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出境医 / 临床实验 / DEPOSITION - Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery (DEPOSITION)

DEPOSITION - Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery (DEPOSITION)

Study Description
Brief Summary:
The aim is to conduct a double-dummy multi-centre randomized controlled clinical trial of application of topical dose of tranexamic acid (TxA) versus the usual intravenous TxA in patients undergoing on-pump cardiac surgery.

Condition or disease Intervention/treatment Phase
Bleeding Surgical Blood Loss Seizures Drug: Tranexamic Acid Phase 4

Detailed Description:
Postoperative bleeding related to open cardiac surgery increases the rates of complications and mortality. It results from the blood thinners that are needed for use. Intravenous tranexamic acid (TxA) has become a mainstay in cardiac surgical procedures for decreasing bleeding and minimizing transfusion requirements. Although intravenous TxA is usually well tolerated, there is a well-known risk (1 to 4%) of postoperative seizures. This is due to the similarity between TxA and the brain tissues. The aim is to eliminate the risk of seizures but to maintain the protection against bleeding. When TxA is used directly on the tissues (topically) for other type of surgeries (joints), TxA is effective to reduce blood loss and transfusions. The aim is to prove that direct application of TxA on the heart can eliminate postoperative seizures and reduce the amount of blood transfusions in patients who have cardiac surgery.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3800 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Tranexamic Acid intravenous + Placebo topical versus Placebo intravenous + Tranexamic Acid topical
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The pharmacy will prepare 2 syringes of 50 ml of topical TxA (5 g) or placebo. They will also prepare for the same patient 2 syringes of 50 ml (5 g) for intravenous (i.v.) injection or placebo. TxA is similar in all aspects to normal saline. Blinding of both teams will be easy. The syringes will be prepared and randomized in pharmacy before the surgery.
Primary Purpose: Prevention
Official Title: Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery (DEPOSITION) Study
Actual Study Start Date : September 17, 2019
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2022
Arms and Interventions
Arm Intervention/treatment
Active Comparator: Topical Tranexamic Acid/Placebo
Topical Tranexamic Acid 5g to 10g (50 to 100mL) or placebo. The topical will be poured into the pericardial and mediastinal cavities after protamine administration.
 Drug: Tranexamic Acid
Tranexamic Acid is a medication used to treat or prevent excessive blood loss from major trauma, post partum, surgery, tooth removal, nose bleeds, and heavy menstruation.
Other Name: Cyklokapron
Active Comparator: Intravenous Tranexamic Acid/Placebo
Intravenous Tranexamic Acid 1 to 10g (10 to 100mL) or placebo administered intravenously at the induction of anesthesia as a bolus-infusion.
 Drug: Tranexamic Acid
Tranexamic Acid is a medication used to treat or prevent excessive blood loss from major trauma, post partum, surgery, tooth removal, nose bleeds, and heavy menstruation.
Other Name: Cyklokapron
Outcome Measures
Primary Outcome Measures :
  1. The composite of patients receiving in-hospital red blood cell transfusions or experiencing a seizure [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    To determine in patients undergoing on-pump cardiac surgery, if topical tranexamic acid (intra-pericardial) is superior to the usual intravenous tranexamic acid administration for reducing the risk of in-hospital red blood cell transfusion or seizure (composite).


Secondary Outcome Measures :
  1. The proportion of patients in-hospital who receive red blood cell transfusions [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    To determine whether topical tranexamic acid (intra-pericardial) compared with intravenous tranexamic acid administration reduces the risk of in-hospital red blood cell transfusion.

  2. The proportion of patients in-hospital who experience a seizure [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    To determine whether topical tranexamic acid (intra-pericardial) compared with intravenous tranexamic acid administration reduces the risk of in-hospital seizure. The proportion of patients who experience a seizure will be analyzed using Fisher's exact test.


Other Outcome Measures:
  1. Blood product transfusions [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    Analyzed using an ANCOVA model. In such a model, bags of blood product will be included as a dependent variable, whereas dose of tranexamic acid and treatment will be included as covariates.

  2. Re-operation for bleeding or tamponade [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    Analyzed with a binomial regression

  3. Length of ICU stay [ Time Frame: Number of hours in ICU are being collected at the Post-Operative Visit. Hour collection will start upon arrival at ICU post surgery and stop at ICU exit, up to 10 days maximum. ]
    Analyzed using an ANCOVA model.

  4. MACE (Death, non-fatal Myocardial Infarction (MI), or non-fatal stroke) [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    A Cox proportional hazard model will be used to analyze the time to the first occurrence of the composite of death, non-fatal MI, or non-fatal stroke (MACE).


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. ≥ 18 years of age
  2. Undergoing a cardiac surgical procedure (i.e. isolated coronary artery bypass graft (CABG), isolated single cardiac valve surgery or a combination of both or isolated ascending aorta replacement) with the use of cardiopulmonary bypass (CPB) and median sternotomy
  3. Provide written informed consent

Exclusion Criteria:

  1. Allergy to tranexamic acid
  2. Undergoing minimally invasive surgery

  3. Fulfill any of the following transfusion risk factors (A-D):

    A. Emergency surgery B. History of bleeding disorder C. Inherited thromboembolic or hemorrhagic disease D. Infective endocarditis

  4. History of previous cardiac surgery
  5. Severe renal impairment (serum creatinine >250 µmol/L)
  6. Pre-operative hemoglobin <120 g/L
  7. Pre-operative thrombocytopenia (<50,000 platelets per µL)
  8. Expected circulatory arrest
  9. Pregnancy or breast feeding
  10. Previously enrolled in the DEPOSITION trial
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Ingrid Copland, CCRA 905-527-4322 ext 40368 cogency@phri.ca
Contact: Austin Browne, PhD 905-527-4322 ext 40582 Austin.Browne@phri.ca

Locations
Layout table for location information
Canada, Ontario
Hamilton Health Sciences - General Hospital Recruiting
Hamilton, Ontario, Canada, L8L 2X2
Contact: Patricia Power    905-521-2100 ext 44495    powerpat@hhsc.ca   
Principal Investigator: Andre Lamy, MD, MHSc         
Sponsors and Collaborators
Population Health Research Institute
Investigators
Layout table for investigator information
Principal Investigator: Andre Lamy, MD Population Health Research Institute
Tracking Information
First Submitted Date  ICMJE May 15, 2019
First Posted Date  ICMJE May 17, 2019
Last Update Posted Date January 29, 2021
Actual Study Start Date  ICMJE September 17, 2019
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 28, 2019) 		The composite of patients receiving in-hospital red blood cell transfusions or experiencing a seizure [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
To determine in patients undergoing on-pump cardiac surgery, if topical tranexamic acid (intra-pericardial) is superior to the usual intravenous tranexamic acid administration for reducing the risk of in-hospital red blood cell transfusion or seizure (composite).
Original Primary Outcome Measures  ICMJE
 (submitted: May 15, 2019) 		In-hospital red blood cell transfusions or seizure [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
To determine in patients undergoing on-pump cardiac surgery, if topical tranexamic acid (intra-pericardial) is superior to the usual intravenous tranexamic acid administration for reducing the risk of in-hospital red blood cell transfusion or seizure (composite).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 28, 2019)
  • The proportion of patients in-hospital who receive red blood cell transfusions [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    To determine whether topical tranexamic acid (intra-pericardial) compared with intravenous tranexamic acid administration reduces the risk of in-hospital red blood cell transfusion.
  • The proportion of patients in-hospital who experience a seizure [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    To determine whether topical tranexamic acid (intra-pericardial) compared with intravenous tranexamic acid administration reduces the risk of in-hospital seizure. The proportion of patients who experience a seizure will be analyzed using Fisher's exact test.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2019)
  • In-hospital red blood cell transfusion [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    To determine whether topical tranexamic acid (intra-pericardial) compared with intravenous tranexamic acid administration reduces the risk of in-hospital red blood cell transfusion.
  • In-hospital seizure [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    To determine whether topical tranexamic acid (intra-pericardial) compared with intravenous tranexamic acid administration reduces the risk of in-hospital seizure. The proportion of patients who experience a seizure will be analyzed using Fisher's exact test.
Current Other Pre-specified Outcome Measures
 (submitted: May 15, 2019)
  • Blood product transfusions [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    Analyzed using an ANCOVA model. In such a model, bags of blood product will be included as a dependent variable, whereas dose of tranexamic acid and treatment will be included as covariates.
  • Re-operation for bleeding or tamponade [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    Analyzed with a binomial regression
  • Length of ICU stay [ Time Frame: Number of hours in ICU are being collected at the Post-Operative Visit. Hour collection will start upon arrival at ICU post surgery and stop at ICU exit, up to 10 days maximum. ]
    Analyzed using an ANCOVA model.
  • MACE (Death, non-fatal Myocardial Infarction (MI), or non-fatal stroke) [ Time Frame: Start of surgery to hospital discharge or 10 days maximum (whichever occurs first) ]
    A Cox proportional hazard model will be used to analyze the time to the first occurrence of the composite of death, non-fatal MI, or non-fatal stroke (MACE).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE DEPOSITION - Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery
Official Title  ICMJE Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery (DEPOSITION) Study
Brief Summary The aim is to conduct a double-dummy multi-centre randomized controlled clinical trial of application of topical dose of tranexamic acid (TxA) versus the usual intravenous TxA in patients undergoing on-pump cardiac surgery.
Detailed Description Postoperative bleeding related to open cardiac surgery increases the rates of complications and mortality. It results from the blood thinners that are needed for use. Intravenous tranexamic acid (TxA) has become a mainstay in cardiac surgical procedures for decreasing bleeding and minimizing transfusion requirements. Although intravenous TxA is usually well tolerated, there is a well-known risk (1 to 4%) of postoperative seizures. This is due to the similarity between TxA and the brain tissues. The aim is to eliminate the risk of seizures but to maintain the protection against bleeding. When TxA is used directly on the tissues (topically) for other type of surgeries (joints), TxA is effective to reduce blood loss and transfusions. The aim is to prove that direct application of TxA on the heart can eliminate postoperative seizures and reduce the amount of blood transfusions in patients who have cardiac surgery.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Tranexamic Acid intravenous + Placebo topical versus Placebo intravenous + Tranexamic Acid topical
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
The pharmacy will prepare 2 syringes of 50 ml of topical TxA (5 g) or placebo. They will also prepare for the same patient 2 syringes of 50 ml (5 g) for intravenous (i.v.) injection or placebo. TxA is similar in all aspects to normal saline. Blinding of both teams will be easy. The syringes will be prepared and randomized in pharmacy before the surgery.
Primary Purpose: Prevention
Condition  ICMJE
  • Bleeding
  • Surgical Blood Loss
  • Seizures
Intervention  ICMJE Drug: Tranexamic Acid
Tranexamic Acid is a medication used to treat or prevent excessive blood loss from major trauma, post partum, surgery, tooth removal, nose bleeds, and heavy menstruation.
Other Name: Cyklokapron
Study Arms  ICMJE
  • Active Comparator: Topical Tranexamic Acid/Placebo
    Topical Tranexamic Acid 5g to 10g (50 to 100mL) or placebo. The topical will be poured into the pericardial and mediastinal cavities after protamine administration.
    Intervention: Drug: Tranexamic Acid
  • Active Comparator: Intravenous Tranexamic Acid/Placebo
    Intravenous Tranexamic Acid 1 to 10g (10 to 100mL) or placebo administered intravenously at the induction of anesthesia as a bolus-infusion.
    Intervention: Drug: Tranexamic Acid
Publications *
  • Spence J, Long S, Tidy A, Raymer K, Devereaux PJ, Lamy A, Whitlock R, Syed S. Tranexamic Acid Administration During On-Pump Cardiac Surgery: A Survey of Current Practices Among Canadian Anesthetists Working in Academic Centers. Anesth Analg. 2017 Dec;125(6):1863-1870. doi: 10.1213/ANE.0000000000002422.
  • Lamy A, Tong W, Gao P, Chrolavicius S, Gafni A, Yusuf S, Connolly SJ. The cost of clopidogrel use in atrial fibrillation in the ACTIVE-A trial. Can J Cardiol. 2012 Jan-Feb;28(1):95-101. doi: 10.1016/j.cjca.2011.08.112. Epub 2011 Oct 8.
  • Habbab LM, Hussain S, Power P, Bashir S, Gao P, Semelhago L, VanHelder T, Parry D, Chu V, Lamy A. Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery (DEPOSITION) study: Results of a pilot study. J Card Surg. 2019 May;34(5):305-311. doi: 10.1111/jocs.14027. Epub 2019 Mar 25.
  • Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, Cooper DJ, Marasco S, McNeil J, Bussières JS, McGuinness S, Byrne K, Chan MT, Landoni G, Wallace S; ATACAS Investigators of the ANZCA Clinical Trials Network. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. N Engl J Med. 2017 Jan 12;376(2):136-148. doi: 10.1056/NEJMoa1606424. Epub 2016 Oct 23. Erratum in: N Engl J Med. 2018 Feb 22;378(8):782.
  • Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussières JS, Côté D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R; BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008 May 29;358(22):2319-31. doi: 10.1056/NEJMoa0802395. Epub 2008 May 14. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290.
  • Mazer CD, Whitlock RP, Fergusson DA, Belley-Cote E, Connolly K, Khanykin B, Gregory AJ, de Médicis É, Carrier FM, McGuinness S, Young PJ, Byrne K, Villar JC, Royse A, Grocott HP, Seeberger MD, Mehta C, Lellouche F, Hare GMT, Painter TW, Fremes S, Syed S, Bagshaw SM, Hwang NC, Royse C, Hall J, Dai D, Mistry N, Thorpe K, Verma S, Jüni P, Shehata N; TRICS Investigators and Perioperative Anesthesia Clinical Trials Group. Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery. N Engl J Med. 2018 Sep 27;379(13):1224-1233. doi: 10.1056/NEJMoa1808561. Epub 2018 Aug 26.
  • Kalavrouziotis D, Voisine P, Mohammadi S, Dionne S, Dagenais F. High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg. 2012 Jan;93(1):148-54. doi: 10.1016/j.athoracsur.2011.07.085. Epub 2011 Nov 4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 15, 2019) 		3800
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2022
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. ≥ 18 years of age
  2. Undergoing a cardiac surgical procedure (i.e. isolated coronary artery bypass graft (CABG), isolated single cardiac valve surgery or a combination of both or isolated ascending aorta replacement) with the use of cardiopulmonary bypass (CPB) and median sternotomy
  3. Provide written informed consent

Exclusion Criteria:

  1. Allergy to tranexamic acid
  2. Undergoing minimally invasive surgery

  3. Fulfill any of the following transfusion risk factors (A-D):

    A. Emergency surgery B. History of bleeding disorder C. Inherited thromboembolic or hemorrhagic disease D. Infective endocarditis

  4. History of previous cardiac surgery
  5. Severe renal impairment (serum creatinine >250 µmol/L)
  6. Pre-operative hemoglobin <120 g/L
  7. Pre-operative thrombocytopenia (<50,000 platelets per µL)
  8. Expected circulatory arrest
  9. Pregnancy or breast feeding
  10. Previously enrolled in the DEPOSITION trial
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ingrid Copland, CCRA 905-527-4322 ext 40368 cogency@phri.ca
Contact: Austin Browne, PhD 905-527-4322 ext 40582 Austin.Browne@phri.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03954314
Other Study ID Numbers  ICMJE DEPOSITION
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Population Health Research Institute
Study Sponsor  ICMJE Population Health Research Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Andre Lamy, MD Population Health Research Institute
PRS Account Population Health Research Institute
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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