<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/NCT03039205</url>
  </required_header>
  <id_info>
    <org_study_id>FAPESP 2014/01021-4</org_study_id>
    <secondary_id>4086/14/066</secondary_id>
    <nct_id>NCT03039205</nct_id>
  </id_info>
  <brief_title>Platelet Aggregation in Patients With Coronary Artery Disease and Kidney Dysfunction Taking Clopidogrel or Ticagrelor</brief_title>
  <official_title>Evaluation of Platelet Aggregation and Adenosine Levels in Patients With Coronary Artery Disease and Chronic Kidney Dysfunction Taking Dual Antiplatelet Therapy With Aspirin and Clopidogrel or Ticagrelor</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Sao Paulo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fundação de Amparo à Pesquisa do Estado de São Paulo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Sao Paulo</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      About 35% of patients hospitalized with Acute Coronary Syndromes (ACS) have some degree of&#xD;
      renal dysfunction. Chronic kidney disease (CKD) is not only associated to worse prognosis in&#xD;
      ACS patients, but leads also to an increased risk of bleeding, which may importantly&#xD;
      influence the risk-benefit ratio of antiplatelet therapy in this population. The responsible&#xD;
      mechanisms for increased rate of ischemic events in this population are not completely&#xD;
      elucidated.&#xD;
&#xD;
      Antiplatelet therapy is of paramount importance in the treatment of ACS, but its benefit in&#xD;
      CKD patients is not well established. This population is often excluded or underrepresented&#xD;
      in large clinical trials, and the indication of antiplatelet therapy is often extrapolated&#xD;
      from studies in patients with preserved renal function. In recent meta-analysis, Palmer et&#xD;
      al. sought to evaluate the benefits and risks of antiplatelet agents in patients with CKD and&#xD;
      concluded that in patients with ACS or scheduled for angioplasty already taking aspirin, the&#xD;
      addition of clopidogrel or glycoprotein IIb / IIIa inhibitors have little or no impact in&#xD;
      reducing the incidence of myocardial infarction, death or need for revascularization.&#xD;
&#xD;
      In the PLATO trial, ticagrelor (a new reversible inhibitor of P2Y12 receptor with faster&#xD;
      onset of action and greater platelet inhibition) was compared to clopidogrel in patients with&#xD;
      high risk ACS and was associated to a 16% risk reduction on the occurrence of death from&#xD;
      vascular causes, myocardial infarction, or stroke. In a pre-specified sub-analysis, data from&#xD;
      patients with CKD were compared to those obtained from the population with normal renal&#xD;
      function and suggests that the benefit of ticagrelor may be even greater in patients with&#xD;
      CKD. Two hypotheses were considered to explain these results:&#xD;
&#xD;
        1. Greater and more consistent platelet inhibition achieved with ticagrelor would be more&#xD;
           effective in reducing ischemic events in this population at increased thrombotic risk;&#xD;
&#xD;
        2. Pleiotropic effects of ticagrelor besides inhibition of the P2Y12 receptor. Ticagrelor&#xD;
           might be associated with an elevation in serum levels of adenosine. This could improve&#xD;
           myocardial perfusion through coronary vasodilation, and this effect would be more&#xD;
           pronounced in patients with renal dysfunction.&#xD;
&#xD;
      This project aims to validate (or not) these hypotheses, analyzing platelet aggregation and&#xD;
      circulating adenosine levels in patients taking dual antiplatelet therapy with aspirin and&#xD;
      clopidogrel or ticagrelor.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Previous publications demonstrated that about 35% to 40% of patients hospitalized with Acute&#xD;
      Coronary Syndromes (ACS) have some degree of renal dysfunction. On the other hand, chronic&#xD;
      kidney disease (CKD) is not only associated to worse prognosis in ACS patients, but leads&#xD;
      also to an increased risk of bleeding, which may importantly influence the risk-benefit ratio&#xD;
      of antiplatelet therapy in this population. Even at early stages, CKD increases the risk of&#xD;
      myocardial infarction and death among different spectra of ACS, and the risk increase is&#xD;
      directly proportional to the degree of renal dysfunction. The responsible mechanisms for the&#xD;
      increased rate of ischemic events in this population are not completely elucidated. However,&#xD;
      accelerated atherosclerosis, oxidative stress, inflammation and increased platelet&#xD;
      aggregation, as well as underutilization of therapies such as antithrombotic agents and&#xD;
      invasive procedures, are some of the proposed mechanisms.&#xD;
&#xD;
      Antiplatelet therapy is of paramount importance in the treatment of ACS, but its benefit in&#xD;
      CKD patients is not well established. The fact that this population is often excluded or&#xD;
      underrepresented in large clinical trials, makes the indication for its use be very often&#xD;
      extrapolated from studies in patients with preserved renal function.&#xD;
&#xD;
      In recent meta-analysis, Palmer et al. sought to summarize the benefits and risks of&#xD;
      antiplatelet agents in patients with CKD, focusing on the occurrence of cardiovascular events&#xD;
      (including mortality) and bleeding. The results led them to conclude that: 1) the evidence&#xD;
      for the use of antiplatelet agents in patients with CKD and cardiovascular disease is of low&#xD;
      quality, 2) in patients with ACS or scheduled for angioplasty already taking acetylsalicylic&#xD;
      acid (ASA), the addition of clopidogrel or glycoprotein IIb / IIIa inhibitors have little or&#xD;
      no impact in reducing the incidence of myocardial infarction, death or need for&#xD;
      revascularization, and 3) there was a significant 40% increase in the incidence of major&#xD;
      bleeding.&#xD;
&#xD;
      In the PLATO trial - &quot;Ticagrelor versus Clopidogrel in Patients with Acute Coronary&#xD;
      Syndromes&quot; - ticagrelor, a new reversible inhibitor of the P2Y12 receptor with faster onset&#xD;
      of action and greater platelet inhibition power was compared to clopidogrel in over 18,000&#xD;
      patients with high risk ACS. In this publication, patients receiving ticagrelor had a 16%&#xD;
      risk reduction on the occurrence of primary composite endpoint (death from vascular causes,&#xD;
      myocardial infarction or stroke) without significant increase in the incidence of major&#xD;
      bleeding. In a secondary outcome analysis, it was found a significant reduction in mortality&#xD;
      from vascular causes and mortality from any cause in patients treated with ticagrelor. Among&#xD;
      the high-risk criteria used in the selection of patients for this study, a creatinine&#xD;
      clearance &lt;60 ml/min/1.73 m2 was included.&#xD;
&#xD;
      In a following article, considering a pre-specified sub-analysis from the PLATO trial, the&#xD;
      results of 3,237 patients who had this high-risk criterion were compared to those obtained&#xD;
      for the population with normal renal function. The developed comparisons suggest that the&#xD;
      benefit of ticagrelor may be even greater in patients with CKD: when considering the MDRD&#xD;
      equation to estimate renal function, the hazard-ratio (HR) for the primary outcome of the&#xD;
      study was 0.71 for patients with renal impairment (creatinine clearance &lt;60 ml/min/1.73m2)&#xD;
      and 0.90 for those without renal dysfunction (p = 0.03 for interaction). Furthermore, the HRs&#xD;
      for mortality were, respectively, 0.79 and 0.91 for patients with and without renal&#xD;
      dysfunction (P = 0.02 for interaction). Interestingly, no significant difference between&#xD;
      groups relatively to major bleeding was observed, and the incidence of dyspnea was higher in&#xD;
      the population without renal dysfunction.&#xD;
&#xD;
      Two hypotheses were considered to explain these results. The first suggests that a greater&#xD;
      and more consistent platelet inhibition achieved with ticagrelor would be more effective in&#xD;
      reducing ischemic events in this population at increased thrombotic risk. The second&#xD;
      hypothesis considers possible pleiotropic effects of ticagrelor besides the reversible&#xD;
      inhibition of the P2Y12 receptor. Ticagrelor might be associated with an elevation in serum&#xD;
      levels of adenosine through the inhibition of its reuptake by erythrocytes and by increased&#xD;
      release of adenosine triphosphate (ATP) from the same erythrocytes, subsequently converted in&#xD;
      adenosine by ecto-ATPases. An increase in the concentrations of circulating adenosine could&#xD;
      improve myocardial perfusion through coronary vasodilation, and this effect would be more&#xD;
      pronounced in patients with renal dysfunction.&#xD;
&#xD;
      Thus, this project aims to validate (or not) these hypotheses, analyzing platelet aggregation&#xD;
      and circulating adenosine levels in patients taking dual antiplatelet therapy with aspirin&#xD;
      and clopidogrel or ticagrelor.&#xD;
&#xD;
      # Safety: as this protocol was designed for a short-term duration, we do not expect to have&#xD;
      many adverse events (AE). An AE is any untoward medical occurrence in a participant that does&#xD;
      not necessarily have a causal relationship with the study intervention. An AE can therefore&#xD;
      be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or&#xD;
      disease temporally associated with the use of a medical treatment or procedure regardless of&#xD;
      whether it is considered related to the medical treatment or procedure. AEs will be reported&#xD;
      as soon as possible.&#xD;
&#xD;
      Serious adverse events (SAE) are defined as any untoward medical occurrence that meets any&#xD;
      one of the following criteria:&#xD;
&#xD;
        1. Results in death or is life-threatening at the time of the event;&#xD;
&#xD;
        2. Requires inpatient hospitalization, or prolongs a hospitalization;&#xD;
&#xD;
        3. Results in a persistent or significant disability/incapacity;&#xD;
&#xD;
        4. Is a congenital anomaly/birth defect (in a participants offspring); or&#xD;
&#xD;
        5. Is medically judged to be an important event that jeopardized the subject and, for&#xD;
           example, required significant measures to avoid one of the above outcomes.&#xD;
&#xD;
      SAEs will be reported within 24 hours of its information received. The causality of SAEs&#xD;
      (their relationship to all study treatment/procedures) will be assessed by the&#xD;
      investigator(s) and the investigator is responsible for informing the local authorities and&#xD;
      ethical committees, of any serious adverse events as per local requirements.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 7, 2017</start_date>
  <completion_date type="Actual">December 19, 2019</completion_date>
  <primary_completion_date type="Actual">December 19, 2019</primary_completion_date>
  <phase>Phase 2</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>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Platelet aggregation evaluated by VerifyNow® P2Y12 (difference between clopidogrel and ticagrelor) in patients with and without renal dysfunction randomized to treatment with either clopidogrel or ticagrelor</measure>
    <time_frame>8 days (±1)</time_frame>
    <description>Compare the level of inhibition of platelet aggregation evaluated by VerifyNow® P2Y12 (difference between clopidogrel and ticagrelor) in patients with coronary artery disease with and without renal dysfunction undergoing treatment with ASA in combination with clopidogrel or ticagrelor.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adenosine plasma concentration evaluated by isocratic high-performance liquid chromatographic technique, in patients with and without renal dysfunction randomized to treatment with either clopidogrel or ticagrelor.</measure>
    <time_frame>8 days (±1)</time_frame>
    <description>Compare adenosine plasma concentration evaluated by isocratic high-performance liquid chromatographic technique, in patients with coronary artery disease with and without renal dysfunction undergoing treatment with ASA in combination with clopidogrel or ticagrelor.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Platelet aggregation (difference between clopidogrel and ticagrelor) evaluated by Multiple electrode platelet aggregometry (Multiplate®) in patients with and without renal dysfunction randomized to treatment with either clopidogrel or ticagrelor</measure>
    <time_frame>8 days (±1)</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Lipoprotein-a - Lp(a) concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Hemoglobin concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Leukocytes concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Platelet count in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Prothrombin time in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Activated partial thromboplastin time in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Creatinine concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Urea concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Total and free cholesterol concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Free fatty acids concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Cholesterol-ester transfer protein activity in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>LDL-cholesterol concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>HDL cholesterol concentration, size and transport in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Triglycerides concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Fasting glucose concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Glycated hemoglobin in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Ultra-sensitive C-reactive protein (usCRP) concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Interleukin-6 (IL-6) concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Plasminogen activator inhibitor (PAI-1) concentration in the groups with or without renal dysfunction</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: gender (male x female)</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: diabetes (present or absent)</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: smoking status (yes or no)</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: hypertension (presence or absence)</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: levels of LDL (&lt;70 or ≥ 70 mg / dl)</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: elderly and non-elderly (≥ or &lt;75 years)</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: weight (&lt;or ≥ 60 kg)</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: body mass index (&lt;30 or ≥ 30kg/m2)</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: creatinine clearance (≥60 ml/min, &lt;60 to 30 ml/min and &lt;30 ml/min).</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Analyze the influence of angiotensin converting enzyme inhibitors or angiotensin receptor subtype 1 (AT1) blockers on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Analyze the influence of oral hypoglycemic agents on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Analyze the influence of insulin on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Analyze the influence of beta-blockers on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Analyze the influence of proton pump inhibitors (PPI) on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Analyze, in the studied groups with or without renal dysfunction, the incidence of dyspnea.</measure>
    <time_frame>8 days (±1)</time_frame>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Platelet Aggregation</condition>
  <condition>Adenosine</condition>
  <condition>Coronary Artery Disease</condition>
  <condition>Kidney Dysfunction</condition>
  <condition>Antiplatelet Therapy</condition>
  <arm_group>
    <arm_group_label>Chronic kidney dysfunction Clopidogrel</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with creatinine clearance &lt;60ml/min/m2 (estimated by MDRD formula) randomized to clopidogrel group</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chronic kidney dysfunction Ticagrelor</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with creatinine clearance &lt;60ml/min/m2 (estimated by MDRD formula) randomized to ticagrelor group</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal kidney function Clopidogrel</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with creatinine clearance ≥60ml/min/m2 (estimated by MDRD formula) randomized to clopidogrel group</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal kidney function Ticagrelor</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with creatinine clearance ≥60ml/min/m2 (estimated by MDRD formula) randomized to ticagrelor group</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clopidogrel</intervention_name>
    <description>Clopidogrel 600 mg loading dose + 75 mg q.d. for 7 to 9 days</description>
    <arm_group_label>Chronic kidney dysfunction Clopidogrel</arm_group_label>
    <arm_group_label>Normal kidney function Clopidogrel</arm_group_label>
    <other_name>Plavix</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ticagrelor</intervention_name>
    <description>Ticagrelor 180 mg loading dose + 90 mg b.i.d. for 7 to 9 days</description>
    <arm_group_label>Chronic kidney dysfunction Ticagrelor</arm_group_label>
    <arm_group_label>Normal kidney function Ticagrelor</arm_group_label>
    <other_name>Brilinta</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients in use of aspirin for at least 7 days prior to randomization;&#xD;
&#xD;
          -  Documented obstructive coronary artery disease by angiography;&#xD;
&#xD;
          -  At least 12 months from the last episode of myocardial infarction (MI);&#xD;
&#xD;
          -  Agree to sign the Informed Consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior ischemic or hemorrhagic stroke;&#xD;
&#xD;
          -  Prior intracranial bleeding;&#xD;
&#xD;
          -  Use of oral anticoagulant in the past month;&#xD;
&#xD;
          -  Use of dual antiplatelet therapy in the last 30 days;&#xD;
&#xD;
          -  Use of NSAIDs and / or dipyridamole in the past month;&#xD;
&#xD;
          -  Mandatory use of proton pump inhibitor;&#xD;
&#xD;
          -  Known platelet dysfunction or platelets &lt;100,000 or &gt;450,000/μL;&#xD;
&#xD;
          -  End-stage renal disease undergoing hemodialysis;&#xD;
&#xD;
          -  Terminal illness;&#xD;
&#xD;
          -  Known liver disease or coagulation disorder;&#xD;
&#xD;
          -  Known pregnancy, breast-feeding, or intend to become pregnant during the study period;&#xD;
&#xD;
          -  Hypersensitivity to clopidogrel, ticagrelor or any excipients;&#xD;
&#xD;
          -  Refusal to sign the Informed Consent;&#xD;
&#xD;
          -  Active pathological bleeding.&#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>José C Nicolau, M.D. / PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Heart Institute (InCor) / University of São Paulo</affiliation>
  </overall_official>
  <overall_official>
    <last_name>André Franci, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Heart Institute (InCor) / University of São Paulo</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Instituto do Coração (InCor) - Hospital das Clínicas da FMUSP</name>
      <address>
        <city>Sao Paulo</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <link>
    <url>http://link.springer.com/article/10.1007/BF02290317</url>
    <description>Isocratic high-performance liquid chromatographic determination of plasma adenosine</description>
  </link>
  <reference>
    <citation>Al Suwaidi J, Reddan DN, Williams K, Pieper KS, Harrington RA, Califf RM, Granger CB, Ohman EM, Holmes DR Jr; GUSTO-IIb, GUSTO-III, PURSUIT. Global Use of Strategies to Open Occluded Coronary Arteries. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; PARAGON-A Investigators. Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network. Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes. Circulation. 2002 Aug 20;106(8):974-80. doi: 10.1161/01.cir.0000027560.41358.b3.</citation>
    <PMID>12186803</PMID>
  </reference>
  <reference>
    <citation>Freeman RV, Mehta RH, Al Badr W, Cooper JV, Kline-Rogers E, Eagle KA. Influence of concurrent renal dysfunction on outcomes of patients with acute coronary syndromes and implications of the use of glycoprotein IIb/IIIa inhibitors. J Am Coll Cardiol. 2003 Mar 5;41(5):718-24. doi: 10.1016/s0735-1097(02)02956-x.</citation>
    <PMID>12628712</PMID>
  </reference>
  <reference>
    <citation>Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004 Sep 23;351(13):1285-95. doi: 10.1056/NEJMoa041365.</citation>
    <PMID>15385655</PMID>
  </reference>
  <reference>
    <citation>Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, Berger PB. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol. 2002 Apr 3;39(7):1113-9. doi: 10.1016/s0735-1097(02)01745-x.</citation>
    <PMID>11923033</PMID>
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    <citation>Ezekowitz J, McAlister FA, Humphries KH, Norris CM, Tonelli M, Ghali WA, Knudtson ML; APPROACH Investigators. The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol. 2004 Oct 19;44(8):1587-92. doi: 10.1016/j.jacc.2004.06.072.</citation>
    <PMID>15489090</PMID>
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    <citation>Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002 Jan 12;324(7329):71-86. doi: 10.1136/bmj.324.7329.71. Erratum In: BMJ 2002 Jan 19;324(7330):141.</citation>
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    <citation>Basra SS, Tsai P, Lakkis NM. Safety and efficacy of antiplatelet and antithrombotic therapy in acute coronary syndrome patients with chronic kidney disease. J Am Coll Cardiol. 2011 Nov 22;58(22):2263-9. doi: 10.1016/j.jacc.2011.08.051. Erratum In: J Am Coll Cardiol. 2012 Apr 17;59(16):1491.</citation>
    <PMID>22093501</PMID>
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    <citation>Palmer SC, Di Micco L, Razavian M, Craig JC, Perkovic V, Pellegrini F, Copetti M, Graziano G, Tognoni G, Jardine M, Webster A, Nicolucci A, Zoungas S, Strippoli GF. Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012 Mar 20;156(6):445-59. doi: 10.7326/0003-4819-156-6-201203200-00007.</citation>
    <PMID>22431677</PMID>
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    <citation>Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators; Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi: 10.1056/NEJMoa0904327. Epub 2009 Aug 30.</citation>
    <PMID>19717846</PMID>
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    <citation>James S, Budaj A, Aylward P, Buck KK, Cannon CP, Cornel JH, Harrington RA, Horrow J, Katus H, Keltai M, Lewis BS, Parikh K, Storey RF, Szummer K, Wojdyla D, Wallentin L. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2010 Sep 14;122(11):1056-67. doi: 10.1161/CIRCULATIONAHA.109.933796. Epub 2010 Aug 30.</citation>
    <PMID>20805430</PMID>
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    <citation>Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999 Mar 16;130(6):461-70. doi: 10.7326/0003-4819-130-6-199903160-00002.</citation>
    <PMID>10075613</PMID>
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    <citation>Ohman J, Kudira R, Albinsson S, Olde B, Erlinge D. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun. 2012 Feb 24;418(4):754-8. doi: 10.1016/j.bbrc.2012.01.093. Epub 2012 Jan 27.</citation>
    <PMID>22306816</PMID>
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    <PMID>19840579</PMID>
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    <citation>Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment. J Clin Pharmacol. 2012 Sep;52(9):1388-98. doi: 10.1177/0091270011415526. Epub 2011 Sep 29.</citation>
    <PMID>21960668</PMID>
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    <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>
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    <citation>Storey RF, Angiolillo DJ, Patil SB, Desai B, Ecob R, Husted S, Emanuelsson H, Cannon CP, Becker RC, Wallentin L. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol. 2010 Oct 26;56(18):1456-62. doi: 10.1016/j.jacc.2010.03.100.</citation>
    <PMID>20832963</PMID>
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    <citation>Sibbing D, Braun S, Jawansky S, Vogt W, Mehilli J, Schomig A, Kastrati A, von Beckerath N. Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thromb Haemost. 2008 Jan;99(1):121-6. doi: 10.1160/TH07-07-0478.</citation>
    <PMID>18217143</PMID>
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  <verification_date>April 2020</verification_date>
  <study_first_submitted>January 23, 2017</study_first_submitted>
  <study_first_submitted_qc>January 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 1, 2017</study_first_posted>
  <last_update_submitted>April 21, 2020</last_update_submitted>
  <last_update_submitted_qc>April 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Sao Paulo</investigator_affiliation>
    <investigator_full_name>Jose Carlos Nicolau</investigator_full_name>
    <investigator_title>Director</investigator_title>
  </responsible_party>
  <keyword>Platelet aggregation</keyword>
  <keyword>Adenosine</keyword>
  <keyword>Coronary artery disease</keyword>
  <keyword>Kidney dysfunction</keyword>
  <keyword>Ticagrelor</keyword>
  <keyword>Clopidogrel</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Renal Insufficiency</mesh_term>
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Coronary Disease</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>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03039205
org study id: FAPESP 2014/01021-4
secondary id: 4086/14/066
nct id: NCT03039205
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
About 35% of patients hospitalized with Acute Coronary Syndromes (ACS) have some degree of
      renal dysfunction. Chronic kidney disease (CKD) is not only associated to worse prognosis in
      ACS patients, but leads also to an increased risk of bleeding, which may importantly
      influence the risk-benefit ratio of antiplatelet therapy in this population. The responsible
      mechanisms for increased rate of ischemic events in this population are not completely
      elucidated.

      Antiplatelet therapy is of paramount importance in the treatment of ACS, but its benefit in
      CKD patients is not well established. This population is often excluded or underrepresented
      in large clinical trials, and the indication of antiplatelet therapy is often extrapolated
      from studies in patients with preserved renal function. In recent meta-analysis, Palmer et
      al. sought to evaluate the benefits and risks of antiplatelet agents in patients with CKD and
      concluded that in patients with ACS or scheduled for angioplasty already taking aspirin, the
      addition of clopidogrel or glycoprotein IIb / IIIa inhibitors have little or no impact in
      reducing the incidence of myocardial infarction, death or need for revascularization.

      In the PLATO trial, ticagrelor (a new reversible inhibitor of P2Y12 receptor with faster
      onset of action and greater platelet inhibition) was compared to clopidogrel in patients with
      high risk ACS and was associated to a 16% risk reduction on the occurrence of death from
      vascular causes, myocardial infarction, or stroke. In a pre-specified sub-analysis, data from
      patients with CKD were compared to those obtained from the population with normal renal
      function and suggests that the benefit of ticagrelor may be even greater in patients with
      CKD. Two hypotheses were considered to explain these results:

        1. Greater and more consistent platelet inhibition achieved with ticagrelor would be more
           effective in reducing ischemic events in this population at increased thrombotic risk;

        2. Pleiotropic effects of ticagrelor besides inhibition of the P2Y12 receptor. Ticagrelor
           might be associated with an elevation in serum levels of adenosine. This could improve
           myocardial perfusion through coronary vasodilation, and this effect would be more
           pronounced in patients with renal dysfunction.

      This project aims to validate (or not) these hypotheses, analyzing platelet aggregation and
      circulating adenosine levels in patients taking dual antiplatelet therapy with aspirin and
      clopidogrel or ticagrelor.
Previous publications demonstrated that about 35% to 40% of patients hospitalized with Acute
      Coronary Syndromes (ACS) have some degree of renal dysfunction. On the other hand, chronic
      kidney disease (CKD) is not only associated to worse prognosis in ACS patients, but leads
      also to an increased risk of bleeding, which may importantly influence the risk-benefit ratio
      of antiplatelet therapy in this population. Even at early stages, CKD increases the risk of
      myocardial infarction and death among different spectra of ACS, and the risk increase is
      directly proportional to the degree of renal dysfunction. The responsible mechanisms for the
      increased rate of ischemic events in this population are not completely elucidated. However,
      accelerated atherosclerosis, oxidative stress, inflammation and increased platelet
      aggregation, as well as underutilization of therapies such as antithrombotic agents and
      invasive procedures, are some of the proposed mechanisms.

      Antiplatelet therapy is of paramount importance in the treatment of ACS, but its benefit in
      CKD patients is not well established. The fact that this population is often excluded or
      underrepresented in large clinical trials, makes the indication for its use be very often
      extrapolated from studies in patients with preserved renal function.

      In recent meta-analysis, Palmer et al. sought to summarize the benefits and risks of
      antiplatelet agents in patients with CKD, focusing on the occurrence of cardiovascular events
      (including mortality) and bleeding. The results led them to conclude that: 1) the evidence
      for the use of antiplatelet agents in patients with CKD and cardiovascular disease is of low
      quality, 2) in patients with ACS or scheduled for angioplasty already taking acetylsalicylic
      acid (ASA), the addition of clopidogrel or glycoprotein IIb / IIIa inhibitors have little or
      no impact in reducing the incidence of myocardial infarction, death or need for
      revascularization, and 3) there was a significant 40% increase in the incidence of major
      bleeding.

      In the PLATO trial - "Ticagrelor versus Clopidogrel in Patients with Acute Coronary
      Syndromes" - ticagrelor, a new reversible inhibitor of the P2Y12 receptor with faster onset
      of action and greater platelet inhibition power was compared to clopidogrel in over 18,000
      patients with high risk ACS. In this publication, patients receiving ticagrelor had a 16%
      risk reduction on the occurrence of primary composite endpoint (death from vascular causes,
      myocardial infarction or stroke) without significant increase in the incidence of major
      bleeding. In a secondary outcome analysis, it was found a significant reduction in mortality
      from vascular causes and mortality from any cause in patients treated with ticagrelor. Among
      the high-risk criteria used in the selection of patients for this study, a creatinine
      clearance <60 ml/min/1.73 m2 was included.

      In a following article, considering a pre-specified sub-analysis from the PLATO trial, the
      results of 3,237 patients who had this high-risk criterion were compared to those obtained
      for the population with normal renal function. The developed comparisons suggest that the
      benefit of ticagrelor may be even greater in patients with CKD: when considering the MDRD
      equation to estimate renal function, the hazard-ratio (HR) for the primary outcome of the
      study was 0.71 for patients with renal impairment (creatinine clearance <60 ml/min/1.73m2)
      and 0.90 for those without renal dysfunction (p = 0.03 for interaction). Furthermore, the HRs
      for mortality were, respectively, 0.79 and 0.91 for patients with and without renal
      dysfunction (P = 0.02 for interaction). Interestingly, no significant difference between
      groups relatively to major bleeding was observed, and the incidence of dyspnea was higher in
      the population without renal dysfunction.

      Two hypotheses were considered to explain these results. The first suggests that a greater
      and more consistent platelet inhibition achieved with ticagrelor would be more effective in
      reducing ischemic events in this population at increased thrombotic risk. The second
      hypothesis considers possible pleiotropic effects of ticagrelor besides the reversible
      inhibition of the P2Y12 receptor. Ticagrelor might be associated with an elevation in serum
      levels of adenosine through the inhibition of its reuptake by erythrocytes and by increased
      release of adenosine triphosphate (ATP) from the same erythrocytes, subsequently converted in
      adenosine by ecto-ATPases. An increase in the concentrations of circulating adenosine could
      improve myocardial perfusion through coronary vasodilation, and this effect would be more
      pronounced in patients with renal dysfunction.

      Thus, this project aims to validate (or not) these hypotheses, analyzing platelet aggregation
      and circulating adenosine levels in patients taking dual antiplatelet therapy with aspirin
      and clopidogrel or ticagrelor.

      # Safety: as this protocol was designed for a short-term duration, we do not expect to have
      many adverse events (AE). An AE is any untoward medical occurrence in a participant that does
      not necessarily have a causal relationship with the study intervention. An AE can therefore
      be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or
      disease temporally associated with the use of a medical treatment or procedure regardless of
      whether it is considered related to the medical treatment or procedure. AEs will be reported
      as soon as possible.

      Serious adverse events (SAE) are defined as any untoward medical occurrence that meets any
      one of the following criteria:

        1. Results in death or is life-threatening at the time of the event;

        2. Requires inpatient hospitalization, or prolongs a hospitalization;

        3. Results in a persistent or significant disability/incapacity;

        4. Is a congenital anomaly/birth defect (in a participants offspring); or

        5. Is medically judged to be an important event that jeopardized the subject and, for
           example, required significant measures to avoid one of the above outcomes.

      SAEs will be reported within 24 hours of its information received. The causality of SAEs
      (their relationship to all study treatment/procedures) will be assessed by the
      investigator(s) and the investigator is responsible for informing the local authorities and
      ethical committees, of any serious adverse events as per local requirements.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Platelet aggregation evaluated by VerifyNow® P2Y12 (difference between clopidogrel and ticagrelor) in patients with and without renal dysfunction randomized to treatment with either clopidogrel or ticagrelor
time frame: 8 days (±1)
description: Compare the level of inhibition of platelet aggregation evaluated by VerifyNow® P2Y12 (difference between clopidogrel and ticagrelor) in patients with coronary artery disease with and without renal dysfunction undergoing treatment with ASA in combination with clopidogrel or ticagrelor.
measure: Adenosine plasma concentration evaluated by isocratic high-performance liquid chromatographic technique, in patients with and without renal dysfunction randomized to treatment with either clopidogrel or ticagrelor.
time frame: 8 days (±1)
description: Compare adenosine plasma concentration evaluated by isocratic high-performance liquid chromatographic technique, in patients with coronary artery disease with and without renal dysfunction undergoing treatment with ASA in combination with clopidogrel or ticagrelor.
measure: Platelet aggregation (difference between clopidogrel and ticagrelor) evaluated by Multiple electrode platelet aggregometry (Multiplate®) in patients with and without renal dysfunction randomized to treatment with either clopidogrel or ticagrelor
time frame: 8 days (±1)
measure: Lipoprotein-a - Lp(a) concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Hemoglobin concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Leukocytes concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Platelet count in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Prothrombin time in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Activated partial thromboplastin time in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Creatinine concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Urea concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Total and free cholesterol concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Free fatty acids concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Cholesterol-ester transfer protein activity in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: LDL-cholesterol concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: HDL cholesterol concentration, size and transport in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Triglycerides concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Fasting glucose concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Glycated hemoglobin in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Ultra-sensitive C-reactive protein (usCRP) concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Interleukin-6 (IL-6) concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Plasminogen activator inhibitor (PAI-1) concentration in the groups with or without renal dysfunction
time frame: 8 days (±1)
measure: Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: gender (male x female)
time frame: 8 days (±1)
measure: Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: diabetes (present or absent)
time frame: 8 days (±1)
measure: Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: smoking status (yes or no)
time frame: 8 days (±1)
measure: Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: hypertension (presence or absence)
time frame: 8 days (±1)
measure: Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: levels of LDL (<70 or ≥ 70 mg / dl)
time frame: 8 days (±1)
measure: Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: elderly and non-elderly (≥ or <75 years)
time frame: 8 days (±1)
measure: Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: weight (<or ≥ 60 kg)
time frame: 8 days (±1)
measure: Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: body mass index (<30 or ≥ 30kg/m2)
time frame: 8 days (±1)
measure: Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: creatinine clearance (≥60 ml/min, <60 to 30 ml/min and <30 ml/min).
time frame: 8 days (±1)
measure: Analyze the influence of angiotensin converting enzyme inhibitors or angiotensin receptor subtype 1 (AT1) blockers on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration
time frame: 8 days (±1)
measure: Analyze the influence of oral hypoglycemic agents on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration
time frame: 8 days (±1)
measure: Analyze the influence of insulin on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration
time frame: 8 days (±1)
measure: Analyze the influence of beta-blockers on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration
time frame: 8 days (±1)
measure: Analyze the influence of proton pump inhibitors (PPI) on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration
time frame: 8 days (±1)
measure: Analyze, in the studied groups with or without renal dysfunction, the incidence of dyspnea.
time frame: 8 days (±1)
arm group label: Chronic kidney dysfunction Clopidogrel
arm group type: Active Comparator
description: Patients with creatinine clearance <60ml/min/m2 (estimated by MDRD formula) randomized to clopidogrel group
arm group label: Chronic kidney dysfunction Ticagrelor
arm group type: Active Comparator
description: Patients with creatinine clearance <60ml/min/m2 (estimated by MDRD formula) randomized to ticagrelor group
arm group label: Normal kidney function Clopidogrel
arm group type: Active Comparator
description: Patients with creatinine clearance ≥60ml/min/m2 (estimated by MDRD formula) randomized to clopidogrel group
arm group label: Normal kidney function Ticagrelor
arm group type: Active Comparator
description: Patients with creatinine clearance ≥60ml/min/m2 (estimated by MDRD formula) randomized to ticagrelor group
intervention type: Drug
intervention name: Clopidogrel
description: Clopidogrel 600 mg loading dose + 75 mg q.d. for 7 to 9 days
arm group label: Chronic kidney dysfunction Clopidogrel
arm group label: Normal kidney function Clopidogrel
other name: Plavix
intervention type: Drug
intervention name: Ticagrelor
description: Ticagrelor 180 mg loading dose + 90 mg b.i.d. for 7 to 9 days
arm group label: Chronic kidney dysfunction Ticagrelor
arm group label: Normal kidney function Ticagrelor
other name: Brilinta
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: José C Nicolau, M.D. / PhD
role: Study Chair
affiliation: Heart Institute (InCor) / University of São Paulo
last name: André Franci, M.D.
role: Principal Investigator
affiliation: Heart Institute (InCor) / University of São Paulo
facility: 
country: Brazil
url: http://link.springer.com/article/10.1007/BF02290317
description: Isocratic high-performance liquid chromatographic determination of plasma adenosine
citation: Al Suwaidi J, Reddan DN, Williams K, Pieper KS, Harrington RA, Califf RM, Granger CB, Ohman EM, Holmes DR Jr; GUSTO-IIb, GUSTO-III, PURSUIT. Global Use of Strategies to Open Occluded Coronary Arteries. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; PARAGON-A Investigators. Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network. Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes. Circulation. 2002 Aug 20;106(8):974-80. doi: 10.1161/01.cir.0000027560.41358.b3.
PMID: 12186803
citation: Freeman RV, Mehta RH, Al Badr W, Cooper JV, Kline-Rogers E, Eagle KA. Influence of concurrent renal dysfunction on outcomes of patients with acute coronary syndromes and implications of the use of glycoprotein IIb/IIIa inhibitors. J Am Coll Cardiol. 2003 Mar 5;41(5):718-24. doi: 10.1016/s0735-1097(02)02956-x.
PMID: 12628712
citation: Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004 Sep 23;351(13):1285-95. doi: 10.1056/NEJMoa041365.
PMID: 15385655
citation: Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, Berger PB. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol. 2002 Apr 3;39(7):1113-9. doi: 10.1016/s0735-1097(02)01745-x.
PMID: 11923033
citation: Fox CS, Muntner P, Chen AY, Alexander KP, Roe MT, Cannon CP, Saucedo JF, Kontos MC, Wiviott SD; Acute Coronary Treatment and Intervention Outcomes Network registry. Use of evidence-based therapies in short-term outcomes of ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction in patients with chronic kidney disease: a report from the National Cardiovascular Data Acute Coronary Treatment and Intervention Outcomes Network registry. Circulation. 2010 Jan 26;121(3):357-65. doi: 10.1161/CIRCULATIONAHA.109.865352. Epub 2010 Jan 11.
PMID: 20065168
citation: Ezekowitz J, McAlister FA, Humphries KH, Norris CM, Tonelli M, Ghali WA, Knudtson ML; APPROACH Investigators. The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol. 2004 Oct 19;44(8):1587-92. doi: 10.1016/j.jacc.2004.06.072.
PMID: 15489090
citation: Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002 Jan 12;324(7329):71-86. doi: 10.1136/bmj.324.7329.71. Erratum In: BMJ 2002 Jan 19;324(7330):141.
PMID: 11786451
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responsible party type: Principal Investigator
investigator affiliation: University of Sao Paulo
investigator full name: Jose Carlos Nicolau
investigator title: Director
mesh term: Renal Insufficiency
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Coronary Disease
mesh term: Clopidogrel
mesh term: Ticagrelor
sharing ipd: Undecided