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| Name | Class |
|---|---|
| Population Health Research Institute | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prophylactic intravenous tranexamic acid and prophylactic intravenous desmopressin. | Experimental | Within 20 minutes preceding anticipated skin incision, patients will receive preoperative prophylactic intravenous tranexamic acid at a dose of 1000 mg infused over 10 minutes for patients with estimated glomerular filtration rate (eGFR) <25 ml/min/1.73m2 who do not receive dialysis before surgery and 500 mg infused over 10 minutes for patients who receive dialysis. Within 20 minutes preceding anticipated skin incision, patients allocated to the desmopressin intervention group will receive intravenous desmopressin at a dose of 20 mcg over 30 minutes. |
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| Prophylactic intravenous tranexamic acid and placebo. | Experimental | Within 20 minutes preceding anticipated skin incision, patients will receive preoperative prophylactic intravenous tranexamic acid at a dose of 1000 mg infused over 10 minutes for patients with eGFR <25 ml/min/1.73m2 who do not receive dialysis before surgery and 500 mg infused over 10 minutes for patients who receive dialysis. Within 20 minutes preceding anticipated skin incision, patients allocated to the desmopressin control group will receive an intravenous infusion of 0.9% saline solution, administered over a duration of 30 minutes. |
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| Prophylactic intravenous desmopressin and placebo. | Experimental | Within 20 minutes preceding anticipated skin incision, patients will receive intravenous desmopressin at a dose of 20 mcg over 30 minutes. Patients will not receive prophylactic tranexamic acid. Within 20 minutes preceding anticipated skin incision, patients allocated to the tranexamic acid control group will receive an intravenous infusion of 0.9% saline solution. This saline solution will be administered over a duration of 10 minutes in a volume equivalent to that received by patients in the tranexamic acid intervention group. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Desmopressin Injectable Solution | Drug | Intravenous desmopressin, 20 mcg, single dose administration. |
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| Measure | Description | Time Frame |
|---|---|---|
| Rate of recruitment | A rate of 0.25 patients per study site per week | Through study completion, an average of 1.5 years |
| Receipt of the allocated study drug within 1 hour before start of surgery for the tranexamic acid factorial | Account of whether the patient began to receive study drug for the TXA factorial within an hour before skin incision. Target ≥80% of participants | Day of surgery |
| Receipt of the allocated study drug within 1 hour before start of surgery for the desmopressin factorial | Account of whether the patient began to receive study drug for the desmopressin factorial within an hour before skin incision. Target ≥80% of participants | Day of surgery |
| Completion of 30-day follow-up | 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 | 30 days after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Bleeding Independently Associated with Mortality after noncardiac Surgery (BIMS) | Number of patients who experience BIMS | 30 days after randomization |
| Bleeding Score | 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.
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Eligibility criteria specific to the tranexamic acid (TXA) factorial component of trial Inclusion Criteria:
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;
Planned noncardiac surgery (elective, urgent, or emergency surgery);
Expected to require at least an overnight hospital admission after surgery;
Age ≥18 years; and
Informed consent is obtained to participate in the BRACKETS-Pilot Trial.
Exclusion Criteria:
Eligibility criteria specific to the desmopressin factorial component of trial
Inclusion criteria:
1. Included in the TXA factorial.
Exclusion criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Ingrid Copland | Contact | 905-296-5754 | brackets@phri.ca |
| Name | Affiliation | Role |
|---|---|---|
| Pavel Roshanov, MC,MSc,FRCPC | Western University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| London Health Sciences Centre | Recruiting | London | Ontario | N6A 5A5 | Canada |
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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.
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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.
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| Placebo and placebo. | Placebo Comparator | Within 20 minutes preceding anticipated skin incision, patients allocated to the tranexamic acid control group will receive an intravenous infusion of 0.9% saline solution. This saline solution will be administered over a duration of 10 minutes in a volume equivalent to that received by patients in the tranexamic acid intervention group. Within 20 minutes preceding anticipated skin incision, patients allocated to the desmopressin control group will receive an intravenous infusion of 0.9% saline solution, administered over a duration of 30 minutes. |
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| Tranexamic Acid Injectable Product | Drug | 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. |
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| Placebo | Other | Intravenous 0.9% saline solution |
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| 30 days after randomization |
| Reoperation for reasons of bleeding | Number of patients who return to the operating room for surgical management of suspected documented bleeding | 30 days after randomization |
| Blood (red blood cells or whole blood) transfused | Number of units of blood transfused. | 30 days after randomization |
| Blood (red blood cells or whole blood) transfused | Number of units of blood transfused. | Up to and including postoperative day 3 after surgery |
| Any blood transfusion (red blood cells or whole blood) | Number of units of blood transfused. | 30 days after randomization |
| Any blood transfusion (red blood cells or whole blood) | Number of units of blood transfused. | Up to and including postoperative day 3 |
| Lowest measured hemoglobin concentration | The mean absolute difference for continuous outcomes using linear regression with treatment allocation | 30 days after randomization |
| Most recent hemoglobin concentration | The mean absolute difference for continuous outcomes using linear regression with treatment allocation | 30 days after randomization |
| Death | Number of patients who die of any cause | 30 days after randomization |
| Major arterial and venous thrombosis | (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) | 30 days after randomization |
| Myocardial Injury after Noncardiac Surgery (MINS) | Number of patients who experience MINS | 30 days after randomization |
| Myocardial Injury after Noncardiac Surgery (MINS) that meets criteria for myocardial infarction | Number of patients who experience MINS that meets criteria for myocardial infarction (based on the Fourth Universal Definition of myocardial infarction) | 30 days after randomization |
| MINS that is an isolated ischemic troponin elevation | Number of patients who experience MINS that is an isolated ischemic troponin elevation | 30 days after randomization |
| Stroke | Number of patients experiencing a stroke | 30 days after randomization |
| Non-hemorrhagic stroke | Number of patients who experience a non-hemorrhagic stroke | 30 days after randomization |
| Hemorrhagic stroke | Number of patients who experience a hemorrhagic stroke | 30 days after randomization |
| Peripheral arterial thrombosis | Number of patients who experience a peripheral arterial thrombosis | 30 days after randomization |
| Thrombosis of arteriovenous fistula or graft | Number of patients who have thrombosis of arteriovenous fistula or graft | 30 days after randomization |
| Symptomatic proximal venous thromboembolism | Number of patients who experience symptomatic proximal venous thromboembolism | 30 days after randomization |
| Symptomatic pulmonary embolism | Number of patients who experience a symptomatic pulmonary embolism | 30 days after randomization |
| Symptomatic proximal leg or arm deep venous thrombosis (DVT) | Number of patients who experience a symptomatic proximal leg or arm DVT | 30 days after randomization |
| Non-fatal cardiac arrest | Number of patients who experience non-fatal cardiac arrest | 30 days after randomization |
| Coronary revascularization procedure | Number of patients who undergo coronary revascularization procedure | 30 days after randomization |
| Clinically important atrial fibrillation or flutter | Number of patients who experience clinically important atrial fibrillation or flutter | 30 days after randomization |
| Acute heart failure or clinically important volume overload | Number of patients who experience acute heart failure or clinically important volume overload. | 30 days after randomization |
| Acute kidney injury (for patients not receiving dialysis before surgery) | Number of patients who experience an acute kidney injury | 30 days after randomization |
| New start of dialysis | Number of patients who require new start of dialysis | 30 days after randomization |
| Seizure | Number of patients who experience a seizure | 30 days after randomization |
| Clinically significant intraoperative hypotension | Number of patients who experience clinically significant intraoperative hypotension | 30 days after randomization |
| Clinically significant postoperative hypotension | Number of patients who experience clinically significant postoperative hypotension | Up to and including the end of postoperative day 1 |
| Sepsis | Number of patients who experience sepsis | 30 days after randomization |
| Duration of surgery | The time from skin incision to closure, in minutes. | 30 days after randomization |
| Receipt of platelets | Any transfusion of this blood product | 30 days after randomization |
| Receipt of fibrinogen | Any transfusion of this blood product | 30 days after randomization |
| Receipt of fresh frozen plasma | Any transfusion of this blood product | 30 days after randomization |
| Receipt of cryoprecipitate | Any transfusion of this blood product | 30 days after randomization |
| Receipt of recombinant Factor VIIa | Number of patients receiving recombinant factor VIIa | 30 days after randomization |
| Receipt of prothrombin complex concentrate | Number of patients who receive prothrombin complex concentrate | 30 days after randomization |
| Prescribed erythropoiesis stimulating agent | Number of patients receiving a weekly dose of erythropoiesis stimulating agent on prescription active at 30 days | 30 days after randomization |
| Severe hyponatremia | Measured serum sodium concentration <125 meq/L | Up to and including the end of postoperative day 1 |
| Duration of hospital stay after surgery | Cumulative number of nights spent in an acute care hospital | Day of surgery and ending the day of discharge |
| Duration of critical care stay after surgery | Cumulative number of nights spent in an intensive care unit | Day of surgery and ending the day of discharge |
| Delayed graft function after kidney transplantation | Receipt of dialysis | Within 7 days following kidney transplantation |
| Persistent dialysis dependence | Participant continues to receive dialysis after surgery. | 30 days after randomization |
| Incisional site pain severity | Rating of pain using the 10-point ordinal scale where 0 corresponds to no pain and 10 corresponds to the worst pain imaginable. | 30 days after randomization in the last 24 hours |
| Centre Hospitalier de L'Universite de Montreal (CHUM) | Active, not recruiting | Montreal | Quebec | H2X 0A9 | Canada |
| McGill University University Health Centre | Recruiting | Montreal | Quebec | H3H 2R9 | Canada |
|
| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| D058186 | Acute Kidney Injury |
| D006470 | Hemorrhage |
| ID | Term |
|---|---|
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D003894 | Deamino Arginine Vasopressin |
| D014148 | Tranexamic Acid |
| ID | Term |
|---|---|
| D001127 | Arginine Vasopressin |
| D014667 | Vasopressins |
| D010909 | Pituitary Hormones, Posterior |
| D010907 | Pituitary Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D003509 | Cyclohexanecarboxylic Acids |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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