A Phase 3 interventional study of Placebo and Desmopresin in Adult Patients Undergoing Cardiac Surgery, High Bleeding Risks and Planned Elective Cardiac Surgery Using CPB, sponsored by Imam Abdulrahman Bin Faisal University. Not yet recruiting at 1 site in Saudi Arabia. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-06-10.
Sponsored by Imam Abdulrahman Bin Faisal University · Phase 3, Interventional, and Prevention
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.
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.
A high risk of postoperative bleeding is defined as any of the following [21-23];
Exclusion Criteria:
Before induction of anesthesia, patients will receive identical and similar clear study solutions in similar size transparent 50-cc bags, including Saline will be infused over five hours at a rate of 10 ml/hr. The local pharmacists who will not be involved in patients' care or data collection will prepare the study solution.
Drug: Placebo
Before induction of anesthesia, patients will receive identical and similar clear study solutions in similar size transparent 50-cc bags, including Desmopressin 0.3 ug/kg of the patient's body weight will be infused over five hours at a rate of 10 ml/hr. The local pharmacists who will not be involved in patients' care or data collection will prepare the study solution.
Drug: Desmopresin
Before induction of anesthesia, patients will receive identical and similar clear study solutions in similar size transparent 50-cc bags, including Saline will be infused over five hours at a rate of 10 ml/hr. The local pharmacists who will not be involved in patients' care or data collection will prepare the study solution.
Before induction of anesthesia, patients will receive identical and similar clear study solutions in similar size transparent 50-cc bags, including Desmopressin 0.3 ug/kg of the patient's body weight will be infused over five hours at a rate of 10 ml/hr. The local pharmacists who will not be involved in patients' care or data collection will prepare the study solution.
Cumulative 48-hour postoperative bleeding
The primary outcome is the cumulative 48-hour postoperative bleeding, defined as the sum of estimated intraoperative salvaged blood and blood loss and postoperative chest tube output for 48 hours from surgery. Intraoperative blood loss was calculated from the total volume in suction bottles (minus the volume of irrigating solution), weighed sponges, and the volume collected in the Cell-Saver reservoir (minus the volume of anticoagulant solution). After the chest is closed, hourly postoperative blood loss will be calculated from the chest tubes and drain reservoirs.
Time frame: Intraoperative and for 48 hours after surgery
The need for allogenic PRBCs transfusion
the need for allogenic PRBCs transfusion during 7 days after surgery (and timings).
Time frame: For 7 days after surgery
The need for allogenic transfusion of fresh frozen plasma
The need for allogenic transfusion of fresh frozen plasma during the first 7 days after surgery (and timings).
Time frame: For the first 7 days after surgery
The need for allogenic individual and pooled platelet units
Allogenic individual and pooled platelet units needed to be transfused during the first 7 days after surgery (and timings).
Time frame: For the first 7 days after surgery
The need for allogenic cryoprecipitates units
Allogenic cryoprecipitates units needed to be transfused during the first 7 days after surgery (and timings).
Time frame: For the first 7 days after surgery
The need for Recombinant Factor VIII administration
Recombinant Factor VIII administration needed to be transfused during the first 7 days after surgery (and timings).
Time frame: For the first 7 days after surgery
The need for fibrongoen concentrate (FC) administration
F.C. administration needed to be transfused during the first 7 days after surgery (and timings).
Time frame: For the first 7 days after surgery
The need for prothrombin complex concentrate (PCC) administration
PCC administration needed to be transfused during the first 7 days after surgery (and timings).
Time frame: For the first 7 days after surgery
Intraoperative urine output volume
Intraoperative urine output volume in ml.
Time frame: Intraopertively
The number of intraoperative hypotension episodes
The number of intraoperative hypotension episodes unrelated to the surgical procedure step defined as a 15% decrease in mean arterial blood pressure (MAP) from baseline values lasted for 5 minutes and required intervention (e.g., fluid therapy, vasopressor, or inotropes as per the discretion of anesthesia provider).
Time frame: Intraoperatively
Timings of intraoperative hypotension episodes
Timings of intraoperative hypotension episodes in relation to study solution or protamine administration.
Time frame: Intraoperatively
Intraoperative fluid balance
Intraoperative fluid balance is the net of differences between intake and output during surgery.
Time frame: Intraoperatively
The 24-hour fluid balance
The 24-hour fluid balance is defined as the net of differences between intake and output 24 hours after surgery.
Time frame: For 24 hour after surgery
The 48-hour fluid balance
The 48-hour fluid balance is defined as the net of differences between intake and output 48 hours after surgery.
Time frame: For 48 hour after surgery
The need for re-explorative surgery
The need for re-explorative surgery during the same admission.
Time frame: For 30 days after surgery
Postoperative ICU lenght of stay (LOS)
Postoperative ICU LOS of days from the date of surgery until discharge from the ICU or death.
Time frame: For 90 days after surgery
Postoperative hospital length of stay (LOS)
Postoperative hospital LOS from the date of surgery until discharge from the hospital or death.
Time frame: For 180 days after surgery
Postoperative documented death from a cardiovascular cause
Postoperative documented death from a cardiovascular cause within 30 days of surgery.
Time frame: For 30 days after surgery
Postoperative documented stroke
Postoperative documented nonfatal stroke within 30 days of surgery.
Time frame: For 30 days after surgery
Postoperative documented nonfatal myocardial infarction (MI)
Postoperative documented nonfatal MI within 30 days of surgery.
Time frame: For 30 days after surgery
Postoperative documented acute kidney injury (AKI)
Postoperative documented AKI within 7 days of surgery.
Time frame: For 7 days after surgery
Postoperative pulmonary complications
Postoperative pulmonary complications are defined according to the PROVHILO study within 7 days of surgery
Time frame: For 7 days after surgery
The overall costs of used desmopressin, allogenic blood units, and hemostatic drugs
The overall costs of used desmopressin, allogenic blood units, and hemostatic drugs are represented in US$ as reported by the local pharmacy department.
Time frame: For 180 days after surgery
Coronary graft thrombosis
Any documented coronary graft thrombosis within 3 months of surgery.
Time frame: For 3 months after surgery.
The need for revascularization
Any documented need for revascularization within 3 months of surgery.
Time frame: For 3 months after surgery.
Need for hospital re-admission at 30 days after surgery
Need for hospital re-admission at 30 days after surgery.
Time frame: For 30 days after surgery.
Need for hospital re-admission at 3 months after surgery
Need for hospital re-admission at 3 months after surgery.
Time frame: For 3 months after surgery.
Mortality at 30 days after surgery.
Mortality at 30 days after surgery.
Time frame: For 30 days after surgery
Mortality at 90 days after surgery.
Mortality at 90 days after surgery.
Time frame: For 90 days after surgery
Plan to share: Yes — The study database will be locked upon completion of data entry and resolution of all discrepancies or missing data, or when the investigators determine that no further resolution is feasible despite reasonable efforts. Prior to locking, a final review of the database will be conducted. Once locked, the dataset will be exported for statistical analysis. De-identified individual participant data (IPD), the study protocol, and statistical analysis plan will be made available upon reasonable request from qualified researchers beginning six months after publication and for a period of five years. Data access will be granted following review and approval of a research proposal and the signing of a data access agreement. Requests should be directed to the corresponding author.
Supporting information: Study protocol, Sap, Csr, Analytic code
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Imam Abdulrahman Bin Faisal University