<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/NCT02974660</url>
  </required_header>
  <id_info>
    <org_study_id>WUM-KZ</org_study_id>
    <nct_id>NCT02974660</nct_id>
  </id_info>
  <brief_title>Protamine Sulfate During Transcatheter Aortic Valve Implantation</brief_title>
  <acronym>PS TAVI</acronym>
  <official_title>Use of Protamine Sulfate During Transcatheter Aortic Valve Implantation - Impact on Bleeding and Thromboembolic Complications</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of Warsaw</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical University of Warsaw</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Transcatheter aortic valve implantation (TAVI) is a new, rapidly emerging standard of care in&#xD;
      inoperable and high-risk patients with severe, symptomatic aortic stenosis. Information&#xD;
      regarding reversal of unfractionated heparin with protamine sulfate in order to facilitate&#xD;
      access site closure is scarce and based on expert consensus. Clinical practice varies between&#xD;
      centers. Protamine sulphate may decrease the amount of bleeding complications related to the&#xD;
      access-site. The impact on possible thromboembolic complications is unknown. Both bleeding&#xD;
      and thromboembolic complications increase mortality after TAVI. A randomized trial is&#xD;
      required in order to assess impact of protamine sulfate on prevalence and extent of bleeding&#xD;
      and thromboembolic complications.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Information regarding reversal of unfractionated heparin (UFH) with protamine sulfate (PS) is&#xD;
      based on expert consensus from 2012, which recommends use of UFH in order to achieve&#xD;
      activated clotting time (ACT) &gt; 300 seconds as well as UFH reversal with PS in case of TAVI&#xD;
      via transapical access as well as transfemoral access with the exception of cases with&#xD;
      minimal bleeding risk. However, the clinical practice varies between centers - some use PS&#xD;
      routinely, others - only in selected cases. The actual impact of PS on bleeding complications&#xD;
      reduction is unknown. Furthermore, a pro-thromboembolic effect of the PS cannot be excluded.&#xD;
      Both bleeding (major and life-threatening according to Valve Academic Research Consortium&#xD;
      [VARC] criteria) and thromboembolic complications increase mortality after TAVI. The&#xD;
      occurrence of these complications in international TAVI registries in 30-day observation&#xD;
      ranges from 9.7% in case of major bleeding, 4.7% in case of life-threatening bleeds and 5% in&#xD;
      case of strokes. There are no randomized studies assessing impact of PS on frequency of&#xD;
      bleeding and thromboembolic complications after TAVI, its side-effects and influence on&#xD;
      mortality. Randomized trial is required in order to assess impact of protamine sulfate on&#xD;
      prevalence of bleeding and thromboembolic complications.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2016</start_date>
  <completion_date type="Actual">September 2020</completion_date>
  <primary_completion_date type="Actual">July 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bleeding complications</measure>
    <time_frame>48 hours or hospital discharge, whichever occurs first</time_frame>
    <description>Composite of life-threatening and major bleeding complications according to Valve Academic Research Consortium (VARC) criteria (unit of measure: 0/1 [absence/presence])</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Successful closure of the access-site</measure>
    <time_frame>15 minutes</time_frame>
    <description>Angiographic assessment of contrast extravasation from the access site after closure with preclose device at the end of the procedure. Unit of measure: 0/1 (absence/presence).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thromboembolic complications</measure>
    <time_frame>5 days or hospital discharge, whichever occurs first</time_frame>
    <description>Clinical assessment of thromboembolic complications in the central nervous system and peripheral vasculature (e.g. mesenteric, extremities). Unit of measure: 0/1 (absence/presence)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of peri-procedural myocardial muscle injury</measure>
    <time_frame>24 hours</time_frame>
    <description>Measurements of levels of high sensitivity cardiac troponin T and isoenzyme MB of creatine kinase before the procedure and 6- and 12-24 hours after the procedure. Unit of measure: high sensitivity cardiac troponin T [ng/L], isoenzyme MB of creatine kinase [mcg/L].</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>30 days</time_frame>
    <description>All-cause mortality. Unit of measure: 0/1 (absence/presence).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">100</enrollment>
  <condition>Aortic Valve Stenosis</condition>
  <arm_group>
    <arm_group_label>Protamine sulfate</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>After obtaining optimal valve deployment patients will receive protamine sulfate (1 mg for each 100 units of UFH i.v.). Measurement of activated clotting time (ACT) will be performed (after heparin administration and after protamine sulfate administration).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>0.9% NaCl</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>After obtaining optimal valve deployment patients will receive 0.9% saline (20 ml i.v.). Measurement of activated clotting time (ACT) will be performed (after heparin administration and after placebo administration).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Protamine sulfate</intervention_name>
    <arm_group_label>Protamine sulfate</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>0.9% NaCl</intervention_name>
    <arm_group_label>0.9% NaCl</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients who underwent successful TAVI&#xD;
&#xD;
          -  with any approved TAVI device&#xD;
&#xD;
          -  via transfemoral access&#xD;
&#xD;
          -  with use of any of the approved vascular closure devices&#xD;
&#xD;
          -  provided written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  no consent&#xD;
&#xD;
          -  periprocedural complications requiring continuation of heparin or administration of&#xD;
             protamine sulfate&#xD;
&#xD;
          -  alergy to fish, protamine, protamine derivates, history of Humulin N, Novolin N,&#xD;
             Novolin NPH, Gensulin N, SciLin N, NPH Iletin II and isophane insulin intake&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>First Department of Cardiology, Medical University of Warsaw</name>
      <address>
        <city>Warsaw</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Poland</country>
  </location_countries>
  <reference>
    <citation>Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Eur Heart J. 2012 Oct;33(19):2403-18. doi: 10.1093/eurheartj/ehs255.</citation>
    <PMID>23026477</PMID>
  </reference>
  <results_reference>
    <citation>Holmes DR Jr, Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, Calhoon JH, Carabello BA, Desai MY, Edwards FH, Francis GS, Gardner TJ, Kappetein AP, Linderbaum JA, Mukherjee C, Mukherjee D, Otto CM, Ruiz CE, Sacco RL, Smith D, Thomas JD, Harrington RA, Bhatt DL, Ferrari VA, Fisher JD, Garcia MJ, Gardner TJ, Gentile F, Gilson MF, Hernandez AF, Jacobs AK, Kaul S, Linderbaum JA, Moliterno DJ, Weitz HH; American Heart Association; American Society of Echocardiography; European Association for Cardio-Thoracic Surgery; Heart Failure Society of America; Mended Hearts; Society of Cardiovascular Anesthesiologists; Society of Cardiovascular Computed Tomography; Society for Cardiovascular Magnetic Resonance. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: developed in collabration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Thorac Cardiovasc Surg. 2012 Sep;144(3):e29-84. doi: 10.1016/j.jtcvs.2012.03.001. No abstract available.</citation>
    <PMID>22898522</PMID>
  </results_reference>
  <results_reference>
    <citation>Rodes-Cabau J, Dauerman HL, Cohen MG, Mehran R, Small EM, Smyth SS, Costa MA, Mega JL, O'Donoghue ML, Ohman EM, Becker RC. Antithrombotic treatment in transcatheter aortic valve implantation: insights for cerebrovascular and bleeding events. J Am Coll Cardiol. 2013 Dec 24;62(25):2349-2359. doi: 10.1016/j.jacc.2013.03.029. Epub 2013 Apr 10.</citation>
    <PMID>23583252</PMID>
  </results_reference>
  <results_reference>
    <citation>Linke A, Wenaweser P, Gerckens U, Tamburino C, Bosmans J, Bleiziffer S, Blackman D, Schafer U, Muller R, Sievert H, Sondergaard L, Klugmann S, Hoffmann R, Tchetche D, Colombo A, Legrand VM, Bedogni F, lePrince P, Schuler G, Mazzitelli D, Eftychiou C, Frerker C, Boekstegers P, Windecker S, Mohr FW, Woitek F, Lange R, Bauernschmitt R, Brecker S; ADVANCE study Investigators. Treatment of aortic stenosis with a self-expanding transcatheter valve: the International Multi-centre ADVANCE Study. Eur Heart J. 2014 Oct 7;35(38):2672-84. doi: 10.1093/eurheartj/ehu162. Epub 2014 Mar 28.</citation>
    <PMID>24682842</PMID>
  </results_reference>
  <results_reference>
    <citation>Borz B, Durand E, Godin M, Tron C, Canville A, Litzler PY, Bessou JP, Cribier A, Eltchaninoff H. Incidence, predictors and impact of bleeding after transcatheter aortic valve implantation using the balloon-expandable Edwards prosthesis. Heart. 2013 Jun;99(12):860-5. doi: 10.1136/heartjnl-2012-303095. Epub 2012 Dec 12.</citation>
    <PMID>23236027</PMID>
  </results_reference>
  <results_reference>
    <citation>Gauthier C, Astarci P, Baele P, Matta A, Kahn D, Kefer J, Momeni M. Mid-term survival after transcatheter aortic valve implantation: Results with respect to the anesthetic management and to the access route (transfemoral versus transapical). Ann Card Anaesth. 2015 Jul-Sep;18(3):343-51. doi: 10.4103/0971-9784.159804.</citation>
    <PMID>26139739</PMID>
  </results_reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>October 10, 2016</study_first_submitted>
  <study_first_submitted_qc>November 25, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2016</study_first_posted>
  <last_update_submitted>October 21, 2020</last_update_submitted>
  <last_update_submitted_qc>October 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aortic Valve Stenosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Protamines</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02974660
org study id: WUM-KZ
nct id: NCT02974660
lead sponsor: 
has dmc: No
Transcatheter aortic valve implantation (TAVI) is a new, rapidly emerging standard of care in
      inoperable and high-risk patients with severe, symptomatic aortic stenosis. Information
      regarding reversal of unfractionated heparin with protamine sulfate in order to facilitate
      access site closure is scarce and based on expert consensus. Clinical practice varies between
      centers. Protamine sulphate may decrease the amount of bleeding complications related to the
      access-site. The impact on possible thromboembolic complications is unknown. Both bleeding
      and thromboembolic complications increase mortality after TAVI. A randomized trial is
      required in order to assess impact of protamine sulfate on prevalence and extent of bleeding
      and thromboembolic complications.
Information regarding reversal of unfractionated heparin (UFH) with protamine sulfate (PS) is
      based on expert consensus from 2012, which recommends use of UFH in order to achieve
      activated clotting time (ACT) > 300 seconds as well as UFH reversal with PS in case of TAVI
      via transapical access as well as transfemoral access with the exception of cases with
      minimal bleeding risk. However, the clinical practice varies between centers - some use PS
      routinely, others - only in selected cases. The actual impact of PS on bleeding complications
      reduction is unknown. Furthermore, a pro-thromboembolic effect of the PS cannot be excluded.
      Both bleeding (major and life-threatening according to Valve Academic Research Consortium
      [VARC] criteria) and thromboembolic complications increase mortality after TAVI. The
      occurrence of these complications in international TAVI registries in 30-day observation
      ranges from 9.7% in case of major bleeding, 4.7% in case of life-threatening bleeds and 5% in
      case of strokes. There are no randomized studies assessing impact of PS on frequency of
      bleeding and thromboembolic complications after TAVI, its side-effects and influence on
      mortality. Randomized trial is required in order to assess impact of protamine sulfate on
      prevalence of bleeding and thromboembolic complications.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Participant)
measure: Bleeding complications
time frame: 48 hours or hospital discharge, whichever occurs first
description: Composite of life-threatening and major bleeding complications according to Valve Academic Research Consortium (VARC) criteria (unit of measure: 0/1 [absence/presence])
measure: Successful closure of the access-site
time frame: 15 minutes
description: Angiographic assessment of contrast extravasation from the access site after closure with preclose device at the end of the procedure. Unit of measure: 0/1 (absence/presence).
measure: Thromboembolic complications
time frame: 5 days or hospital discharge, whichever occurs first
description: Clinical assessment of thromboembolic complications in the central nervous system and peripheral vasculature (e.g. mesenteric, extremities). Unit of measure: 0/1 (absence/presence)
measure: Assessment of peri-procedural myocardial muscle injury
time frame: 24 hours
description: Measurements of levels of high sensitivity cardiac troponin T and isoenzyme MB of creatine kinase before the procedure and 6- and 12-24 hours after the procedure. Unit of measure: high sensitivity cardiac troponin T [ng/L], isoenzyme MB of creatine kinase [mcg/L].
measure: All-cause mortality
time frame: 30 days
description: All-cause mortality. Unit of measure: 0/1 (absence/presence).
arm group label: Protamine sulfate
arm group type: Active Comparator
description: After obtaining optimal valve deployment patients will receive protamine sulfate (1 mg for each 100 units of UFH i.v.). Measurement of activated clotting time (ACT) will be performed (after heparin administration and after protamine sulfate administration).
arm group label: 0.9% NaCl
arm group type: Placebo Comparator
description: After obtaining optimal valve deployment patients will receive 0.9% saline (20 ml i.v.). Measurement of activated clotting time (ACT) will be performed (after heparin administration and after placebo administration).
intervention type: Drug
intervention name: Protamine sulfate
arm group label: Protamine sulfate
intervention type: Drug
intervention name: 0.9% NaCl
arm group label: 0.9% NaCl
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Poland
citation: Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Eur Heart J. 2012 Oct;33(19):2403-18. doi: 10.1093/eurheartj/ehs255.
PMID: 23026477
citation: Holmes DR Jr, Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, Calhoon JH, Carabello BA, Desai MY, Edwards FH, Francis GS, Gardner TJ, Kappetein AP, Linderbaum JA, Mukherjee C, Mukherjee D, Otto CM, Ruiz CE, Sacco RL, Smith D, Thomas JD, Harrington RA, Bhatt DL, Ferrari VA, Fisher JD, Garcia MJ, Gardner TJ, Gentile F, Gilson MF, Hernandez AF, Jacobs AK, Kaul S, Linderbaum JA, Moliterno DJ, Weitz HH; American Heart Association; American Society of Echocardiography; European Association for Cardio-Thoracic Surgery; Heart Failure Society of America; Mended Hearts; Society of Cardiovascular Anesthesiologists; Society of Cardiovascular Computed Tomography; Society for Cardiovascular Magnetic Resonance. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: developed in collabration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Thorac Cardiovasc Surg. 2012 Sep;144(3):e29-84. doi: 10.1016/j.jtcvs.2012.03.001. No abstract available.
PMID: 22898522
citation: Rodes-Cabau J, Dauerman HL, Cohen MG, Mehran R, Small EM, Smyth SS, Costa MA, Mega JL, O'Donoghue ML, Ohman EM, Becker RC. Antithrombotic treatment in transcatheter aortic valve implantation: insights for cerebrovascular and bleeding events. J Am Coll Cardiol. 2013 Dec 24;62(25):2349-2359. doi: 10.1016/j.jacc.2013.03.029. Epub 2013 Apr 10.
PMID: 23583252
citation: Linke A, Wenaweser P, Gerckens U, Tamburino C, Bosmans J, Bleiziffer S, Blackman D, Schafer U, Muller R, Sievert H, Sondergaard L, Klugmann S, Hoffmann R, Tchetche D, Colombo A, Legrand VM, Bedogni F, lePrince P, Schuler G, Mazzitelli D, Eftychiou C, Frerker C, Boekstegers P, Windecker S, Mohr FW, Woitek F, Lange R, Bauernschmitt R, Brecker S; ADVANCE study Investigators. Treatment of aortic stenosis with a self-expanding transcatheter valve: the International Multi-centre ADVANCE Study. Eur Heart J. 2014 Oct 7;35(38):2672-84. doi: 10.1093/eurheartj/ehu162. Epub 2014 Mar 28.
PMID: 24682842
citation: Borz B, Durand E, Godin M, Tron C, Canville A, Litzler PY, Bessou JP, Cribier A, Eltchaninoff H. Incidence, predictors and impact of bleeding after transcatheter aortic valve implantation using the balloon-expandable Edwards prosthesis. Heart. 2013 Jun;99(12):860-5. doi: 10.1136/heartjnl-2012-303095. Epub 2012 Dec 12.
PMID: 23236027
citation: Gauthier C, Astarci P, Baele P, Matta A, Kahn D, Kefer J, Momeni M. Mid-term survival after transcatheter aortic valve implantation: Results with respect to the anesthetic management and to the access route (transfemoral versus transapical). Ann Card Anaesth. 2015 Jul-Sep;18(3):343-51. doi: 10.4103/0971-9784.159804.
PMID: 26139739
responsible party type: Sponsor
mesh term: Aortic Valve Stenosis
mesh term: Protamines