Clinical trial NCT07012837: Transfusion Reduction in High-Bleeding-Risk Cardiac Surgery With Desmopressin
Official title: Reducing Point-of-Care Transfusion Requirements With Prolonged Desmopressin in High-Bleeding-Risk Cardiac Surgery: A Multicentre Randomized Controlled Trial (REDES-BLEED)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Adult Patients Undergoing Cardiac Surgery
High Bleeding Risks
Planned Elective Cardiac Surgery Using CPB
Keywords: Adult cardiac surgery
Cardiopulmonary bypass
High bleeding risks
Desmopressin
Prophylactic
Point-of-care coagulation tests
Lead sponsor: Imam Abdulrahman Bin Faisal University
Sponsor class: OTHER
Collaborators: name: Johns Hopkins Aramco Healthcare
First posted: 2025-06-10
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A multicenter, parallel, two-group, prospective, multicenter, randomized, blinded comparative trial in patients with high risks of postoperative bleeding scheduled for elective cardiac surgery at the King Fahad Hospital of Imam Abdulrahman Bin Faisal University, Al Khobar and Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.
Primary purpose: PREVENTION

Brief summary: Rationale

Bleeding after cardiac surgery is a complication that might result in increased morbidity, mortality, and cost of cardiac surgery by 1.76 (confidence interval (CI), 1.64-1.90) times and a median increase in costs by Australian $33,338 (CI, $21,943-$38,415) \[1\]. Strategies and techniques to reduce postoperative bleeding in identified high-risk patients for bleeding after cardiac surgery might improve outcomes and resource utilization.

Desmopressin (DDAVP) is used as a hemostatic agent to prevent and treat bleeding in patients with mild hemophilia patients with von Willebrand's deﬁciency through stimulating the release of von Willebrand factor from endothelial cells.

Previous studies showed controversial results in terms of reduced transfusion requirements in patients with low risk for bleeding with post cardiopulmonary bypass (CPB) bleeding following prophylactic infusing desmopressin over 10 to 15 minutes after induction of anesthesia or protamine administration due to its positive effects on the coagulation system responsible for such bleeding. Contradictory, prophylactic desmopressin use demonstrated fewer transfusion requirements in patients treated with antiplatelets, which raises the need to examine its efficacy in high-risk cardiac surgery patients for perioperative bleeding. These controversial results might be attributed to delayed administration of desmopressin after evolving CPB-associated thrombocytopenia, platelet dysfunction, coagulation factor consumption and dilution, hyperfibrinolysis, and hypofibrinogenemia \[2\]

Concerns were raised about the associated transient decreases in systemic vascular resistance and blood pressure after desmopressin administration following discontinuing CPB and administering protamine, which might be related to the rapid infusion rate during the critical surgery stage.

The cost of a single dose of Desmopressin 0.3 ug/kg for a patient with an average weight of 70 Kg is about 82US$ which is cheaper than the alternative hemostatic agents proved to be effective in reducing bleeding and transfusion needs after cardiac surgery (e.g., fibrinogen concrete (average of 3 g = 1,167US$) and prothrombin complex concentrate (6,255US$ considering low fixed dosfixed-doseof 1040 IU F IX).

It is yet unclear if extended infusions of desmopressin started earlier before the development of CPB-associated coagulopathy and platelets dysfunction from anesthesia induction time and continued to the end of CPB before protamine administration would offer an "efficacy," "safety, and "cost-effective" benefits over placebo in patients with high risks for bleeding after cardiac surgery terms of the need for transfusion, cumulative postoperative 48-hour chest tube outputs, need for reoperation, thrombotic complications, 30-day mortality, hemodynamic stability, and urine output during and after completing infusion, and costs of the study drug and allogenic transfusion requirement. That raises the need to examine its impact on these crucial clinical outcomes.

Objective

The primary objective of this prospective multicentre randomized clinical trial (RCT) is, compared with placebo, to examine the impact of prolonged infusion desmopressin on reducing postoperative bleeding and the need for allogenic allogeneic transfusion in high-bleeding-risk cardiac surgery patients scheduled for elective cardiac surgical procedures using CPB. Secondary objectives include comparing placebo and desmopressin in terms of safety and cost-effectiveness.

Hypothesis

It is hypothesized that extended 'desmopressin' infusion compared to 'placebo' results in less postoperative bleeding and transfusion needs (more effective) and leads to less hemodynamic compromise (safer) and cheaper (cost-effective) in high-risk cardiac surgery patients.

Detailed description: 3. INTRODUCTION AND RATIONALE

3.1 The current role of prophylactic use of desmopressin in low-risk cardiac surgery patients.

The efficacy of "routine prophylactic administration" of desmopressin 0.3 ug/kg after anesthesia induction or protamine administration to reduce bleeding and transfusion has been revisited in a Cochrane review of 39 randomized controlled trials (RCTs) focusing on cardiac surgery \[5\] which demonstrated that compared with placebo, desmopressin used resulted in a slight decreased total volume of red blood cells (RBCs) transfused (mean difference (MD) -0.52 units, 95%CI -0.96 to -0.08 units; 14 trials, 957 participants) and total blood loss (MD -135.24 mL, 95% CI -210.80 mL to -59.68 mL; 22 trials, 1,358 participants) in adult cardiac surgery. These RCTs had low methodological quality.

Desmopressin may reduce postoperative bleeding in cardiac surgery patients who have received preoperative aspirin within 7 days of surgery, longer cardiopulmonary bypass (CPB) bypass than 140 minutes, and those with platelet dysfunction \[6\].

A recent European Association for Cardio-Thoracic Surgery (EACTS) and the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) guidelines on patient blood management (PBM) in adult cardiac surgery, in collaboration with the European Board of Cardiovascular Perfusion (EBCP), \[7\] concluded a task force of professionals specializing in patient blood management recommend that the prophylactic use of desmopressin is not recommended to reduce bleeding complications in cardiac surgery patients (a class III of recommendation and level A of evidence). However, it suggests considering desmopressin for bleeding patients with platelet dysfunction to reduce bleeding complications. (a class IIa of recommendation and level C of evidence).

3.2 Efficacy of Desmopressin in Reducing Postoperative Bleeding and Allogenic Blood Transfusion Needs

Although desmopressin showed a slight decrease in transfusion requirement in patients with post-CPB bleeding due to its positive effects on the coagulation system responsible for such bleeding, there is a continued debate on the "efficacy" and "safety" of prophylactic use of desmopressin for cardiac surgery \[8-9\].

A previous small study demonstrated the efficacy of desmopressin in reducing homologous blood requirement in cardiac surgical patients treated with aspirin within 5 days before surgery \[10\].

3.3. Does the timing of the Desmopressin Administration Make A Difference?

The timing of the administration of desmopressin might explain such controversial results. Infusing desmopressin following protamine administration failed to show significant differences in transfusion requirements in small studies, including few patients \[11-13\]. Similar results were reported when desmopressin was administered after chest closure \[14\]. Delaying desmopressin administration until the termination of CPB or chest closure, with its impact on the coagulation system and platelet functions, might explain these reported low or no efficacy in reducing bleeding compared with placebo. Additionally, this is contradictory to the highly recommended routine use of antifibrinolytics (class 1, Level of evidence A) and using protamine to heparin ratio of less than one (class 1, Level of evidence B) by the current EACTS/EACTAIC/EBCP Guidelines on PBM \[6\], that was not considered in these studies \[10-14\].

3.4. Can Repeating Desmopressin Administration Increase the Efficacy?

Repeating the administration of desmopressin after CPB and then 12 hours after surgery did not result in a significant difference despite the blood loss being less than that of the placebo in the former in a small, unpowered study \[15-16\].

3.5. Safety of Desmopressin Administration

Rapid infusing desmopressin over ten or 15 minutes, particularly shortly after administering protamine with its unique vasodilatation and histamine release effect, might explain the notable reduced systemic vascular resistance (SVR) and blood pressure and increased pulmonary vascular resistance (PVR) in some studies \[10-14, 16\], which was unlikely due to the associated histamine release \[17\].

Desmopressin use did not result in significant changes in urine output \[12\] or increased myocardial infarction incidence \[15\]; these studies included few patients to examine these secondary outcomes.

3.6. Can Slower Desmopressin Administration Increase Its Safety

A slower infusion of desmopressin over 30 rather than 10 minutes was only associated with less increased PVR in this small cohort \[18\]. That raises the need to examine the "safety" of a more extended infusion of desmopressin.

3.7. Can Point-of-Care Coagulation Testing Improve Efficacy of Desmopressin Administration

Point-of-care (POC) thromboelastography (TEG) guided hemostasis and transfusion reduced RBCs, plasma, and platelet transfusion, operating room (OR) length of stay (LOS), intensive care unit (ICU) LOS, and bleeding rate (P = 0.002) were reduced with compared with controls in a metanalysis include 9 RCTs, two of them on cardiac surgery patients \[19\]. However, that was not translated into associated reduced mortality rates \[19\].

Interestingly, a single-Canadian-center, retrospective, observational propensity-matched study demonstrated increased desmopressin administration after the introduction of point-of-care (POC) rotational thromboelastometry (ROTEM) testing with and associated statistically higher platelets transfusion \[20\].

3.8. Feasibility

Extended infusion of desmopressin from induction of anesthesia to the end of CPB has never been compared in terms of "efficacy," "safety," and "cost-effectiveness" in high-risk cardiac surgery patients for bleeding. Cardiac surgery in patients with a high risk for bleeding is more complex to perform, and it might take longer durations to be accomplished, increasing the overall healthcare costs, which could be unacceptable for the stakeholders. Using desmopressin infusion over a more extended period might be an "effective," "safe," and "affordable" choice.

3.6. Why this randomized clinical trial?

Infusing the same desmopressin dose of 0.3 ug/kg over a more extended duration from anesthesia induction until before administering protamine might have its potential benefits and disadvantages in patients with higher risks for bleeding. The proposed randomized clinical trial here will compare extended intraoperative infusion of 'desmopressin' with 'placebo' procedures concerning effects on cumulative blood loss, need for allogenic blood transfusion, and hemostatic drugs and their overall costs, safety, and feasibility. If 'desmopressin' is more effective and less safe and is cost-effective than the "placebo,' it should be used in this group of patients. If 'desmopressin' is comparable and less safe than the "placebo,' it should not be used in this group of patients.

Eligibility criteria: Inclusion Criteria:

* Adult 18 years or older.
* Scheduled for any type of elective cardiac surgery.
* Using CPB.
* General anesthesia is provided in an endotracheally intubated patient.
* A high risk of postoperative bleeding is defined as any of the following \[21-23\];

  * Redo or repeated surgery.
  * Treatment with platelet P2Y12 receptor--inhibiting drugs was discontinued for 7 days (ticlopidine, clopidogrel, and prasugrel) or 5 days (ticagrelor).
  * Any known coagulation disorders.
  * Hypofibrinogenemia less than 150 mg/dl.
  * Platelet count \<100.000 cells/μL.
  * Chronic renal failure, whether dialysis-dependent or not.
  * Liver cell failure Child-Pugh class B or C or the Model for End-Stage Liver Disease (MELD) \>=29
  * Infective endocarditis.
  * Acute type-A aortic dissection.
  * Expected surgery with CPB time longer than 150 minutes.
  * Preoperative estimated Papworth Bleeding Risk Score of 8% or greater \[23\].

Exclusion Criteria:

* Planned for cardiac surgery without CPB;
* Planned for a combined coronary revascularization surgery and a valve or intra-cardiac surgery;
* Pregnancy;
* Consent for another interventional study during anesthesia;
* No written informed consent;
* Preoperative need for mechanical circulatory support;

Primary outcomes:
measure: Cumulative 48-hour postoperative bleeding
timeFrame: Intraoperative and for 48 hours after surgery
Secondary outcomes:
measure: The need for allogenic PRBCs transfusion
timeFrame: For 7 days after surgery
measure: The need for allogenic transfusion of fresh frozen plasma
timeFrame: For the first 7 days after surgery
measure: The need for allogenic individual and pooled platelet units
timeFrame: For the first 7 days after surgery
measure: The need for allogenic cryoprecipitates units
timeFrame: For the first 7 days after surgery
measure: The need for Recombinant Factor VIII administration
timeFrame: For the first 7 days after surgery
measure: The need for fibrongoen concentrate (FC) administration
timeFrame: For the first 7 days after surgery
measure: The need for prothrombin complex concentrate (PCC) administration
timeFrame: For the first 7 days after surgery
measure: Intraoperative urine output volume
timeFrame: Intraopertively
measure: The number of intraoperative hypotension episodes
timeFrame: Intraoperatively
measure: Timings of intraoperative hypotension episodes
timeFrame: Intraoperatively
measure: Intraoperative fluid balance
timeFrame: Intraoperatively
measure: The 24-hour fluid balance
timeFrame: For 24 hour after surgery
measure: The 48-hour fluid balance
timeFrame: For 48 hour after surgery
measure: The need for re-explorative surgery
timeFrame: For 30 days after surgery
measure: Postoperative ICU lenght of stay (LOS)
timeFrame: For 90 days after surgery
measure: Postoperative hospital length of stay (LOS)
timeFrame: For 180 days after surgery
measure: Postoperative documented death from a cardiovascular cause
timeFrame: For 30 days after surgery
measure: Postoperative documented stroke
timeFrame: For 30 days after surgery
measure: Postoperative documented nonfatal myocardial infarction (MI)
timeFrame: For 30 days after surgery
measure: Postoperative documented acute kidney injury (AKI)
timeFrame: For 7 days after surgery
measure: Postoperative pulmonary complications
timeFrame: For 7 days after surgery
measure: The overall costs of used desmopressin, allogenic blood units, and hemostatic drugs
timeFrame: For 180 days after surgery
measure: Coronary graft thrombosis
timeFrame: For 3 months after surgery.
measure: The need for revascularization
timeFrame: For 3 months after surgery.
measure: Need for hospital re-admission at 30 days after surgery
timeFrame: For 30 days after surgery.
measure: Need for hospital re-admission at 3 months after surgery
timeFrame: For 3 months after surgery.
measure: Mortality at 30 days after surgery.
timeFrame: For 30 days after surgery
measure: Mortality at 90 days after surgery.
timeFrame: For 90 days after surgery
Other outcomes:
Locations:
city: Dammam
country: Saudi Arabia
facility: Imam Abdulrahamn Bin Faisal University (Former, Dammam University)
state: Eastern
Study officials:
affiliation: Imam Abdulrahman Bin Faisal University
name: Mohamed R El Tahan, MD
role: STUDY_CHAIR
affiliation: Imam Abdulrahman Bin Faisal University
name: Fahad Makhdoum, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Imam Abdulrahman Bin Faisal University
name: Yasser F ElGhoneimy, MD
role: STUDY_DIRECTOR
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