Chronic Kidney Diseases, Acute Kidney Injury, Bleeding, Surgery
Conditions
Keywords
Major Noncardiac Surgery, Tranexamic Acid, Desmopressin
Brief summary
The BRACKETS pilot study is a multicentre, prospective, randomized controlled trial of prophylactic preoperative tranexamic acid (TXA) versus placebo and, using a partial factorial design, of prophylactic preoperative desmopressin versus placebo.
Detailed description
Perioperative administration of TXA reduces bleeding risk in surgical patients. However, large clinical trials have excluded patients with advanced kidney disease, so the benefits remain uncertain in this population, and there is potential for harm. The benefit of desmopressin, which is purported to more directly address the defect of primary hemostasis believed important in severe kidney disease more directly than TXA, has not been examined in adequate randomized control trials (RCTs). Both medications are generic and have been available for many years. To convincingly test these medications in patients with severe kidney disease, large, global trials are required. This pilot-phase trial will 1) inform the feasibility and design of a large international trial to evaluate the efficacy and safety of TXA and desmopressin in patients with advanced kidney disease undergoing noncardiac surgery, 2) provide preliminary data regarding the efficacy and safety of TXA and desmopressin in people with advanced kidney disease having noncardiac surgery, and 3) provide pharmacokinetic data to inform dose selection.
Interventions
DRUGDesmopressin Injectable Solution
Intravenous desmopressin, 20 mcg, single dose administration.
Intravenous tranexamic acid, 1000 mg single dose administration for patients with eGFR\<25 not yet receiving dialysis OR 500 mg single dose administration for patients receiving dialysis.
OTHERPlacebo
Intravenous 0.9% saline solution
Sponsors
Hamilton Health Sciences Corporation
Population Health Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Study drugs will be sourced locally and will be prepared by appropriately qualified center personnel who are independent of the study team to ensure blinding is maintained.
Intervention model description
2x2 partial factorial design where patients are first randomized to receive prophylactic intravenous TXA versus placebo, and (when the study drug is available) to be randomized to receive prophylactic intravenous desmopressin versus placebo before noncardiac surgery.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligibility criteria specific to the tranexamic acid (TXA) factorial component of trial Inclusion Criteria: 1. One of either: 1.1. eGFR \<25 ml/min/1.73m2 estimated using the CKD-Epi 2009 or 2021creatinine-based equation from the most recent serum creatinine measurement done in the previous 6 months; or 1.2. Receipt of dialysis (including hemodialysis, peritoneal dialysis, hemofiltration, or hemodiafiltration) within the last 7 days; 2. Planned noncardiac surgery (elective, urgent, or emergency surgery); 3. Expected to require at least an overnight hospital admission after surgery; 4. Age ≥18 years; and 5. Informed consent is obtained to participate in the BRACKETS-Pilot Trial.
Exclusion criteria
1. Undergoing cardiac surgery; 2. Undergoing intracranial neurosurgery; 3. Undergoing surgery for creation or revision of arteriovenous fistula or graft for dialysis access; 4. Planned use of prophylactic systemic TXA or ϵ-aminocaproic acid; 5. Hypersensitivity or known allergy to TXA; 6. History of seizure disorder; 7. Recent (within 90 days) stroke, myocardial infarction, acute arterial thrombosis, deep venous thrombosis, pulmonary embolism, or thrombosis of an arteriovenous fistula or graft; 8. History of thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome, or antiphospholipid antibody syndrome; 9. Women who are known to be pregnant, breastfeeding, or who meet both of the following criteria: i) are of childbearing potential and do not have a negative pregnancy test documented in the 7 days before surgery, AND ii) are not using effective contraception; or 10. Previously enrolled in the BRACKETS-Pilot Trial. Eligibility criteria specific to the desmopressin factorial component of trial Inclusion criteria: 1\. Included in the TXA factorial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of recruitment | Through study completion, an average of 1.5 years | A rate of 0.25 patients per study site per week |
| Receipt of the allocated study drug within 1 hour before start of surgery for the tranexamic acid factorial | Day of surgery | Account of whether the patient began to receive study drug for the TXA factorial within an hour before skin incision. Target ≥80% of participants |
| Receipt of the allocated study drug within 1 hour before start of surgery for the desmopressin factorial | Day of surgery | Account of whether the patient began to receive study drug for the desmopressin factorial within an hour before skin incision. Target ≥80% of participants |
| Completion of 30-day follow-up | 30 days after randomization | Account of whether the patient or their next-of-kin could be contacted and completed the 30-day post-randomization assessment. Target ≥80% of participants |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bleeding Independently Associated with Mortality after noncardiac Surgery (BIMS) | 30 days after randomization | Number of patients who experience BIMS |
| Bleeding Score | 30 days after randomization | 10-category ordinal score. Minimum scores mean a better outcome. 0 denotes no bleeding or bleeding in which the nadir hemoglobin is ≥70 g/L, no red blood transfusion was given, no reoperation for reasons of bleeding occurred, and there was no death imminently or directly caused by bleeding. 1. denotes bleeding and post-operative hemoglobin \<70 g/L or 1 unit of blood (red blood cells or whole blood) transfused. 2. denotes bleeding and 2 units transfused. 3. denotes bleeding and 3 units transfused. 4. denotes bleeding and 4 units transfused 5. denotes bleeding and 5 units transfused. 6. denotes bleeding and 6 units transfused. 7. denotes bleeding and 7 units transfused. 8. denotes bleeding and 8 or more units of blood transfused. 9. denotes reoperation for reasons of bleeding. 10. denotes death imminently or directly caused by bleeding. |
| Reoperation for reasons of bleeding | 30 days after randomization | Number of patients who return to the operating room for surgical management of suspected documented bleeding |
| Blood (red blood cells or whole blood) transfused | 30 days after randomization | Number of units of blood transfused. |
| Any blood transfusion (red blood cells or whole blood) | 30 days after randomization | Number of units of blood transfused. |
| Lowest measured hemoglobin concentration | 30 days after randomization | The mean absolute difference for continuous outcomes using linear regression with treatment allocation |
| Most recent hemoglobin concentration | 30 days after randomization | The mean absolute difference for continuous outcomes using linear regression with treatment allocation |
| Death | 30 days after randomization | Number of patients who die of any cause |
| Major arterial and venous thrombosis | 30 days after randomization | (i.e., composite of myocardial injury after noncardiac surgery \[MINS\], stroke, peripheral arterial thrombosis, dialysis vascular access thrombosis requiring anticoagulation or intervention, and symptomatic venous thromboembolism) |
| Myocardial Injury after Noncardiac Surgery (MINS) | 30 days after randomization | Number of patients who experience MINS |
| Myocardial Injury after Noncardiac Surgery (MINS) that meets criteria for myocardial infarction | 30 days after randomization | Number of patients who experience MINS that meets criteria for myocardial infarction (based on the Fourth Universal Definition of myocardial infarction) |
| MINS that is an isolated ischemic troponin elevation | 30 days after randomization | Number of patients who experience MINS that is an isolated ischemic troponin elevation |
| Stroke | 30 days after randomization | Number of patients experiencing a stroke |
| Non-hemorrhagic stroke | 30 days after randomization | Number of patients who experience a non-hemorrhagic stroke |
| Hemorrhagic stroke | 30 days after randomization | Number of patients who experience a hemorrhagic stroke |
| Peripheral arterial thrombosis | 30 days after randomization | Number of patients who experience a peripheral arterial thrombosis |
| Thrombosis of arteriovenous fistula or graft | 30 days after randomization | Number of patients who have thrombosis of arteriovenous fistula or graft |
| Symptomatic proximal venous thromboembolism | 30 days after randomization | Number of patients who experience symptomatic proximal venous thromboembolism |
| Symptomatic pulmonary embolism | 30 days after randomization | Number of patients who experience a symptomatic pulmonary embolism |
| Symptomatic proximal leg or arm deep venous thrombosis (DVT) | 30 days after randomization | Number of patients who experience a symptomatic proximal leg or arm DVT |
| Non-fatal cardiac arrest | 30 days after randomization | Number of patients who experience non-fatal cardiac arrest |
| Coronary revascularization procedure | 30 days after randomization | Number of patients who undergo coronary revascularization procedure |
| Clinically important atrial fibrillation or flutter | 30 days after randomization | Number of patients who experience clinically important atrial fibrillation or flutter |
| Acute heart failure or clinically important volume overload | 30 days after randomization | Number of patients who experience acute heart failure or clinically important volume overload. |
| Acute kidney injury (for patients not receiving dialysis before surgery) | 30 days after randomization | Number of patients who experience an acute kidney injury |
| New start of dialysis | 30 days after randomization | Number of patients who require new start of dialysis |
| Seizure | 30 days after randomization | Number of patients who experience a seizure |
| Clinically significant intraoperative hypotension | 30 days after randomization | Number of patients who experience clinically significant intraoperative hypotension |
| Clinically significant postoperative hypotension | Up to and including the end of postoperative day 1 | Number of patients who experience clinically significant postoperative hypotension |
| Sepsis | 30 days after randomization | Number of patients who experience sepsis |
| Duration of surgery | 30 days after randomization | The time from skin incision to closure, in minutes. |
| Receipt of platelets | 30 days after randomization | Any transfusion of this blood product |
| Receipt of fibrinogen | 30 days after randomization | Any transfusion of this blood product |
| Receipt of fresh frozen plasma | 30 days after randomization | Any transfusion of this blood product |
| Receipt of cryoprecipitate | 30 days after randomization | Any transfusion of this blood product |
| Receipt of recombinant Factor VIIa | 30 days after randomization | Number of patients receiving recombinant factor VIIa |
| Receipt of prothrombin complex concentrate | 30 days after randomization | Number of patients who receive prothrombin complex concentrate |
| Prescribed erythropoiesis stimulating agent | 30 days after randomization | Number of patients receiving a weekly dose of erythropoiesis stimulating agent on prescription active at 30 days |
| Severe hyponatremia | Up to and including the end of postoperative day 1 | Measured serum sodium concentration \<125 meq/L |
| Duration of hospital stay after surgery | Day of surgery and ending the day of discharge | Cumulative number of nights spent in an acute care hospital |
| Duration of critical care stay after surgery | Day of surgery and ending the day of discharge | Cumulative number of nights spent in an intensive care unit |
| Delayed graft function after kidney transplantation | Within 7 days following kidney transplantation | Receipt of dialysis |
| Persistent dialysis dependence | 30 days after randomization | Participant continues to receive dialysis after surgery. |
| Incisional site pain severity | 30 days after randomization in the last 24 hours | Rating of pain using the 10-point ordinal scale where 0 corresponds to no pain and 10 corresponds to the worst pain imaginable. |
Countries
Canada
Contacts
CONTACTIngrid Copland
PRINCIPAL_INVESTIGATORPavel Roshanov, MC,MSc,FRCPC
Western University
Outcome results
None listed