<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/NCT02224274</url>
  </required_header>
  <id_info>
    <org_study_id>Hypothermia: Clopi vs Tica</org_study_id>
    <nct_id>NCT02224274</nct_id>
  </id_info>
  <brief_title>Antiplatelet Therapy After Cardiac Arrest</brief_title>
  <official_title>Comparison of Antiplatelet Therapy With Clopidogrel and Ticagrelor in Patients After Cardiac Arrest Treated With Therapeutic Hypothermia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Medical Centre Ljubljana</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Medical Centre Ljubljana</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      There is growing evidence that standard dual antiplatelet therapy with acetylsalicylic acid&#xD;
      (ASA) and clopidogrel is not as effective in the setting of therapeutic hypothermia after&#xD;
      cardiac arrest as in normothermic patients. The reasons for this are probably slower&#xD;
      gastrointestinal motility, absorption and liver metabolism required for clopidogrel to take&#xD;
      action. Since ticagrelor has faster intestinal absorption and no need for liver metabolism we&#xD;
      expect its effect to be good even in patients with therapeutic hypothermia after cardiac&#xD;
      arrest. Patients treated with therapeutic hypothermia after cardiac arrest and percutaneous&#xD;
      coronary intervention will be randomised into two groups. One will be treated with ASA and&#xD;
      clopidogrel and the other with ASA and ticagrelor. Blood samples will be collected before and&#xD;
      2, 4, 12, 22 and 48 hours after P2Y12 inhibitor administration. Platelet function will be&#xD;
      measured by VerifyNow P2Y12 assay and by Multiplate ADPTest. Differences between the groups&#xD;
      will be analysed.&#xD;
&#xD;
      Hypothesis: Antiplatelet therapy with ticagrelor is more effective than therapy with&#xD;
      clopidogrel in the comatose survivors of cardiac arrest treated with therapeutic hypothermia&#xD;
      and percutaneous coronary intervention (PCI).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">June 2016</completion_date>
  <primary_completion_date type="Actual">June 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>VerifyNow P2Y12Test - Platelet Reactivity</measure>
    <time_frame>12 h after P2Y12 inhibitor loading</time_frame>
    <description>Platelet reactivity reflects P2Y12 inhibitor effect. Higher values mean normal platelet reactivity due to low P2Y12 inhibition response, while lower values mean decreased platelet reactivity due to the effect of a P2Y12 inhibitor. High on-treatment platelet reactivity was defined as &gt;208 PRU.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>VerifyNow P2Y12Test - % Inhibition</measure>
    <time_frame>12 hours after P2Y12 inhibitor loading</time_frame>
    <description>% inhibition reflects P2Y12 inhibitor effect regarding basal platelet reactivity (defined as: (1- (platelet reactivity/basal platelet reactivity)) x 100). Higher values mean better P2Y12 inhibition response. High on-treatment platelet reactivity was defined as &lt;11% inhibition.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Multiplate ADP Test</measure>
    <time_frame>12 hours after P2Y12 inhibitor loading</time_frame>
    <description>Platelet activation by adenosine diphosphate (ADP) expressed in arbitrary aggregation units (U). P2Y12 inhibitors block ADP receptors and decrease platelet activation by ADP. Higher values mean less effect of P2Y12 inhibitors, lower values mean more effect of P2Y12 inhibitors on platelets.&#xD;
High on-treatment platelet reactivity was defined as &gt;46 U.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">57</enrollment>
  <condition>Cardiac Arrest</condition>
  <condition>Postresuscitation Syndrome</condition>
  <condition>Myocardial Infarction (ST-Elevation Myocardial Infarction and Non-ST-Elevation Myocardial Infarction)</condition>
  <arm_group>
    <arm_group_label>Clopidogrel</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>These patients will be treated with clopidogrel 600 mg loading and than 75 mg/24 h.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ticagrelor</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>These patients will be treated with ticagrelor 180 mg loading and than 90 mg/12 h.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clopidogrel</intervention_name>
    <arm_group_label>Clopidogrel</arm_group_label>
    <other_name>Clopidogrel (Plavix)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ticagrelor</intervention_name>
    <arm_group_label>Ticagrelor</arm_group_label>
    <other_name>Ticagrelor (Brilique)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female and male over 18 years old&#xD;
&#xD;
          -  Unconscious survivors of cardiac arrest treated with therapeutic hypothermia&#xD;
&#xD;
          -  Acute coronary syndrome (NSTEMI or STEMI) as a reason of cardiac arrest&#xD;
&#xD;
          -  PCI with stent implantation&#xD;
&#xD;
          -  Provision of informed consent prior to any study specific procedures is impossible&#xD;
             because subjects are unconscious at the moment of inclusion&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of any P2Y12 inhibitors in last 10 days&#xD;
&#xD;
          -  Use of prasugrel before and 48 hours after loading dose of P2Y12 inhibitor&#xD;
&#xD;
          -  Use of eptifibatide before and 48 hours after loading dose of P2Y12 inhibitor&#xD;
&#xD;
          -  Thrombocytopenia (&lt;50*109/L)&#xD;
&#xD;
          -  Allergic reaction to acetylsalicylic acid, clopidogrel or ticagrelor&#xD;
&#xD;
          -  Ticagrelor contraindications: previous intracranial bleeding, active pathological&#xD;
             bleeding, moderate to severe hepatic impairment, heart rate &lt; 40/min at presentation&#xD;
&#xD;
          -  Suspected or confirmed pregnancy&#xD;
&#xD;
          -  Use of bivalirudin before and 48 hours after loading dose of P2Y12 inhibitor&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University Medical Centre Ljubljana</name>
      <address>
        <city>Ljubljana</city>
        <zip>1000</zip>
        <country>Slovenia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Slovenia</country>
  </location_countries>
  <reference>
    <citation>Steblovnik K, Blinc A, Bozic-Mijovski M, Kranjec I, Melkic E, Noc M. Platelet reactivity in comatose survivors of cardiac arrest undergoing percutaneous coronary intervention and hypothermia. EuroIntervention. 2015 Apr;10(12):1418-24. doi: 10.4244/EIJY14M05_02.</citation>
    <PMID>24800722</PMID>
  </reference>
  <reference>
    <citation>Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Gurbel PA, Xu K, Parise H, Kirtane AJ, Brodie BR, Mehran R, Stuckey TD; ADAPT-DES Investigators. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013 Aug 17;382(9892):614-23. doi: 10.1016/S0140-6736(13)61170-8. Epub 2013 Jul 26. Erratum In: Lancet. 2014 Mar 29;383(9923):1128.</citation>
    <PMID>23890998</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>Gorjup V, Radsel P, Kocjancic ST, Erzen D, Noc M. Acute ST-elevation myocardial infarction after successful cardiopulmonary resuscitation. Resuscitation. 2007 Mar;72(3):379-85. doi: 10.1016/j.resuscitation.2006.07.013. Epub 2006 Dec 11.</citation>
    <PMID>17161902</PMID>
  </reference>
  <reference>
    <citation>Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002 Feb 21;346(8):557-63. doi: 10.1056/NEJMoa003289.</citation>
    <PMID>11856794</PMID>
  </reference>
  <reference>
    <citation>Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos K, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G. Response to letter regarding article, &quot;Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction&quot;. Circ Cardiovasc Interv. 2013 Apr;6(2):e29. doi: 10.1161/CIRCINTERVENTIONS.113.000134. No abstract available.</citation>
    <PMID>23591428</PMID>
  </reference>
  <reference>
    <citation>Souckova L, Opatrilova R, Suk P, Cundrle I Jr, Pavlik M, Zvonicek V, Hlinomaz O, Sramek V. Impaired bioavailability and antiplatelet effect of high-dose clopidogrel in patients after cardiopulmonary resuscitation (CPR). Eur J Clin Pharmacol. 2013 Mar;69(3):309-17. doi: 10.1007/s00228-012-1360-0. Epub 2012 Aug 14.</citation>
    <PMID>22890586</PMID>
  </reference>
  <reference>
    <citation>Bjelland TW, Hjertner O, Klepstad P, Kaisen K, Dale O, Haugen BO. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation. 2010 Dec;81(12):1627-31. doi: 10.1016/j.resuscitation.2010.07.002. Epub 2010 Aug 19.</citation>
    <PMID>20727659</PMID>
  </reference>
  <reference>
    <citation>Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009 Jul;37(7 Suppl):S186-202. doi: 10.1097/CCM.0b013e3181aa5241.</citation>
    <PMID>19535947</PMID>
  </reference>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>August 19, 2014</study_first_submitted>
  <study_first_submitted_qc>August 22, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 25, 2014</study_first_posted>
  <results_first_submitted>January 23, 2017</results_first_submitted>
  <results_first_submitted_qc>October 17, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">February 27, 2019</results_first_posted>
  <last_update_submitted>October 17, 2018</last_update_submitted>
  <last_update_submitted_qc>October 17, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Medical Centre Ljubljana</investigator_affiliation>
    <investigator_full_name>Marko Noc</investigator_full_name>
    <investigator_title>Marko Noc, MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Antiplatelet Therapy</keyword>
  <keyword>Cardiac Arrest</keyword>
  <keyword>Therapeutic hypothermia</keyword>
  <keyword>Myocardial infarction (ST-Elevation Myocardial Infarction and Non-ST-Elevation Myocardial Infarction)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myocardial Infarction</mesh_term>
    <mesh_term>Heart Arrest</mesh_term>
    <mesh_term>ST Elevation Myocardial Infarction</mesh_term>
    <mesh_term>Non-ST Elevated Myocardial Infarction</mesh_term>
    <mesh_term>Infarction</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clopidogrel</mesh_term>
    <mesh_term>Ticagrelor</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Recruitment from August 2014 to May 2016 at UMC Ljubljana, Slovenia, Europe</recruitment_details>
      <pre_assignment_details>Reasons for exclusion were intraprocedural eptifibatide/thrombolysis (11), decision of attending physician (8) and bradycardia (1)</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Clopidogrel</title>
          <description>These patients will be treated with clopidogrel 600 mg loading and than 75 mg/24 h.&#xD;
Clopidogrel</description>
        </group>
        <group group_id="P2">
          <title>Ticagrelor</title>
          <description>These patients will be treated with ticagrelor 180 mg loading and than 90 mg/12 h.&#xD;
Ticagrelor</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Clopidogrel</title>
          <description>These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.</description>
        </group>
        <group group_id="B2">
          <title>Ticagrelor</title>
          <description>These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="16"/>
            <count group_id="B2" value="20"/>
            <count group_id="B3" value="36"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64" spread="9"/>
                    <measurement group_id="B2" value="61" spread="12"/>
                    <measurement group_id="B3" value="62" spread="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ST-Elevation Myocardial Infarction in postresuscitation ECG</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>VerifyNow P2Y12Test - Platelet Reactivity</title>
        <description>Platelet reactivity reflects P2Y12 inhibitor effect. Higher values mean normal platelet reactivity due to low P2Y12 inhibition response, while lower values mean decreased platelet reactivity due to the effect of a P2Y12 inhibitor. High on-treatment platelet reactivity was defined as &gt;208 PRU.</description>
        <time_frame>12 h after P2Y12 inhibitor loading</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Clopidogrel</title>
            <description>These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.</description>
          </group>
          <group group_id="O2">
            <title>Ticagrelor</title>
            <description>These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.</description>
          </group>
        </group_list>
        <measure>
          <title>VerifyNow P2Y12Test - Platelet Reactivity</title>
          <description>Platelet reactivity reflects P2Y12 inhibitor effect. Higher values mean normal platelet reactivity due to low P2Y12 inhibition response, while lower values mean decreased platelet reactivity due to the effect of a P2Y12 inhibitor. High on-treatment platelet reactivity was defined as &gt;208 PRU.</description>
          <units>PRU</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="238" spread="67"/>
                    <measurement group_id="O2" value="101" spread="75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>VerifyNow P2Y12Test - % Inhibition</title>
        <description>% inhibition reflects P2Y12 inhibitor effect regarding basal platelet reactivity (defined as: (1- (platelet reactivity/basal platelet reactivity)) x 100). Higher values mean better P2Y12 inhibition response. High on-treatment platelet reactivity was defined as &lt;11% inhibition.</description>
        <time_frame>12 hours after P2Y12 inhibitor loading</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Clopidogrel</title>
            <description>These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.</description>
          </group>
          <group group_id="O2">
            <title>Ticagrelor</title>
            <description>These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.</description>
          </group>
        </group_list>
        <measure>
          <title>VerifyNow P2Y12Test - % Inhibition</title>
          <description>% inhibition reflects P2Y12 inhibitor effect regarding basal platelet reactivity (defined as: (1- (platelet reactivity/basal platelet reactivity)) x 100). Higher values mean better P2Y12 inhibition response. High on-treatment platelet reactivity was defined as &lt;11% inhibition.</description>
          <units>% inhibition</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4" spread="11"/>
                    <measurement group_id="O2" value="55" spread="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Multiplate ADP Test</title>
        <description>Platelet activation by adenosine diphosphate (ADP) expressed in arbitrary aggregation units (U). P2Y12 inhibitors block ADP receptors and decrease platelet activation by ADP. Higher values mean less effect of P2Y12 inhibitors, lower values mean more effect of P2Y12 inhibitors on platelets.&#xD;
High on-treatment platelet reactivity was defined as &gt;46 U.</description>
        <time_frame>12 hours after P2Y12 inhibitor loading</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Clopidogrel</title>
            <description>These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.</description>
          </group>
          <group group_id="O2">
            <title>Ticagrelor</title>
            <description>These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.</description>
          </group>
        </group_list>
        <measure>
          <title>Multiplate ADP Test</title>
          <description>Platelet activation by adenosine diphosphate (ADP) expressed in arbitrary aggregation units (U). P2Y12 inhibitors block ADP receptors and decrease platelet activation by ADP. Higher values mean less effect of P2Y12 inhibitors, lower values mean more effect of P2Y12 inhibitors on platelets.&#xD;
High on-treatment platelet reactivity was defined as &gt;46 U.</description>
          <units>U</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28" spread="17"/>
                    <measurement group_id="O2" value="15" spread="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From the date of randomization until hospital discharge or death during hospitalization.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Clopidogrel</title>
          <description>These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.</description>
        </group>
        <group group_id="E2">
          <title>Ticagrelor</title>
          <description>These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="16"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebrovascular insult</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Bleeding Academic Research Consortium (BARC) 3a and 5</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Stent thrombosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Minor bleeding</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Bradycardia/asystoly</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Ventricular tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Aspiration Pneumonia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="16"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Arterial embolism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Did not address effectiveness of prasugrel. Not powered to address stent thrombosis or bleeding.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Marko Noc</name_or_title>
      <organization>UMC Ljubljana</organization>
      <phone>+386 1 522 22 96</phone>
      <email>marko.noc@mf.uni-lj.si</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02224274
org study id: Hypothermia: Clopi vs Tica
nct id: NCT02224274
lead sponsor: 
has dmc: No
There is growing evidence that standard dual antiplatelet therapy with acetylsalicylic acid
      (ASA) and clopidogrel is not as effective in the setting of therapeutic hypothermia after
      cardiac arrest as in normothermic patients. The reasons for this are probably slower
      gastrointestinal motility, absorption and liver metabolism required for clopidogrel to take
      action. Since ticagrelor has faster intestinal absorption and no need for liver metabolism we
      expect its effect to be good even in patients with therapeutic hypothermia after cardiac
      arrest. Patients treated with therapeutic hypothermia after cardiac arrest and percutaneous
      coronary intervention will be randomised into two groups. One will be treated with ASA and
      clopidogrel and the other with ASA and ticagrelor. Blood samples will be collected before and
      2, 4, 12, 22 and 48 hours after P2Y12 inhibitor administration. Platelet function will be
      measured by VerifyNow P2Y12 assay and by Multiplate ADPTest. Differences between the groups
      will be analysed.

      Hypothesis: Antiplatelet therapy with ticagrelor is more effective than therapy with
      clopidogrel in the comatose survivors of cardiac arrest treated with therapeutic hypothermia
      and percutaneous coronary intervention (PCI).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: VerifyNow P2Y12Test - Platelet Reactivity
time frame: 12 h after P2Y12 inhibitor loading
description: Platelet reactivity reflects P2Y12 inhibitor effect. Higher values mean normal platelet reactivity due to low P2Y12 inhibition response, while lower values mean decreased platelet reactivity due to the effect of a P2Y12 inhibitor. High on-treatment platelet reactivity was defined as >208 PRU.
measure: VerifyNow P2Y12Test - % Inhibition
time frame: 12 hours after P2Y12 inhibitor loading
description: % inhibition reflects P2Y12 inhibitor effect regarding basal platelet reactivity (defined as: (1- (platelet reactivity/basal platelet reactivity)) x 100). Higher values mean better P2Y12 inhibition response. High on-treatment platelet reactivity was defined as <11% inhibition.
measure: Multiplate ADP Test
time frame: 12 hours after P2Y12 inhibitor loading
description: Platelet activation by adenosine diphosphate (ADP) expressed in arbitrary aggregation units (U). P2Y12 inhibitors block ADP receptors and decrease platelet activation by ADP. Higher values mean less effect of P2Y12 inhibitors, lower values mean more effect of P2Y12 inhibitors on platelets.
High on-treatment platelet reactivity was defined as >46 U.
arm group label: Clopidogrel
arm group type: Active Comparator
description: These patients will be treated with clopidogrel 600 mg loading and than 75 mg/24 h.
arm group label: Ticagrelor
arm group type: Experimental
description: These patients will be treated with ticagrelor 180 mg loading and than 90 mg/12 h.
intervention type: Drug
intervention name: Clopidogrel
arm group label: Clopidogrel
other name: Clopidogrel (Plavix)
intervention type: Drug
intervention name: Ticagrelor
arm group label: Ticagrelor
other name: Ticagrelor (Brilique)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Slovenia
citation: Steblovnik K, Blinc A, Bozic-Mijovski M, Kranjec I, Melkic E, Noc M. Platelet reactivity in comatose survivors of cardiac arrest undergoing percutaneous coronary intervention and hypothermia. EuroIntervention. 2015 Apr;10(12):1418-24. doi: 10.4244/EIJY14M05_02.
PMID: 24800722
citation: Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Gurbel PA, Xu K, Parise H, Kirtane AJ, Brodie BR, Mehran R, Stuckey TD; ADAPT-DES Investigators. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013 Aug 17;382(9892):614-23. doi: 10.1016/S0140-6736(13)61170-8. Epub 2013 Jul 26. Erratum In: Lancet. 2014 Mar 29;383(9923):1128.
PMID: 23890998
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: Gorjup V, Radsel P, Kocjancic ST, Erzen D, Noc M. Acute ST-elevation myocardial infarction after successful cardiopulmonary resuscitation. Resuscitation. 2007 Mar;72(3):379-85. doi: 10.1016/j.resuscitation.2006.07.013. Epub 2006 Dec 11.
PMID: 17161902
citation: Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002 Feb 21;346(8):557-63. doi: 10.1056/NEJMoa003289.
PMID: 11856794
citation: Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos K, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G. Response to letter regarding article, "Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction". Circ Cardiovasc Interv. 2013 Apr;6(2):e29. doi: 10.1161/CIRCINTERVENTIONS.113.000134. No abstract available.
PMID: 23591428
citation: Souckova L, Opatrilova R, Suk P, Cundrle I Jr, Pavlik M, Zvonicek V, Hlinomaz O, Sramek V. Impaired bioavailability and antiplatelet effect of high-dose clopidogrel in patients after cardiopulmonary resuscitation (CPR). Eur J Clin Pharmacol. 2013 Mar;69(3):309-17. doi: 10.1007/s00228-012-1360-0. Epub 2012 Aug 14.
PMID: 22890586
citation: Bjelland TW, Hjertner O, Klepstad P, Kaisen K, Dale O, Haugen BO. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation. 2010 Dec;81(12):1627-31. doi: 10.1016/j.resuscitation.2010.07.002. Epub 2010 Aug 19.
PMID: 20727659
citation: Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009 Jul;37(7 Suppl):S186-202. doi: 10.1097/CCM.0b013e3181aa5241.
PMID: 19535947
responsible party type: Principal Investigator
investigator affiliation: University Medical Centre Ljubljana
investigator full name: Marko Noc
investigator title: Marko Noc, MD, PhD
mesh term: Myocardial Infarction
mesh term: Heart Arrest
mesh term: ST Elevation Myocardial Infarction
mesh term: Non-ST Elevated Myocardial Infarction
mesh term: Infarction
mesh term: Clopidogrel
mesh term: Ticagrelor
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Did not address effectiveness of prasugrel. Not powered to address stent thrombosis or bleeding.
point of contact: 