<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02201667</url>
  </required_header>
  <id_info>
    <org_study_id>ISSBRIL0208</org_study_id>
    <nct_id>NCT02201667</nct_id>
  </id_info>
  <brief_title>Efficacy of Ticagrelor vs Clopidogrel in High-risk NSTE-ACS Patients Undergoing Early PCI</brief_title>
  <official_title>An Open-label Study Evaluating the Acute Efficacy of Treatment With Ticagrelor Versus Clopidogrel on Myocardial Tissue-level Perfusion Assessed by TMPFC and MRI in Patients With High-risk NSTE-ACS Undergoing Early PCI（EARLY-MYO II）</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>RenJi Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>RenJi Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The goal of acute coronary syndrome (ACS) therapy is to successfully restore both epicardial&#xD;
      blood flow and myocardial perfusion. Percutaneous coronary intervention (PCI) has been&#xD;
      documented as being the most effective method for restoration of epicardial blood flow.&#xD;
      However, epicardial blood flow does not necessarily equate to myocardial perfusion.&#xD;
      Clopidogrel binds irreversibly to platelet P 2 Y 12 receptors to inhibit platelet&#xD;
      aggregation, with main limitations of slow onset, prevention of recovery of platelet&#xD;
      functions, and interindividual variability. Clinical pharmacology and early dose-finding&#xD;
      studies suggested a faster onset and greater and more consistent inhibition of platelet&#xD;
      aggregation (IPA) with ticagrelor compared with clopidogrel. Two currently main methods of&#xD;
      angiographic assessment of myocardial perfusion includes thrombolysis in myocardial&#xD;
      infarction(TIMI) myocardial perfusion grading (TMPG) and myocardial blush grading (MBG).&#xD;
      These established myocardial perfusion parameters have been widely used in various important&#xD;
      trials and are reported to be highly useful in predicting clinical outcomes. However, visual&#xD;
      assessment of these methods is categorical, subjective, and operator dependent of contrast in&#xD;
      the myocardium using cine-angiographic frame-counting, was developed by the investigators'&#xD;
      center to quantify myocardial tissue- level perfusion and was proved to be a predictive value&#xD;
      on clinical prognosis.&#xD;
&#xD;
      Thus, the investigators aim to initiate an open-label study evaluating the acute efficacy of&#xD;
      treatment with ticagrelor versus clopidogrel on myocardial tissue-level perfusion assessed by&#xD;
      Myocardial Perfusion Frame Count(TMPFC) and magnetic resonance imaging (MRI) in patients with&#xD;
      high-risk non-ST elevation acute coronary syndrome (NSTE-ACS) undergoing early percutaneous&#xD;
      coronary intervention (PCI) .&#xD;
&#xD;
      The investigators hypothesize that compared with clopidogrel, ticagrelor can significantly&#xD;
      improve myocardial perfusion assessed by Myocardial Perfusion Frame Count(TMPFC) in high-risk&#xD;
      non-ST elevation acute coronary syndrome (NSTE-ACS) patients undergoing early percutaneous&#xD;
      coronary intervention (PCI), without additional increased major bleeding.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The goal of acute coronary syndrome (ACS) therapy is to successfully restore both epicardial&#xD;
      blood flow and myocardial perfusion. Percutaneous coronary intervention (PCI) has been&#xD;
      documented as being the most effective method for restoration of epicardial blood flow.&#xD;
      However, epicardial blood flow does not necessarily equate to myocardial perfusion; not every&#xD;
      patient with thrombolysis in myocardial infarction(TIMI) 3 flow after successful percutaneous&#xD;
      coronary intervention (PCI) achieves effective myocardial tissue-level perfusion. Although&#xD;
      epicardial thrombolysis in myocardial infarction(TIMI) 3 flow could be restored in &gt;90% of&#xD;
      acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) ,&#xD;
      normalization of myocardial perfusion was achieved less frequently, with detrimental impacts&#xD;
      on survival.&#xD;
&#xD;
      Clopidogrel, the most widely used antiplatelet agent in acute coronary syndrome (ACS), is a&#xD;
      thienopyridine prodrug, which is inactive until in undergoes biotransformation into its&#xD;
      active metabolite, which then binds irreversibly to platelet P 2 Y 12 receptors. This&#xD;
      irreversible binding means that the receptors are inhibited for the lifespan of the platelet.&#xD;
      The main limitations of clopidogrel administration include slow onset, prevention of recovery&#xD;
      of platelet functions, and interindividual variability.&#xD;
&#xD;
      Clinical pharmacology and early dose-finding studies suggested a faster onset and greater and&#xD;
      more consistent inhibition of platelet aggregation (IPA) with ticagrelor compared with&#xD;
      clopidogrel. ONSET/OFFSET study showed that in patients with stable coronary artery disease&#xD;
      on aspirin, ticagrelor demonstrates a rapid onset of pharmacological effect, as demonstrated&#xD;
      by a mean platelet aggregation (IPA) for ticagrelor at 0.5 h after 180 mg loading dose of&#xD;
      about 41%, with the maximum platelet aggregation (IPA) effect of 87.9-89.6% by 2-4 hours post&#xD;
      dose. A total of 90% of patients had final extent Inhibition of platelet aggregation (IPA)&#xD;
      &gt;70% by 2 h post-dose. The high inhibition of platelet aggregation (IPA) effect of ticagrelor&#xD;
      (between 87% and 89%) was maintained for 2-8 hours. Ticagrelor might overcome the slow-onset&#xD;
      limitation of clopidogrel and bring extra benefit for improving myocardial perfusion in the&#xD;
      acute phase of acute coronary syndrome (ACS) when undergoing early percutaneous coronary&#xD;
      intervention (PCI).&#xD;
&#xD;
      Currently, there are two main methods of angiographic assessment of myocardial perfusion:&#xD;
      Thrombolysis in myocardial infarction (TIMI) myocardial perfusion grading (TMPG), described&#xD;
      by Gibson et al. and myocardial blush grading (MBG), described by Van't Hof et al. These&#xD;
      established myocardial perfusion parameters, myocardial perfusion grading (TMPG), and&#xD;
      myocardial blush grading (MBG), have been widely used in various important trials and are&#xD;
      reported to be highly useful in predicting clinical outcomes. However, visual assessment of&#xD;
      these methods is categorical, subjective, and operator dependent. Thrombolysis in myocardial&#xD;
      infarction(TIMI) Myocardial Perfusion Frame Count (TMPFC), a novel and objective method that&#xD;
      measures the filling and clearance of contrast in the myocardium using cine-angiographic&#xD;
      frame-counting, was developed by the investigators' center to quantify myocardial tissue-&#xD;
      level perfusion and was proved to be a predictive value on clinical prognosis.&#xD;
&#xD;
      Thus, the investigators aim to initiate an open-label study evaluating the acute efficacy of&#xD;
      treatment with ticagrelor versus clopidogrel on myocardial tissue-level perfusion assessed by&#xD;
      Myocardial Perfusion Frame Count (TMPFC) and magnetic resonance imaging (MRI) in patients&#xD;
      with high-risk non-ST elevation acute coronary syndrome (NSTE-ACS) undergoing early&#xD;
      percutaneous coronary intervention (PCI).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>August 2014</start_date>
  <completion_date type="Anticipated">October 2016</completion_date>
  <primary_completion_date type="Anticipated">August 2016</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>TIMI Myocardial Perfusion Frame Count (TMPFC)</measure>
    <time_frame>Within 0 to 24 hours after randomization</time_frame>
    <description>The Myocardial Perfusion Frame Count (TMPFC) is developed to standardize and quantify myocardial perfusion by timing the filling and clearance of contrast in the myocardium using cine-angiographic frame-counting. The first frame of Myocardial Perfusion Frame Count (TMPFC) is defined as the frame that clearly demonstrates the first appearance of myocardial blush beyond the infarct-related artery (IRA) (F1). The last frame of Myocardial Perfusion Frame Count (TMPFC) is then defined as the frame where contrast or myocardial blush disappears (F2). TMPFC is therefore F2-F1 frame counts at filming rate of 15frames/sec.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cardiac Magnetic Resonance Imaging</measure>
    <time_frame>At 30th day after randomization</time_frame>
    <description>Cardiovascular MRI will be performed at 30th day, to detect microvascular obstruction (MO) and intramyocardial hemorrhage (IMH). Infarct size and myocardial strain will also be measured by the method previously described.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Echocardiography</measure>
    <time_frame>At 30th day after randomization</time_frame>
    <description>echocardiography will be performed within 24h post PCI and at 30th day to assess changes in left ventricular size and function</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Myocardial-specific isoenzyme of creatine kinase (CK-MB) enzyme levels peri-PCI</measure>
    <time_frame>Within 0 to 48 hours after enrollment</time_frame>
    <description>Infarct size is measured by the myocardial-specific isoenzyme of creatine kinase (CK-MB) area under the curve, calculated by the linear-trapezoidal method. If the baseline or last value is missing, the corresponding value will be set to zero. For missing values of intermediate time points, linear interpolation is used.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Bleeding events: Incidence of bleeding events</measure>
    <time_frame>Within 0 to 30 dys after randomization</time_frame>
    <description>Incidence of bleeding events, classified by TIMI criteria and GUSTO severity criteria.</description>
  </other_outcome>
  <other_outcome>
    <measure>Other adverse events</measure>
    <time_frame>Within 0 to 30 days after randomization</time_frame>
    <description>Including any other adverse events (AEs) during the study.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">444</enrollment>
  <condition>Acute Coronary Syndrome</condition>
  <arm_group>
    <arm_group_label>Ticagrelor group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients wil be given 180 mg loading dose of ticagrelor and 300mg loading dose of aspirin followed by PCI, then will receive 90 mg ticagrelor twice daily with aspirin maintenance dose to 30 days after randomization.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Clopidogrel group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will be given clopidogrel 300mg loading dose and 300mg loading dose of aspirin followed by PCI, then will receive 75mg clopidogrel once with aspirin maintenance dose to 30 days after randomization.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ticagrelor</intervention_name>
    <description>180-mg loading dose followed by 90mg twice daily for 30 days</description>
    <arm_group_label>Ticagrelor group</arm_group_label>
    <other_name>BRILINTA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>clopidogrel</intervention_name>
    <description>300-mg loading dose followed by 75mg once daily for 30 days.</description>
    <arm_group_label>Clopidogrel group</arm_group_label>
    <other_name>Plavix</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aspirin</intervention_name>
    <description>300mg loading dose aspirin and followed by 100mg once daily</description>
    <arm_group_label>Clopidogrel group</arm_group_label>
    <arm_group_label>Ticagrelor group</arm_group_label>
    <other_name>Aspirin Enteric Coated Tablets</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>PCI</intervention_name>
    <description>PCI is performed according to indication for early PCI according to 2012 Chinese NSTE-ACS guideline recommendation</description>
    <arm_group_label>Clopidogrel group</arm_group_label>
    <arm_group_label>Ticagrelor group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        For inclusion in the study subjects should fulfill the following criteria:&#xD;
&#xD;
          1. Provision of informed consent prior to any study specific procedures;&#xD;
&#xD;
          2. Men or women &gt; 18 years of age, with documented evidence of non-ST segment elevation&#xD;
             Acute Coronary Syndrome(ACS) in the 24 hours before randomisation;&#xD;
&#xD;
          3. Hospitalized for high-risk non-ST segment elevation Acute Coronary Syndrome(ACS)(GRACE&#xD;
             risk score&gt;140) with indication for early percutaneous coronary intervention (PCI)&#xD;
             according to 2012 Chinese non-S T segment elevation Acute Coronary Syndrome(ACS)&#xD;
             guideline recommendation.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Subjects should not enter the study if any of the following exclusion criteria are&#xD;
        fulfilled:&#xD;
&#xD;
          1. Evidence of cardiac rupture;&#xD;
&#xD;
          2. History of major hemorrhage (intracranial, gastrointestinal, etc.);&#xD;
&#xD;
          3. Active pathological bleeding;&#xD;
&#xD;
          4. Acute or chronic hematologic disorder including a Hemoglobin less than 10 g/L or a&#xD;
             platelet count less than 10×109/L before procedure;&#xD;
&#xD;
          5. Contraindication against the use of clopidogrel and ticagrelor;&#xD;
&#xD;
          6. Subject has any condition for which, in the opinion of the investigator, participation&#xD;
             would not be in the best interest of the subject (eg, compromise the well-being) or&#xD;
             that could prevent, limit, or confound the protocol-specified assessments.&#xD;
&#xD;
          7. Severe complication 7.1 Other diseases with life expectancy ≤12 months; 7.2 Any&#xD;
             history of Severe renal or hepatic dysfunction(hepatic failure, cirrhosis, portal&#xD;
             hypertension and active hepatitis); Neutropenia, thrombocytopenia ; Known acute&#xD;
             pancreatitis; 7.3 Arterial aneurysm, arterial/venous malformation and aorta&#xD;
             dissection;&#xD;
&#xD;
          8. Complex heart condition 8.1 PCI within previous 1 month or Previous coronary-artery&#xD;
             bypass surgery(CABG); 8.2 History of myocardial infarction; 8.3 Previously known&#xD;
             multivessel coronary artery disease not suitable for percutaneous coronary&#xD;
             intervention (PCI);&#xD;
&#xD;
          9. Previous enrolment in this study or treatment with an investigational drug or device&#xD;
             under another study protocol in the past 30 days;&#xD;
&#xD;
         10. Treatment with anticoagulants;&#xD;
&#xD;
         11. Pregnancy or lactating;&#xD;
&#xD;
         12. Body weight &lt;40kg or &gt;125kg;&#xD;
&#xD;
         13. Known hypersensitivity to any drug that may appear in the study;&#xD;
&#xD;
         14. Inability to follow the protocol and comply with follow-up requirements or any other&#xD;
             reason that the investigator feels would place the patient at increased risk;&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ben He, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ben He, MD,PhD</last_name>
    <phone>68383609</phone>
    <email>heben1025@hotmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Ren Ji Hospital Afflited to School of Medicine, Shanghai Jiao Tong University</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <zip>200127</zip>
        <country>China</country>
      </address>
    </facility>
    <contact>
      <last_name>Ben He, MD,PhD</last_name>
      <phone>68383609</phone>
      <email>heben1025@hotmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Ding S, Pu J, Qiao ZQ, Shan P, Song W, Du Y, Shen JY, Jin SX, Sun Y, Shen L, Lim YL, He B. TIMI myocardial perfusion frame count: a new method to assess myocardial perfusion and its predictive value for short-term prognosis. Catheter Cardiovasc Interv. 2010 Apr 1;75(5):722-32. doi: 10.1002/ccd.22298.</citation>
    <PMID>19960517</PMID>
  </reference>
  <reference>
    <citation>Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009 Dec 22;120(25):2577-85. doi: 10.1161/CIRCULATIONAHA.109.912550. Epub 2009 Nov 18.</citation>
    <PMID>19923168</PMID>
  </reference>
  <reference>
    <citation>Gibson CM, Cannon CP, Murphy SA, Ryan KA, Mesley R, Marble SJ, McCabe CH, Van De Werf F, Braunwald E. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation. 2000 Jan 18;101(2):125-30. doi: 10.1161/01.cir.101.2.125.</citation>
    <PMID>10637197</PMID>
  </reference>
  <reference>
    <citation>van 't Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle Myocardial Infarction Study Group. Circulation. 1998 Jun 16;97(23):2302-6. doi: 10.1161/01.cir.97.23.2302.</citation>
    <PMID>9639373</PMID>
  </reference>
  <reference>
    <citation>Chinese Society of Cardiology of Chinese Medical Association; Editorial Board of Chinese Journal of Cardiology. [Guideline of non-ST segment elevation acute coronary syndrome]. Zhonghua Xin Xue Guan Bing Za Zhi. 2012 May;40(5):353-67. No abstract available. Chinese.</citation>
    <PMID>22883082</PMID>
  </reference>
  <reference>
    <citation>Kidambi A, Mather AN, Motwani M, Swoboda P, Uddin A, Greenwood JP, Plein S. The effect of microvascular obstruction and intramyocardial hemorrhage on contractile recovery in reperfused myocardial infarction: insights from cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2013 Jun 27;15(1):58. doi: 10.1186/1532-429X-15-58.</citation>
    <PMID>23806080</PMID>
  </reference>
  <reference>
    <citation>Roe MT, Ohman EM, Maas AC, Christenson RH, Mahaffey KW, Granger CB, Harrington RA, Califf RM, Krucoff MW. Shifting the open-artery hypothesis downstream: the quest for optimal reperfusion. J Am Coll Cardiol. 2001 Jan;37(1):9-18. doi: 10.1016/s0735-1097(00)01101-3.</citation>
    <PMID>11153779</PMID>
  </reference>
  <reference>
    <citation>Pu J, Shan P, Ding S, Qiao Z, Jiang L, Song W, Du Y, Shen J, Shen L, Jin S, He B. Gender differences in epicardial and tissue-level reperfusion in patients undergoing primary angioplasty for acute myocardial infarction. Atherosclerosis. 2011 Mar;215(1):203-8. doi: 10.1016/j.atherosclerosis.2010.11.019. Epub 2010 Nov 26.</citation>
    <PMID>21176835</PMID>
  </reference>
  <reference>
    <citation>Pu J, Ding S, Shan P, Qiao Z, Song W, Du Y, Shen J, Jin S, He B. Comparison of epicardial and myocardial perfusions after primary coronary angioplasty for ST-elevation myocardial infarction in patients under and over 75 years of age. Aging Clin Exp Res. 2010 Aug;22(4):295-302. doi: 10.1007/BF03337726. Epub 2009 Dec 1.</citation>
    <PMID>20009495</PMID>
  </reference>
  <reference>
    <citation>Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449. No abstract available.</citation>
    <PMID>21670242</PMID>
  </reference>
  <reference>
    <citation>Shen LH, Wan F, Shen L, Ding S, Gong XR, Qiao ZQ, Du YP, Song W, Shen JY, Jin SX, Pu J, Yao TB, Jiang LS, Li WZ, Zhou GW, Liu SW, Han YL, He B. Pharmacoinvasive therapy for ST elevation myocardial infarction in China: a pilot study. J Thromb Thrombolysis. 2012 Jan;33(1):101-8. doi: 10.1007/s11239-011-0657-7.</citation>
    <PMID>22094974</PMID>
  </reference>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>July 24, 2014</study_first_submitted>
  <study_first_submitted_qc>July 24, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 28, 2014</study_first_posted>
  <last_update_submitted>July 31, 2014</last_update_submitted>
  <last_update_submitted_qc>July 31, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 4, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>non-ST elevation acute coronary syndrome</keyword>
  <keyword>myocardial perfusion</keyword>
  <keyword>magnetic Resonance Imaging</keyword>
  <keyword>antiplatelet</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Coronary Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</mesh_term>
    <mesh_term>Clopidogrel</mesh_term>
    <mesh_term>Ticagrelor</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02201667
org study id: ISSBRIL0208
nct id: NCT02201667
lead sponsor: 
has dmc: Yes
The goal of acute coronary syndrome (ACS) therapy is to successfully restore both epicardial
      blood flow and myocardial perfusion. Percutaneous coronary intervention (PCI) has been
      documented as being the most effective method for restoration of epicardial blood flow.
      However, epicardial blood flow does not necessarily equate to myocardial perfusion.
      Clopidogrel binds irreversibly to platelet P 2 Y 12 receptors to inhibit platelet
      aggregation, with main limitations of slow onset, prevention of recovery of platelet
      functions, and interindividual variability. Clinical pharmacology and early dose-finding
      studies suggested a faster onset and greater and more consistent inhibition of platelet
      aggregation (IPA) with ticagrelor compared with clopidogrel. Two currently main methods of
      angiographic assessment of myocardial perfusion includes thrombolysis in myocardial
      infarction(TIMI) myocardial perfusion grading (TMPG) and myocardial blush grading (MBG).
      These established myocardial perfusion parameters have been widely used in various important
      trials and are reported to be highly useful in predicting clinical outcomes. However, visual
      assessment of these methods is categorical, subjective, and operator dependent of contrast in
      the myocardium using cine-angiographic frame-counting, was developed by the investigators'
      center to quantify myocardial tissue- level perfusion and was proved to be a predictive value
      on clinical prognosis.

      Thus, the investigators aim to initiate an open-label study evaluating the acute efficacy of
      treatment with ticagrelor versus clopidogrel on myocardial tissue-level perfusion assessed by
      Myocardial Perfusion Frame Count(TMPFC) and magnetic resonance imaging (MRI) in patients with
      high-risk non-ST elevation acute coronary syndrome (NSTE-ACS) undergoing early percutaneous
      coronary intervention (PCI) .

      The investigators hypothesize that compared with clopidogrel, ticagrelor can significantly
      improve myocardial perfusion assessed by Myocardial Perfusion Frame Count(TMPFC) in high-risk
      non-ST elevation acute coronary syndrome (NSTE-ACS) patients undergoing early percutaneous
      coronary intervention (PCI), without additional increased major bleeding.
The goal of acute coronary syndrome (ACS) therapy is to successfully restore both epicardial
      blood flow and myocardial perfusion. Percutaneous coronary intervention (PCI) has been
      documented as being the most effective method for restoration of epicardial blood flow.
      However, epicardial blood flow does not necessarily equate to myocardial perfusion; not every
      patient with thrombolysis in myocardial infarction(TIMI) 3 flow after successful percutaneous
      coronary intervention (PCI) achieves effective myocardial tissue-level perfusion. Although
      epicardial thrombolysis in myocardial infarction(TIMI) 3 flow could be restored in >90% of
      acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) ,
      normalization of myocardial perfusion was achieved less frequently, with detrimental impacts
      on survival.

      Clopidogrel, the most widely used antiplatelet agent in acute coronary syndrome (ACS), is a
      thienopyridine prodrug, which is inactive until in undergoes biotransformation into its
      active metabolite, which then binds irreversibly to platelet P 2 Y 12 receptors. This
      irreversible binding means that the receptors are inhibited for the lifespan of the platelet.
      The main limitations of clopidogrel administration include slow onset, prevention of recovery
      of platelet functions, and interindividual variability.

      Clinical pharmacology and early dose-finding studies suggested a faster onset and greater and
      more consistent inhibition of platelet aggregation (IPA) with ticagrelor compared with
      clopidogrel. ONSET/OFFSET study showed that in patients with stable coronary artery disease
      on aspirin, ticagrelor demonstrates a rapid onset of pharmacological effect, as demonstrated
      by a mean platelet aggregation (IPA) for ticagrelor at 0.5 h after 180 mg loading dose of
      about 41%, with the maximum platelet aggregation (IPA) effect of 87.9-89.6% by 2-4 hours post
      dose. A total of 90% of patients had final extent Inhibition of platelet aggregation (IPA)
      >70% by 2 h post-dose. The high inhibition of platelet aggregation (IPA) effect of ticagrelor
      (between 87% and 89%) was maintained for 2-8 hours. Ticagrelor might overcome the slow-onset
      limitation of clopidogrel and bring extra benefit for improving myocardial perfusion in the
      acute phase of acute coronary syndrome (ACS) when undergoing early percutaneous coronary
      intervention (PCI).

      Currently, there are two main methods of angiographic assessment of myocardial perfusion:
      Thrombolysis in myocardial infarction (TIMI) myocardial perfusion grading (TMPG), described
      by Gibson et al. and myocardial blush grading (MBG), described by Van't Hof et al. These
      established myocardial perfusion parameters, myocardial perfusion grading (TMPG), and
      myocardial blush grading (MBG), have been widely used in various important trials and are
      reported to be highly useful in predicting clinical outcomes. However, visual assessment of
      these methods is categorical, subjective, and operator dependent. Thrombolysis in myocardial
      infarction(TIMI) Myocardial Perfusion Frame Count (TMPFC), a novel and objective method that
      measures the filling and clearance of contrast in the myocardium using cine-angiographic
      frame-counting, was developed by the investigators' center to quantify myocardial tissue-
      level perfusion and was proved to be a predictive value on clinical prognosis.

      Thus, the investigators aim to initiate an open-label study evaluating the acute efficacy of
      treatment with ticagrelor versus clopidogrel on myocardial tissue-level perfusion assessed by
      Myocardial Perfusion Frame Count (TMPFC) and magnetic resonance imaging (MRI) in patients
      with high-risk non-ST elevation acute coronary syndrome (NSTE-ACS) undergoing early
      percutaneous coronary intervention (PCI).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: TIMI Myocardial Perfusion Frame Count (TMPFC)
time frame: Within 0 to 24 hours after randomization
description: The Myocardial Perfusion Frame Count (TMPFC) is developed to standardize and quantify myocardial perfusion by timing the filling and clearance of contrast in the myocardium using cine-angiographic frame-counting. The first frame of Myocardial Perfusion Frame Count (TMPFC) is defined as the frame that clearly demonstrates the first appearance of myocardial blush beyond the infarct-related artery (IRA) (F1). The last frame of Myocardial Perfusion Frame Count (TMPFC) is then defined as the frame where contrast or myocardial blush disappears (F2). TMPFC is therefore F2-F1 frame counts at filming rate of 15frames/sec.
measure: Cardiac Magnetic Resonance Imaging
time frame: At 30th day after randomization
description: Cardiovascular MRI will be performed at 30th day, to detect microvascular obstruction (MO) and intramyocardial hemorrhage (IMH). Infarct size and myocardial strain will also be measured by the method previously described.
measure: Echocardiography
time frame: At 30th day after randomization
description: echocardiography will be performed within 24h post PCI and at 30th day to assess changes in left ventricular size and function
measure: Myocardial-specific isoenzyme of creatine kinase (CK-MB) enzyme levels peri-PCI
time frame: Within 0 to 48 hours after enrollment
description: Infarct size is measured by the myocardial-specific isoenzyme of creatine kinase (CK-MB) area under the curve, calculated by the linear-trapezoidal method. If the baseline or last value is missing, the corresponding value will be set to zero. For missing values of intermediate time points, linear interpolation is used.
measure: Bleeding events: Incidence of bleeding events
time frame: Within 0 to 30 dys after randomization
description: Incidence of bleeding events, classified by TIMI criteria and GUSTO severity criteria.
measure: Other adverse events
time frame: Within 0 to 30 days after randomization
description: Including any other adverse events (AEs) during the study.
arm group label: Ticagrelor group
arm group type: Experimental
description: Patients wil be given 180 mg loading dose of ticagrelor and 300mg loading dose of aspirin followed by PCI, then will receive 90 mg ticagrelor twice daily with aspirin maintenance dose to 30 days after randomization.
arm group label: Clopidogrel group
arm group type: Active Comparator
description: Patients will be given clopidogrel 300mg loading dose and 300mg loading dose of aspirin followed by PCI, then will receive 75mg clopidogrel once with aspirin maintenance dose to 30 days after randomization.
intervention type: Drug
intervention name: Ticagrelor
description: 180-mg loading dose followed by 90mg twice daily for 30 days
arm group label: Ticagrelor group
other name: BRILINTA
intervention type: Drug
intervention name: clopidogrel
description: 300-mg loading dose followed by 75mg once daily for 30 days.
arm group label: Clopidogrel group
other name: Plavix
intervention type: Drug
intervention name: Aspirin
description: 300mg loading dose aspirin and followed by 100mg once daily
arm group label: Clopidogrel group
arm group label: Ticagrelor group
other name: Aspirin Enteric Coated Tablets
intervention type: Procedure
intervention name: PCI
description: PCI is performed according to indication for early PCI according to 2012 Chinese NSTE-ACS guideline recommendation
arm group label: Clopidogrel group
arm group label: Ticagrelor group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ben He, MD,PhD
role: Principal Investigator
affiliation: Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University
last name: Ben He, MD,PhD
phone: 68383609
email: heben1025@hotmail.com
facility: 
contact: 
country: China
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PMID: 19960517
citation: Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009 Dec 22;120(25):2577-85. doi: 10.1161/CIRCULATIONAHA.109.912550. Epub 2009 Nov 18.
PMID: 19923168
citation: Gibson CM, Cannon CP, Murphy SA, Ryan KA, Mesley R, Marble SJ, McCabe CH, Van De Werf F, Braunwald E. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation. 2000 Jan 18;101(2):125-30. doi: 10.1161/01.cir.101.2.125.
PMID: 10637197
citation: van 't Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle Myocardial Infarction Study Group. Circulation. 1998 Jun 16;97(23):2302-6. doi: 10.1161/01.cir.97.23.2302.
PMID: 9639373
citation: Chinese Society of Cardiology of Chinese Medical Association; Editorial Board of Chinese Journal of Cardiology. [Guideline of non-ST segment elevation acute coronary syndrome]. Zhonghua Xin Xue Guan Bing Za Zhi. 2012 May;40(5):353-67. No abstract available. Chinese.
PMID: 22883082
citation: Kidambi A, Mather AN, Motwani M, Swoboda P, Uddin A, Greenwood JP, Plein S. The effect of microvascular obstruction and intramyocardial hemorrhage on contractile recovery in reperfused myocardial infarction: insights from cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2013 Jun 27;15(1):58. doi: 10.1186/1532-429X-15-58.
PMID: 23806080
citation: Roe MT, Ohman EM, Maas AC, Christenson RH, Mahaffey KW, Granger CB, Harrington RA, Califf RM, Krucoff MW. Shifting the open-artery hypothesis downstream: the quest for optimal reperfusion. J Am Coll Cardiol. 2001 Jan;37(1):9-18. doi: 10.1016/s0735-1097(00)01101-3.
PMID: 11153779
citation: Pu J, Shan P, Ding S, Qiao Z, Jiang L, Song W, Du Y, Shen J, Shen L, Jin S, He B. Gender differences in epicardial and tissue-level reperfusion in patients undergoing primary angioplasty for acute myocardial infarction. Atherosclerosis. 2011 Mar;215(1):203-8. doi: 10.1016/j.atherosclerosis.2010.11.019. Epub 2010 Nov 26.
PMID: 21176835
citation: Pu J, Ding S, Shan P, Qiao Z, Song W, Du Y, Shen J, Jin S, He B. Comparison of epicardial and myocardial perfusions after primary coronary angioplasty for ST-elevation myocardial infarction in patients under and over 75 years of age. Aging Clin Exp Res. 2010 Aug;22(4):295-302. doi: 10.1007/BF03337726. Epub 2009 Dec 1.
PMID: 20009495
citation: Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449. No abstract available.
PMID: 21670242
citation: Shen LH, Wan F, Shen L, Ding S, Gong XR, Qiao ZQ, Du YP, Song W, Shen JY, Jin SX, Pu J, Yao TB, Jiang LS, Li WZ, Zhou GW, Liu SW, Han YL, He B. Pharmacoinvasive therapy for ST elevation myocardial infarction in China: a pilot study. J Thromb Thrombolysis. 2012 Jan;33(1):101-8. doi: 10.1007/s11239-011-0657-7.
PMID: 22094974
responsible party type: Sponsor
mesh term: Acute Coronary Syndrome
mesh term: Aspirin
mesh term: Clopidogrel
mesh term: Ticagrelor