<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/NCT02987712</url>
  </required_header>
  <id_info>
    <org_study_id>TASMC-16-IM-0703-CTIL</org_study_id>
    <nct_id>NCT02987712</nct_id>
  </id_info>
  <brief_title>Management of Coagulopathy in Cirrhotic Patients Undergoing Invasive Procedures</brief_title>
  <official_title>Management of Coagulopathy in Cirrhotic Patients Undergoing Invasive Procedures: a Prospective Trial Comparing Standard Management to Thromboelastography Protocol Based Management</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tel-Aviv Sourasky Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tel-Aviv Sourasky Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Recently it has been acknowledged that cirrhotic patients present with &quot;rebalanced&#xD;
      hemostasis&quot; that results from decreased levels of both pro-coagulant and anti-coagulant&#xD;
      factors, that is not well reflected by conventional coagulation tests (CCTs).&#xD;
      Thromboelastography (TEG) might be a more accurate tool in these patients.&#xD;
&#xD;
      Numerous guidelines on the management of the cirrhotic patient undergoing invasive procedures&#xD;
      have been published but most of them are not evidence based. Current literature, although&#xD;
      conflicting, is leaning towards a restrictive approach to prophylactic correction of&#xD;
      coagulopathy when performing invasive procedures in cirrhotic patients. The investigators&#xD;
      suspect that common practice is more liberal . Considering the well-known adverse effects of&#xD;
      blood product administration, the aim of the study is to re-evaluate the clinical management&#xD;
      of cirrhotic patients undergoing invasive procedures.&#xD;
&#xD;
      Study objectives: asserting whether the use of blood products prior to invasive procedures in&#xD;
      cirrhotic coagulopathic patients can be reduced using TEG to evaluate coagulopathy in place&#xD;
      of CCTs, evaluating the rate of complications due to blood product use, and checking how well&#xD;
      CCT results correlate with TEG results in these patients.&#xD;
&#xD;
      This will be a prospective pre/post TEG protocol implementation study which will include two&#xD;
      prospective surveys with a 1:1 ratio. Survey 1: prophylactic administration of FFP/PLT prior&#xD;
      to minor invasive procedures will be based on CCTs and physicians' clinical judgement. Survey&#xD;
      2: management will be based on a new TEG protocol. The investigators will include cirrhotic&#xD;
      patients with coagulopathy who are candidates for an invasive procedure. Subject will be&#xD;
      provided with sufficient time to reach a rational, informed decision regarding participation&#xD;
      in the study.&#xD;
&#xD;
      Data will be collected from the computer based medical record systems, the patient file and&#xD;
      directly from the caring physician and will include a thorough medical history and&#xD;
      conventional blood tests, including a TEG test. All subjects will be managed according to&#xD;
      standard of care.&#xD;
&#xD;
      Primary endpoint: amount of blood product (fresh frozen plasma/platelets) units transfused in&#xD;
      preparation for the invasive procedures.&#xD;
&#xD;
      Secondary endpoints: bleeding complications, transfusion related side effects, 90 day&#xD;
      survival and other complications.&#xD;
&#xD;
      This will be a prospective (pre/post) study. The calculated sample size needed is 120&#xD;
      subjects, 60 in each group.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
      Recently there has been a change of concept regarding the hemostatic profile of patients with&#xD;
      liver disease from &quot;auto-anti-coagulation&quot; to &quot;rebalanced hemostasis&quot;. The liver synthesizes&#xD;
      most of the factors and inhibitors of the coagulation system as well as thrombopoietin. Thus,&#xD;
      liver disease influences the hemostatic profile both through an effect on factor/inhibitor&#xD;
      levels and through an effect on platelet number and function. The &quot;rebalanced hemostasis&quot; of&#xD;
      liver disease results from decreased levels of most proteins involved in coagulation;&#xD;
      promotors and inhibitors. Two proteins which are elevated in this state are factor VIII and&#xD;
      von Willebrand factor. Elevated levels of the latter compensate to some extent for the&#xD;
      thrombocytopenia and platelet function defects. This &quot;rebalanced&quot; state is not well reflected&#xD;
      by conventional coagulation tests (CCT), which are insensitive to the anticoagulant component&#xD;
      of hemostasis. In fact, it has been shown that thrombin generation in cirrhotic patients is&#xD;
      normal. Considering this conceptual change together with the well-known adverse effects of&#xD;
      blood product administration the investigators seek to re-evaluate the clinical management of&#xD;
      cirrhotic patients undergoing invasive procedures.&#xD;
&#xD;
      Thromboelastography (TEG) provides a graphic representation of clot formation and lysis.&#xD;
      Compared with CCTs, TEG better reflects the interaction of plasma, blood cells and PLTs and&#xD;
      better resembles the in-vivo state. Viscoelastic tests have been used for many years for&#xD;
      coagulation monitoring and hemostatic therapy guidance during liver transplantation. Their&#xD;
      use in hospitalized patients with liver disease has been much more limited.&#xD;
&#xD;
      Different guidelines address the issue of coagulation test abnormalities in cirrhotic&#xD;
      patients prior to various specific invasive procedures. According to the European Association&#xD;
      for the Study of the Liver clinical practice guidelines, in cirrhosis, hemorrhagic&#xD;
      complications after large volume paracentesis (LVP) are infrequent and there is no data to&#xD;
      support pre-procedural use of fresh frozen plasma (FFP) or PLTs. The authors do note that&#xD;
      often these products are given in case of severe coagulopathy and/or thrombocytopenia, and&#xD;
      that caution should still be exercised in patients with severe coagulopathy, and LVP avoided&#xD;
      in the presence of disseminated intravascular coagulation. The American Association for the&#xD;
      Study of Liver Diseases practice guidelines state that because bleeding is uncommon, routine&#xD;
      administration of FFP or PLTs prior to paracentesis is not recommended.&#xD;
&#xD;
      Very few randomized, double-blind controlled clinical trials regarding the management of&#xD;
      coagulation issues in patients with liver disease exist. Some guidelines note that INR should&#xD;
      not be used alone to assess bleeding risk, that a PLT count greater than 50-60x10^9/L should&#xD;
      be achieved prior to high-risk procedures, and that TEG may be helpful in targeting&#xD;
      transfusion practice. Pertaining to esophageal varices, few data support the notion that&#xD;
      coagulopathy is directly related to bleeding risk, and despite the existence of various&#xD;
      specific guidelines on management of esophageal varices, specific recommendations on&#xD;
      coagulation parameters for prophylactic esophageal variceal band ligation (EVBL) are missing.&#xD;
      When prophylactic EVBL is deemed unsafe due to a coagulation disorder, they recommend&#xD;
      avoiding it. Although it is uncertain what the optimal platelet counts should be in this&#xD;
      situation, they recommend levels exceeding 56x10^9/L and possibly a fibrinogen level above&#xD;
      100-150 mg/dL. They note that FFP transfusion is problematic because of the large volume&#xD;
      needed to &quot;correct&quot; the INR.&#xD;
&#xD;
      Consensus guidelines for peri-procedural management of coagulation status and hemostasis risk&#xD;
      in percutaneous image-guided interventions conclude that central venous catheterization (CVC)&#xD;
      can be performed safely by experienced physicians in the presence of abnormal coagulation&#xD;
      parameters. According to an editorial in Chest, CVC insertion, even under ultrasound&#xD;
      guidance, carries a significant risk of mechanical complications, some of which could be life&#xD;
      threatening. The editorial states that reversal of severe thrombocytopenia or factor&#xD;
      deficiencies may decrease the risk of bleeding in patients with severe coagulopathies, and&#xD;
      that according to the published data, the risk-to-benefit ratio favors reversal of severe&#xD;
      coagulopathies (e.g., PLTs 50x10^9/L and/or INR 1.5, and/or PTT 50 s). It is of note that the&#xD;
      two aforementioned articles refer to coagulopathies as a whole and not specifically the&#xD;
      coagulopathy of liver disease. Another study assessed the safety of CVC insertion under&#xD;
      ultrasound guidance and the incidence of complications in patients with liver disease&#xD;
      coagulopathy. It concluded that the incidence of major vascular and non-vascular&#xD;
      complications was low even in the absence of prophylactic correction of coagulopathy and that&#xD;
      the incidence of minor vascular complications was higher but acceptable and easily&#xD;
      manageable.&#xD;
&#xD;
      A different study states that coagulopathy in cirrhotic patients undergoing surgery is a&#xD;
      major concern for surgeons. Nonetheless, thrombocytopenia that is not severe, should not be&#xD;
      automatically considered an index of increased bleeding risk. They state that compared with&#xD;
      CCTs, TEG provides a better assessment of the degree of coagulopathy and offers information&#xD;
      that can assist in managing these patients. Additionally, preoperative administration of FFP&#xD;
      to correct the INR should be avoided due to ineffectiveness and associated complications.&#xD;
&#xD;
      There are also general guidelines for cirrhotic patients about to undergo invasive&#xD;
      procedures, and among them guidelines regarding hemostatic management in this patient&#xD;
      population. These apply to three clinical phases:&#xD;
&#xD;
        1. Pre-procedural phase - no prophylactic correction of hemostasis should be applied,&#xD;
           infections should be treated and renal status optimized.&#xD;
&#xD;
        2. Intra-procedural phase - active bleeding is treated using transfusion or&#xD;
           antifibrinolytics, a low central venous pressure (CVP) should be maintained and normal&#xD;
           body temperature, calcium and pH should be maintained.&#xD;
&#xD;
        3. Post-procedural phase - CVP should be restored to normal and thrombotic or bleeding&#xD;
           complications should be sought and treated.&#xD;
&#xD;
      The University of Texas Southwestern Medical Center at Dallas recently developed&#xD;
      multidisciplinary guidelines for periprocedural transfusion of blood components in cirrhotic&#xD;
      patients undergoing gastrointestinal procedures. For procedures with mild to moderate-risk&#xD;
      they recommend not transfusing PLTs with counts&gt;30x10^9/L. As for high-risk procedures, they&#xD;
      state that PLTs may be required during the procedure with a count&lt;30x10^9/L. They recommend&#xD;
      transfusion of FFP only when the INR is≥2.6. Notably, a randomized controlled trial performed&#xD;
      by De Pietry et al. evaluated TEG-guided blood product use before invasive procedures in&#xD;
      cirrhosis with severe coagulopathy. It concluded that in patients with a significant&#xD;
      coagulopathy before the procedure, a TEG guided infusion strategy led to a significantly&#xD;
      lower use of blood products compared to CCT, without an increase in bleeding complications.&#xD;
&#xD;
      Finally, several publications address coagulopathy management in liver transplantation. These&#xD;
      publications demonstrate that the method of coagulation monitoring used effects transfusion&#xD;
      practice and that viscoelastic tests can reduce overall transfusion requirements.&#xD;
&#xD;
      Thus, it seems that the ability of CCTs to predict bleeding diathesis in cirrhotic patients&#xD;
      is diminished, whereas TEG might be a more accurate tool. It is important to bear in mind the&#xD;
      adverse implications of the liberal use of blood products. It seems that the current&#xD;
      literature, although conflicting, is leaning towards a more restrictive approach to&#xD;
      prophylactic correction of coagulopathy when performing invasive procedures in cirrhotic&#xD;
      patients. Based on the literature and on clinical experience, the investigators suspect that&#xD;
      common practice is more liberal and that in practice prophylactic correction of coagulation&#xD;
      laboratory tests abnormalities is more common than it should be based on published&#xD;
      guidelines.&#xD;
&#xD;
      Objectives&#xD;
&#xD;
        -  Assert whether the use of blood products prior to invasive procedures in cirrhotic&#xD;
           coagulopathic patients can be reduced using TEG to evaluate coagulopathy in place of&#xD;
           CCTs.&#xD;
&#xD;
        -  Evaluate the rate of complications due to blood product use in these patients.&#xD;
&#xD;
        -  Check the correlation between CCT results and TEG in these patients.&#xD;
&#xD;
      Methods and Materials&#xD;
&#xD;
      Study Design&#xD;
&#xD;
      This will be a prospective pre/post TEG protocol implementation study. It will include two&#xD;
      prospective surveys with a 1:1 ratio. A full and thorough medical history will be obtained.&#xD;
      Medical conditions, past surgeries, medications currently in use and laboratory test results&#xD;
      (including TEG) will be noted. In addition, the type of procedure the patient is undergoing&#xD;
      will be recorded along with bleeding complications, blood product transfusion record,&#xD;
      transfusion related side effects and complications, any other complication that can be&#xD;
      attributed the procedure or to its avoidance, total hospital stay from the time of the&#xD;
      procedure until hospital release and 90-day survival following the procedure.&#xD;
&#xD;
      Subjects will be consecutively enrolled, in accordance with selection criteria in the two&#xD;
      surveys:&#xD;
&#xD;
        1. Survey 1 - will be performed at baseline. Management will be based on CCTs, as per&#xD;
           common practice.&#xD;
&#xD;
        2. Survey 2 - management will be based on the TEG result. According to the new TEG&#xD;
           protocol, subjects with a reaction time (r)&gt;12 min will receive FFP, and patients with a&#xD;
           maximum amplitude (MA)&lt;36 mm will receive PLTs.&#xD;
&#xD;
      All subjects will be managed according to standard of care.&#xD;
&#xD;
      Regulatory Requirements&#xD;
&#xD;
      This study protocol complies with the declaration of Helsinki and will be conducted according&#xD;
      to rules and guidelines of good clinical practice (GCP).&#xD;
&#xD;
      Informed Consent&#xD;
&#xD;
      Informed consent will be obtained from the subjects by an authorized research team member&#xD;
      only. Subject will be provided with sufficient time to reach a rational, informed decision&#xD;
      regarding participation in the study.&#xD;
&#xD;
      Subject Confidentiality&#xD;
&#xD;
      Access to data will be granted to authorized study members only. The Case Report Form (CRF)&#xD;
      will contain patient identification number. Any subjects' personal information will be&#xD;
      removed from the CRF after the completion of the form and its integration to the database.&#xD;
&#xD;
      Sample Size&#xD;
&#xD;
      The study will include a total of 120 subjects, 60 in each group, in order to compensate for&#xD;
      dropouts. Sample size was calculated using the WINPEPI program. Version 11.24.&#xD;
&#xD;
      Statistical Analysis&#xD;
&#xD;
      the investigators intend to assess the influence of the use of a TEG related protocol on the&#xD;
      use of blood products in cirrhotic patients. They will examine the relationship of each of&#xD;
      the factors predicting blood product use and demographic data to use of blood product.&#xD;
      Quantitative data with normal distribution will be evaluated using t-test for independent&#xD;
      samples. In case the assumptions for parametric tests will not hold true, quantitative data&#xD;
      will be evaluated using an a-parametric Mann-Whitney test. Continuous data will be presented&#xD;
      as average±SD. Dichotomous data will be evaluated using the chi-square test. Fisher exact&#xD;
      test will be used when more than 20% of the expected observations were less than 5 or any&#xD;
      expected observation was less than 2. Categorical data will be presented as a number of cases&#xD;
      and percent. Multivariate logistic regression analysis will be used for the primary outcome&#xD;
      and exposure (blood product use prevalence and predicting and demographic factors) in order&#xD;
      to determine independent risk factors. The data included in the multivariate logistic&#xD;
      regression model will be significant demographic data and data found to have a Pv&lt;0.1 in the&#xD;
      univariate analysis. A Pv of 0.05 will be considered significant.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>December 2016</start_date>
  <completion_date type="Anticipated">December 2018</completion_date>
  <primary_completion_date type="Anticipated">December 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Amount of blood product (FFP/PLT) units transfused in preparation for the invasive procedures.</measure>
    <time_frame>Intraoperative</time_frame>
    <description>Number of FFP/PLT units transfused</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Bleeding complications.</measure>
    <time_frame>up to 30 days from procedure performance or death, whichever comes first</time_frame>
    <description>Number of episodes of overt bleeding / hemoglobin drop requiring transfusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transfusion-related side effects</measure>
    <time_frame>up to 30 days from procedure performance or death, whichever comes first</time_frame>
    <description>Number and type of side effects attributable to blood product administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>90-day survival</measure>
    <time_frame>Up to 90 days from procedure performance</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other complications</measure>
    <time_frame>up to 30 days from procedure performance or death, whichever comes first</time_frame>
    <description>Number and type of complication that can be attributed the procedure or to avoidance of the procedure</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Liver Cirrhosis</condition>
  <condition>Coagulopathy</condition>
  <arm_group>
    <arm_group_label>Survey 1</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Common practice</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Survey 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Thromboelastography based protocol</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Thromboelastography based protocol</intervention_name>
    <description>patients will be treated according to a new thromboelastography based protocol</description>
    <arm_group_label>Survey 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Follow up at the Gastroenterology Unit at TLVMC&#xD;
&#xD;
          -  Diagnosis of cirrhosis&#xD;
&#xD;
          -  Abnormal coagulation test results: INR &gt; 1.5 and/or a PLT count &lt; 50x10^9/L&#xD;
&#xD;
          -  Planned to undergo an invasive procedure&#xD;
&#xD;
          -  Hospitalization in one of the following units at TLVMC: Internal Medicine D, Internal&#xD;
             Medicine T, Internal Medicine Consultations, Intensive Care Unit, Surgical Intensive&#xD;
             Care Unit, General Surgery Division and the Gastroenterology unit.&#xD;
&#xD;
          -  Invasive procedures: central venous catheter placement, drainage of ascitic fluid,&#xD;
             endoscopic procedures (variceal ligation or polypectomy) or any surgical procedure&#xD;
             (excluding liver transplantation).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Ongoing bleeding&#xD;
&#xD;
          -  Current/recent (past 7 days) antiplatelet/anticoagulant therapy&#xD;
&#xD;
          -  Hemodialysis in the previous 7 days.&#xD;
&#xD;
          -  planned procedure is liver transplantation.&#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>Idit Matot, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Tel-Aviv Sourasky Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Idit Matot, MD, PhD</last_name>
    <phone>97236974758</phone>
    <email>iditm@tlvmc.gov.il</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Miri Davidovich</last_name>
    <phone>97236974758</phone>
    <email>mirid@tlvmc.gov.il</email>
  </overall_contact_backup>
  <reference>
    <citation>Weeder PD, Porte RJ, Lisman T. Hemostasis in liver disease: implications of new concepts for perioperative management. Transfus Med Rev. 2014 Jul;28(3):107-13. doi: 10.1016/j.tmrv.2014.03.002. Epub 2014 Mar 15.</citation>
    <PMID>24721432</PMID>
  </reference>
  <reference>
    <citation>Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011 Jul 14;365(2):147-56. doi: 10.1056/NEJMra1011170. No abstract available.</citation>
    <PMID>21751907</PMID>
  </reference>
  <reference>
    <citation>Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005 Mar;41(3):553-8. doi: 10.1002/hep.20569.</citation>
    <PMID>15726661</PMID>
  </reference>
  <reference>
    <citation>Salooja N, Perry DJ. Thrombelastography. Blood Coagul Fibrinolysis. 2001 Jul;12(5):327-37. doi: 10.1097/00001721-200107000-00001. Erratum In: Blood Coagul Fibrinolysis 2002 Jan;13(1):75.</citation>
    <PMID>11505075</PMID>
  </reference>
  <reference>
    <citation>Mallett SV, Chowdary P, Burroughs AK. Clinical utility of viscoelastic tests of coagulation in patients with liver disease. Liver Int. 2013 Aug;33(7):961-74. doi: 10.1111/liv.12158. Epub 2013 May 3.</citation>
    <PMID>23638693</PMID>
  </reference>
  <reference>
    <citation>European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397-417. doi: 10.1016/j.jhep.2010.05.004. Epub 2010 Jun 1. No abstract available.</citation>
    <PMID>20633946</PMID>
  </reference>
  <reference>
    <citation>Runyon BA; AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. 2009 Jun;49(6):2087-107. doi: 10.1002/hep.22853. No abstract available.</citation>
    <PMID>19475696</PMID>
  </reference>
  <reference>
    <citation>Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013 Sep;11(9):1064-74. doi: 10.1016/j.cgh.2013.02.026. Epub 2013 Mar 16.</citation>
    <PMID>23506859</PMID>
  </reference>
  <reference>
    <citation>Patel IJ, Davidson JC, Nikolic B, Salazar GM, Schwartzberg MS, Walker TG, Saad WA; Standards of Practice Committee, with Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Endorsement. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol. 2012 Jun;23(6):727-36. doi: 10.1016/j.jvir.2012.02.012. Epub 2012 Apr 17. No abstract available.</citation>
    <PMID>22513394</PMID>
  </reference>
  <reference>
    <citation>Baron RM. Point: should coagulopathy be repaired prior to central venous line insertion? Yes: why take chances? Chest. 2012 May;141(5):1139-1142. doi: 10.1378/chest.11-3225. No abstract available.</citation>
    <PMID>22553259</PMID>
  </reference>
  <reference>
    <citation>Singh SA, Sharma S, Singh A, Singh AK, Sharma U, Bhadoria AS. The safety of ultrasound guided central venous cannulation in patients with liver disease. Saudi J Anaesth. 2015 Apr-Jun;9(2):155-60. doi: 10.4103/1658-354X.152842.</citation>
    <PMID>25829903</PMID>
  </reference>
  <reference>
    <citation>Lopez-Delgado JC, Ballus J, Esteve F, Betancur-Zambrano NL, Corral-Velez V, Manez R, Betbese AJ, Roncal JA, Javierre C. Outcomes of abdominal surgery in patients with liver cirrhosis. World J Gastroenterol. 2016 Mar 7;22(9):2657-67. doi: 10.3748/wjg.v22.i9.2657.</citation>
    <PMID>26973406</PMID>
  </reference>
  <reference>
    <citation>Yates SG, Gavva C, Agrawal D, Sarode R. How do we transfuse blood components in cirrhotic patients undergoing gastrointestinal procedures? Transfusion. 2016 Apr;56(4):791-8. doi: 10.1111/trf.13495. Epub 2016 Feb 15.</citation>
    <PMID>26876945</PMID>
  </reference>
  <reference>
    <citation>De Pietri L, Bianchini M, Montalti R, De Maria N, Di Maira T, Begliomini B, Gerunda GE, di Benedetto F, Garcia-Tsao G, Villa E. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial. Hepatology. 2016 Feb;63(2):566-73. doi: 10.1002/hep.28148. Epub 2015 Dec 9.</citation>
    <PMID>26340411</PMID>
  </reference>
  <reference>
    <citation>Coakley M, Reddy K, Mackie I, Mallett S. Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests. J Cardiothorac Vasc Anesth. 2006 Aug;20(4):548-53. doi: 10.1053/j.jvca.2006.01.016. Epub 2006 Apr 19.</citation>
    <PMID>16884987</PMID>
  </reference>
  <reference>
    <citation>Wang SC, Shieh JF, Chang KY, Chu YC, Liu CS, Loong CC, Chan KH, Mandell S, Tsou MY. Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial. Transplant Proc. 2010 Sep;42(7):2590-3. doi: 10.1016/j.transproceed.2010.05.144.</citation>
    <PMID>20832550</PMID>
  </reference>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>December 7, 2016</study_first_submitted>
  <study_first_submitted_qc>December 8, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 9, 2016</study_first_posted>
  <last_update_submitted>December 19, 2016</last_update_submitted>
  <last_update_submitted_qc>December 19, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 20, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Thromboelastography</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Cirrhosis</mesh_term>
    <mesh_term>Hemostatic Disorders</mesh_term>
    <mesh_term>Blood Coagulation Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>we do not plan to share IPD</ipd_description>
  </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/NCT02987712
org study id: TASMC-16-IM-0703-CTIL
nct id: NCT02987712
lead sponsor: 
has dmc: No
Recently it has been acknowledged that cirrhotic patients present with "rebalanced
      hemostasis" that results from decreased levels of both pro-coagulant and anti-coagulant
      factors, that is not well reflected by conventional coagulation tests (CCTs).
      Thromboelastography (TEG) might be a more accurate tool in these patients.

      Numerous guidelines on the management of the cirrhotic patient undergoing invasive procedures
      have been published but most of them are not evidence based. Current literature, although
      conflicting, is leaning towards a restrictive approach to prophylactic correction of
      coagulopathy when performing invasive procedures in cirrhotic patients. The investigators
      suspect that common practice is more liberal . Considering the well-known adverse effects of
      blood product administration, the aim of the study is to re-evaluate the clinical management
      of cirrhotic patients undergoing invasive procedures.

      Study objectives: asserting whether the use of blood products prior to invasive procedures in
      cirrhotic coagulopathic patients can be reduced using TEG to evaluate coagulopathy in place
      of CCTs, evaluating the rate of complications due to blood product use, and checking how well
      CCT results correlate with TEG results in these patients.

      This will be a prospective pre/post TEG protocol implementation study which will include two
      prospective surveys with a 1:1 ratio. Survey 1: prophylactic administration of FFP/PLT prior
      to minor invasive procedures will be based on CCTs and physicians' clinical judgement. Survey
      2: management will be based on a new TEG protocol. The investigators will include cirrhotic
      patients with coagulopathy who are candidates for an invasive procedure. Subject will be
      provided with sufficient time to reach a rational, informed decision regarding participation
      in the study.

      Data will be collected from the computer based medical record systems, the patient file and
      directly from the caring physician and will include a thorough medical history and
      conventional blood tests, including a TEG test. All subjects will be managed according to
      standard of care.

      Primary endpoint: amount of blood product (fresh frozen plasma/platelets) units transfused in
      preparation for the invasive procedures.

      Secondary endpoints: bleeding complications, transfusion related side effects, 90 day
      survival and other complications.

      This will be a prospective (pre/post) study. The calculated sample size needed is 120
      subjects, 60 in each group.
Background

      Recently there has been a change of concept regarding the hemostatic profile of patients with
      liver disease from "auto-anti-coagulation" to "rebalanced hemostasis". The liver synthesizes
      most of the factors and inhibitors of the coagulation system as well as thrombopoietin. Thus,
      liver disease influences the hemostatic profile both through an effect on factor/inhibitor
      levels and through an effect on platelet number and function. The "rebalanced hemostasis" of
      liver disease results from decreased levels of most proteins involved in coagulation;
      promotors and inhibitors. Two proteins which are elevated in this state are factor VIII and
      von Willebrand factor. Elevated levels of the latter compensate to some extent for the
      thrombocytopenia and platelet function defects. This "rebalanced" state is not well reflected
      by conventional coagulation tests (CCT), which are insensitive to the anticoagulant component
      of hemostasis. In fact, it has been shown that thrombin generation in cirrhotic patients is
      normal. Considering this conceptual change together with the well-known adverse effects of
      blood product administration the investigators seek to re-evaluate the clinical management of
      cirrhotic patients undergoing invasive procedures.

      Thromboelastography (TEG) provides a graphic representation of clot formation and lysis.
      Compared with CCTs, TEG better reflects the interaction of plasma, blood cells and PLTs and
      better resembles the in-vivo state. Viscoelastic tests have been used for many years for
      coagulation monitoring and hemostatic therapy guidance during liver transplantation. Their
      use in hospitalized patients with liver disease has been much more limited.

      Different guidelines address the issue of coagulation test abnormalities in cirrhotic
      patients prior to various specific invasive procedures. According to the European Association
      for the Study of the Liver clinical practice guidelines, in cirrhosis, hemorrhagic
      complications after large volume paracentesis (LVP) are infrequent and there is no data to
      support pre-procedural use of fresh frozen plasma (FFP) or PLTs. The authors do note that
      often these products are given in case of severe coagulopathy and/or thrombocytopenia, and
      that caution should still be exercised in patients with severe coagulopathy, and LVP avoided
      in the presence of disseminated intravascular coagulation. The American Association for the
      Study of Liver Diseases practice guidelines state that because bleeding is uncommon, routine
      administration of FFP or PLTs prior to paracentesis is not recommended.

      Very few randomized, double-blind controlled clinical trials regarding the management of
      coagulation issues in patients with liver disease exist. Some guidelines note that INR should
      not be used alone to assess bleeding risk, that a PLT count greater than 50-60x10^9/L should
      be achieved prior to high-risk procedures, and that TEG may be helpful in targeting
      transfusion practice. Pertaining to esophageal varices, few data support the notion that
      coagulopathy is directly related to bleeding risk, and despite the existence of various
      specific guidelines on management of esophageal varices, specific recommendations on
      coagulation parameters for prophylactic esophageal variceal band ligation (EVBL) are missing.
      When prophylactic EVBL is deemed unsafe due to a coagulation disorder, they recommend
      avoiding it. Although it is uncertain what the optimal platelet counts should be in this
      situation, they recommend levels exceeding 56x10^9/L and possibly a fibrinogen level above
      100-150 mg/dL. They note that FFP transfusion is problematic because of the large volume
      needed to "correct" the INR.

      Consensus guidelines for peri-procedural management of coagulation status and hemostasis risk
      in percutaneous image-guided interventions conclude that central venous catheterization (CVC)
      can be performed safely by experienced physicians in the presence of abnormal coagulation
      parameters. According to an editorial in Chest, CVC insertion, even under ultrasound
      guidance, carries a significant risk of mechanical complications, some of which could be life
      threatening. The editorial states that reversal of severe thrombocytopenia or factor
      deficiencies may decrease the risk of bleeding in patients with severe coagulopathies, and
      that according to the published data, the risk-to-benefit ratio favors reversal of severe
      coagulopathies (e.g., PLTs 50x10^9/L and/or INR 1.5, and/or PTT 50 s). It is of note that the
      two aforementioned articles refer to coagulopathies as a whole and not specifically the
      coagulopathy of liver disease. Another study assessed the safety of CVC insertion under
      ultrasound guidance and the incidence of complications in patients with liver disease
      coagulopathy. It concluded that the incidence of major vascular and non-vascular
      complications was low even in the absence of prophylactic correction of coagulopathy and that
      the incidence of minor vascular complications was higher but acceptable and easily
      manageable.

      A different study states that coagulopathy in cirrhotic patients undergoing surgery is a
      major concern for surgeons. Nonetheless, thrombocytopenia that is not severe, should not be
      automatically considered an index of increased bleeding risk. They state that compared with
      CCTs, TEG provides a better assessment of the degree of coagulopathy and offers information
      that can assist in managing these patients. Additionally, preoperative administration of FFP
      to correct the INR should be avoided due to ineffectiveness and associated complications.

      There are also general guidelines for cirrhotic patients about to undergo invasive
      procedures, and among them guidelines regarding hemostatic management in this patient
      population. These apply to three clinical phases:

        1. Pre-procedural phase - no prophylactic correction of hemostasis should be applied,
           infections should be treated and renal status optimized.

        2. Intra-procedural phase - active bleeding is treated using transfusion or
           antifibrinolytics, a low central venous pressure (CVP) should be maintained and normal
           body temperature, calcium and pH should be maintained.

        3. Post-procedural phase - CVP should be restored to normal and thrombotic or bleeding
           complications should be sought and treated.

      The University of Texas Southwestern Medical Center at Dallas recently developed
      multidisciplinary guidelines for periprocedural transfusion of blood components in cirrhotic
      patients undergoing gastrointestinal procedures. For procedures with mild to moderate-risk
      they recommend not transfusing PLTs with counts>30x10^9/L. As for high-risk procedures, they
      state that PLTs may be required during the procedure with a count<30x10^9/L. They recommend
      transfusion of FFP only when the INR is≥2.6. Notably, a randomized controlled trial performed
      by De Pietry et al. evaluated TEG-guided blood product use before invasive procedures in
      cirrhosis with severe coagulopathy. It concluded that in patients with a significant
      coagulopathy before the procedure, a TEG guided infusion strategy led to a significantly
      lower use of blood products compared to CCT, without an increase in bleeding complications.

      Finally, several publications address coagulopathy management in liver transplantation. These
      publications demonstrate that the method of coagulation monitoring used effects transfusion
      practice and that viscoelastic tests can reduce overall transfusion requirements.

      Thus, it seems that the ability of CCTs to predict bleeding diathesis in cirrhotic patients
      is diminished, whereas TEG might be a more accurate tool. It is important to bear in mind the
      adverse implications of the liberal use of blood products. It seems that the current
      literature, although conflicting, is leaning towards a more restrictive approach to
      prophylactic correction of coagulopathy when performing invasive procedures in cirrhotic
      patients. Based on the literature and on clinical experience, the investigators suspect that
      common practice is more liberal and that in practice prophylactic correction of coagulation
      laboratory tests abnormalities is more common than it should be based on published
      guidelines.

      Objectives

        -  Assert whether the use of blood products prior to invasive procedures in cirrhotic
           coagulopathic patients can be reduced using TEG to evaluate coagulopathy in place of
           CCTs.

        -  Evaluate the rate of complications due to blood product use in these patients.

        -  Check the correlation between CCT results and TEG in these patients.

      Methods and Materials

      Study Design

      This will be a prospective pre/post TEG protocol implementation study. It will include two
      prospective surveys with a 1:1 ratio. A full and thorough medical history will be obtained.
      Medical conditions, past surgeries, medications currently in use and laboratory test results
      (including TEG) will be noted. In addition, the type of procedure the patient is undergoing
      will be recorded along with bleeding complications, blood product transfusion record,
      transfusion related side effects and complications, any other complication that can be
      attributed the procedure or to its avoidance, total hospital stay from the time of the
      procedure until hospital release and 90-day survival following the procedure.

      Subjects will be consecutively enrolled, in accordance with selection criteria in the two
      surveys:

        1. Survey 1 - will be performed at baseline. Management will be based on CCTs, as per
           common practice.

        2. Survey 2 - management will be based on the TEG result. According to the new TEG
           protocol, subjects with a reaction time (r)>12 min will receive FFP, and patients with a
           maximum amplitude (MA)<36 mm will receive PLTs.

      All subjects will be managed according to standard of care.

      Regulatory Requirements

      This study protocol complies with the declaration of Helsinki and will be conducted according
      to rules and guidelines of good clinical practice (GCP).

      Informed Consent

      Informed consent will be obtained from the subjects by an authorized research team member
      only. Subject will be provided with sufficient time to reach a rational, informed decision
      regarding participation in the study.

      Subject Confidentiality

      Access to data will be granted to authorized study members only. The Case Report Form (CRF)
      will contain patient identification number. Any subjects' personal information will be
      removed from the CRF after the completion of the form and its integration to the database.

      Sample Size

      The study will include a total of 120 subjects, 60 in each group, in order to compensate for
      dropouts. Sample size was calculated using the WINPEPI program. Version 11.24.

      Statistical Analysis

      the investigators intend to assess the influence of the use of a TEG related protocol on the
      use of blood products in cirrhotic patients. They will examine the relationship of each of
      the factors predicting blood product use and demographic data to use of blood product.
      Quantitative data with normal distribution will be evaluated using t-test for independent
      samples. In case the assumptions for parametric tests will not hold true, quantitative data
      will be evaluated using an a-parametric Mann-Whitney test. Continuous data will be presented
      as average±SD. Dichotomous data will be evaluated using the chi-square test. Fisher exact
      test will be used when more than 20% of the expected observations were less than 5 or any
      expected observation was less than 2. Categorical data will be presented as a number of cases
      and percent. Multivariate logistic regression analysis will be used for the primary outcome
      and exposure (blood product use prevalence and predicting and demographic factors) in order
      to determine independent risk factors. The data included in the multivariate logistic
      regression model will be significant demographic data and data found to have a Pv<0.1 in the
      univariate analysis. A Pv of 0.05 will be considered significant.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Amount of blood product (FFP/PLT) units transfused in preparation for the invasive procedures.
time frame: Intraoperative
description: Number of FFP/PLT units transfused
measure: Bleeding complications.
time frame: up to 30 days from procedure performance or death, whichever comes first
description: Number of episodes of overt bleeding / hemoglobin drop requiring transfusion
measure: Transfusion-related side effects
time frame: up to 30 days from procedure performance or death, whichever comes first
description: Number and type of side effects attributable to blood product administration
measure: 90-day survival
time frame: Up to 90 days from procedure performance
measure: Other complications
time frame: up to 30 days from procedure performance or death, whichever comes first
description: Number and type of complication that can be attributed the procedure or to avoidance of the procedure
arm group label: Survey 1
arm group type: No Intervention
description: Common practice
arm group label: Survey 2
arm group type: Experimental
description: Thromboelastography based protocol
intervention type: Other
intervention name: Thromboelastography based protocol
description: patients will be treated according to a new thromboelastography based protocol
arm group label: Survey 2
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Idit Matot, MD, PhD
role: Principal Investigator
affiliation: Tel-Aviv Sourasky Medical Center
last name: Idit Matot, MD, PhD
phone: 97236974758
email: iditm@tlvmc.gov.il
last name: Miri Davidovich
phone: 97236974758
email: mirid@tlvmc.gov.il
citation: Weeder PD, Porte RJ, Lisman T. Hemostasis in liver disease: implications of new concepts for perioperative management. Transfus Med Rev. 2014 Jul;28(3):107-13. doi: 10.1016/j.tmrv.2014.03.002. Epub 2014 Mar 15.
PMID: 24721432
citation: Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011 Jul 14;365(2):147-56. doi: 10.1056/NEJMra1011170. No abstract available.
PMID: 21751907
citation: Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005 Mar;41(3):553-8. doi: 10.1002/hep.20569.
PMID: 15726661
citation: Salooja N, Perry DJ. Thrombelastography. Blood Coagul Fibrinolysis. 2001 Jul;12(5):327-37. doi: 10.1097/00001721-200107000-00001. Erratum In: Blood Coagul Fibrinolysis 2002 Jan;13(1):75.
PMID: 11505075
citation: Mallett SV, Chowdary P, Burroughs AK. Clinical utility of viscoelastic tests of coagulation in patients with liver disease. Liver Int. 2013 Aug;33(7):961-74. doi: 10.1111/liv.12158. Epub 2013 May 3.
PMID: 23638693
citation: European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397-417. doi: 10.1016/j.jhep.2010.05.004. Epub 2010 Jun 1. No abstract available.
PMID: 20633946
citation: Runyon BA; AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. 2009 Jun;49(6):2087-107. doi: 10.1002/hep.22853. No abstract available.
PMID: 19475696
citation: Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013 Sep;11(9):1064-74. doi: 10.1016/j.cgh.2013.02.026. Epub 2013 Mar 16.
PMID: 23506859
citation: Patel IJ, Davidson JC, Nikolic B, Salazar GM, Schwartzberg MS, Walker TG, Saad WA; Standards of Practice Committee, with Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Endorsement. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol. 2012 Jun;23(6):727-36. doi: 10.1016/j.jvir.2012.02.012. Epub 2012 Apr 17. No abstract available.
PMID: 22513394
citation: Baron RM. Point: should coagulopathy be repaired prior to central venous line insertion? Yes: why take chances? Chest. 2012 May;141(5):1139-1142. doi: 10.1378/chest.11-3225. No abstract available.
PMID: 22553259
citation: Singh SA, Sharma S, Singh A, Singh AK, Sharma U, Bhadoria AS. The safety of ultrasound guided central venous cannulation in patients with liver disease. Saudi J Anaesth. 2015 Apr-Jun;9(2):155-60. doi: 10.4103/1658-354X.152842.
PMID: 25829903
citation: Lopez-Delgado JC, Ballus J, Esteve F, Betancur-Zambrano NL, Corral-Velez V, Manez R, Betbese AJ, Roncal JA, Javierre C. Outcomes of abdominal surgery in patients with liver cirrhosis. World J Gastroenterol. 2016 Mar 7;22(9):2657-67. doi: 10.3748/wjg.v22.i9.2657.
PMID: 26973406
citation: Yates SG, Gavva C, Agrawal D, Sarode R. How do we transfuse blood components in cirrhotic patients undergoing gastrointestinal procedures? Transfusion. 2016 Apr;56(4):791-8. doi: 10.1111/trf.13495. Epub 2016 Feb 15.
PMID: 26876945
citation: De Pietri L, Bianchini M, Montalti R, De Maria N, Di Maira T, Begliomini B, Gerunda GE, di Benedetto F, Garcia-Tsao G, Villa E. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial. Hepatology. 2016 Feb;63(2):566-73. doi: 10.1002/hep.28148. Epub 2015 Dec 9.
PMID: 26340411
citation: Coakley M, Reddy K, Mackie I, Mallett S. Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests. J Cardiothorac Vasc Anesth. 2006 Aug;20(4):548-53. doi: 10.1053/j.jvca.2006.01.016. Epub 2006 Apr 19.
PMID: 16884987
citation: Wang SC, Shieh JF, Chang KY, Chu YC, Liu CS, Loong CC, Chan KH, Mandell S, Tsou MY. Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial. Transplant Proc. 2010 Sep;42(7):2590-3. doi: 10.1016/j.transproceed.2010.05.144.
PMID: 20832550
responsible party type: Sponsor
mesh term: Liver Cirrhosis
mesh term: Hemostatic Disorders
mesh term: Blood Coagulation Disorders
sharing ipd: No
ipd description: we do not plan to share IPD