria

April 9, 2015

First Posted (Estimate)

April 14, 2015

Study Record Updates

Last Update Posted (Estimate)

April 14, 2015

Last Update Submitted That Met QC Criteria

April 9, 2015

Last Verified

December 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACS-1

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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