Tranexamic Acid in Patients Undergoing Noncardiac Surgery
The New England journal of medicine. 2022
BACKGROUND Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, -2.6 percentage points; 95% CI, -3.8 to -1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, -1.1 to 1.7; one-sided P = 0.04 for noninferiority). CONCLUSIONS Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.).
Patients undergoing non-cardiac surgery (n= 9,535).
Tranexamic acid at the start and end of surgery (n= 4,757).
Placebo (n= 4,778).
The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, non-haemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. A composite bleeding outcome event occurred in 433 patients (9.1%) in the tranexamic acid group and in 561 patients (11.7%) in the placebo group. A composite cardiovascular outcome event occurred in 649 patients (14.2%) in the tranexamic acid group and in 639 patients (13.9%) in the placebo group.
Tranexamic acid and rosuvastatin in patients at risk of cardiovascular events after noncardiac surgery: a pilot of the POISE-3 randomized controlled trial
Pilot Feasibility Stud. 2020;6:104
BACKGROUND Surgical bleeding is associated with postoperative cardiovascular complications. The efficacy and safety of tranexamic acid (TXA) in noncardiac surgery are still uncertain. Statins may prevent perioperative cardiovascular complications. We conducted a pilot to assess the feasibility of a perioperative trial of TXA and rosuvastatin. METHODS Using a factorial design, we randomized patients at cardiovascular risk undergoing noncardiac surgery to intravenous TXA (1 g at the start and end of surgery) or placebo, and oral rosuvastatin (40 mg before and 20 mg daily for 30 days after surgery) or placebo. Feasibility outcomes included recruitment rates, follow-up, and compliance to interventions. Clinical outcomes were secondarily explored. RESULTS After 3 months, we changed the design to a partial factorial due to the difficult recruitment of statin-naive patients. Over 6 months, 100 patients were randomized in the TXA trial (49 TXA, 51 placebo), 34 in the rosuvastatin trial (18 rosuvastatin, 16 placebo). Ninety-two percent (95% CI 80-98) of TXA and 86% (95% CI 74-94) of TXA-placebo patients received the 2 study doses. Thirty-three percent (95% CI 13-59) of rosuvastatin patients and 37% (95% CI 15-65) of rosuvastatin-placebo patients discontinued the study drug. A major cardiovascular complication occurred at 30 days in 1 TXA and 6 TXA-placebo patients, and 1 rosuvastatin and no rosuvastatin-placebo patients. CONCLUSIONS Our pilot study supports the feasibility of a perioperative TXA trial in noncardiac surgery. Feasibility of a perioperative rosuvastatin trial is uncertain because of a high prevalence of statin use in the target population and concerns about compliance. TRIAL REGISTRATION ClinicalTrials.govNCT02546648.
Mortality outcomes in patients transfused with fresher versus older red blood cells: a meta-analysis
Vox Sanguinis. 2017;112((3):):268-278
BACKGROUND Among transfused patients, the effect of the duration of red blood cell storage on mortality remains unclear. This study aims to compare the mortality of patients who were transfused with fresher versus older red blood cells. METHODS We performed an updated systematic search in the CENTRAL, MEDLINE, EMBASE and CINAHL databases, from January 2015 to October 2016. RCTs of hospitalized patients of any age comparing transfusion of fresher versus older red blood cells were eligible. We used a random-effects model to calculate pooled risk ratios (RRs) with corresponding 95% confidence interval (CI). RESULTS We identified 14 randomized trials that enrolled 26 374 participants. All-cause mortality occurred in 1219 of 9531 (12.8%) patients who received a transfusion of fresher red blood cells and 1810 of 16 843 (10.7%) in those who received older red blood cells (RR: 1.04, 95% CI: 0.98-1.12, P = 0.90, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). In six studies, in-hospital death occurred in 691 of 7479 (9.2%) patients receiving fresher red cells and 1291 of 14 757 (8.8%) receiving older red cells (RR: 1.06, 95% CI: 0.97-1.15, P = 0.81, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). CONCLUSION Transfusion of fresher red blood cells does not reduce overall or in-hospital mortality when compared with older red blood cells. Our results support the practice of transfusing patients with the oldest red blood cells available in the blood bank.
Red blood cell storage and in-hospital mortality: a secondary analysis of the INFORM randomised controlled trial
The Lancet. Haematology. 2017;4((11):):e544-e552. e544
BACKGROUND No randomised trials have addressed whether exposure to red blood cells (RBCs) stored longer than 35 days is associated with harm in patients. We aimed to assess the risk of in-hospital mortality associated with transfusing blood stored longer than 35 days. METHODS We did a secondary analysis of the INforming Fresh versus Old Red cell Management (INFORM) trial, a pragmatic, multicentre, randomised controlled trial of patients (≥18 years) admitted to one of six hospitals in Australia, Canada, Israel, and the USA and expected to need RBC transfusions. Patients were randomly assigned (2:1) to receive blood in inventory stored for the longest time (standard care) or the shortest time, using a random allocation schedule and stratified by centre and patient ABO blood group. The primary objective of the INFORM trial was to assess all-cause in-hospital mortality in patients with blood group A and O who were transfused. For our exploratory secondary analysis, we classified individuals into one of three mutually exclusive exposure categories on the basis of the maximum storage duration of any blood unit patients had received on each day in hospital: exclusively exposed to RBCs stored no longer than 7 days, exposed to at least one unit of RBCs stored 8-35 days, and exposed to least one unit of RBCs stored longer than 35 days. Our primary objective was to determine the effect on risk of in-hospital death of time-dependent exposure to RBCs stored longer than 35 days compared with exclusive exposure to RBCs stored no longer than 7 days, both in patients of blood groups A and O and all patients. The INFORM trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN08118744. FINDINGS Between April 2, 2012, and Oct 21, 2015, 31 497 patients were recruited, and 24 736 patients were eligible for inclusion in this analysis. We excluded nine patients for whom information about the storage duration of transfused blood was missing and one patient whose sex was unknown. 4480 (18%) patients were exposed to RBCs with longest storage, 1392 (6%) patients were exposed exclusively to RBCs with shortest storage, and 18 854 (76%) patients were exposed to RBCs stored 8-35 days. Median follow-up was 11 days (IQR 6-20). Exposure to RBCs stored longer than 35 days was not associated with increased risk of in-hospital death compared with exclusive exposure to the freshest RBC units after adjusting for demographic variables, diagnosis category, and blood product use history (in patients with blood group A or O: hazard ratio 0.94, 95% CI 0.73-1.20, p=0.60; in all patients: 0.91, 0.72-1.14, p=0.40). The risk of in-hospital death also did not differ between patients exposed to blood stored 8-35 days and patients exposed to blood stored 7 days or less (in patients with blood group A or O: 0.92, 0.74-1.15, p=0.48; in all patients: 0.90, 0.73-1.10, p=0.29). INTERPRETATION These data provide evidence that transfusion of blood stored for longer than 35 days has no effect on in-hospital mortality, which suggests that current approaches to blood storage and inventory management are reasonable. FUNDING Canadian Institutes for Health Research, Canadian Blood Services, and Health Canada.
Informing Fresh versus Old Red Cell Management (INFORM) trial: a large international pragmatic randomized trial
Transfusion. 2016;56((S4)):5A.. p6-030a.
Effect of short-term vs. long-term blood storage on mortality after transfusion
The New England Journal of Medicine. 2016;375((20):):1937-1945
Background Randomized, controlled trials have suggested that the transfusion of blood after prolonged storage does not increase the risk of adverse outcomes among patients, although most of these trials were restricted to high-risk populations and were not powered to detect small but clinically important differences in mortality. We sought to find out whether the duration of blood storage would have an effect on mortality after transfusion in a general population of hospitalized patients. Methods In this pragmatic, randomized, controlled trial conducted at six hospitals in four countries, we randomly assigned patients who required a red-cell transfusion to receive blood that had been stored for the shortest duration (short-term storage group) or the longest duration (long-term storage group) in a 1:2 ratio. Only patients with type A or O blood were included in the primary analysis, since pilot data suggested that our goal of achieving a difference in the mean duration of blood storage of at least 10 days would not be possible with other blood types. Written informed consent was waived because all the patients received treatment consistent with the current standard of care. The primary outcome was in-hospital mortality, which was estimated by means of a logistic-regression model after adjustment for study center and patient blood type. Results From April 2012 through October 2015, a total of 31,497 patients underwent randomization. Of these patients, 6761 who did not meet all the enrollment criteria were excluded after randomization. The primary analysis included 20,858 patients with type A or O blood. Of these patients, 6936 were assigned to the short-term storage group and 13,922 to the long-term storage group. The mean storage duration was 13.0 days in the short-term storage group and 23.6 days in the long-term storage group. There were 634 deaths (9.1%) in the short-term storage group and 1213 (8.7%) in the long-term storage group (odds ratio, 1.05; 95% confidence interval [CI], 0.95 to 1.16; P=0.34). When the analysis was expanded to include the 24,736 patients with any blood type, the results were similar, with rates of death of 9.1% and 8.8%, respectively (odds ratio, 1.04; 95% CI, 0.95 to 1.14; P=0.38). Additional results were consistent in three prespecified high-risk subgroups (patients undergoing cardiovascular surgery, those admitted to intensive care, and those with cancer). Conclusions Among patients in a general hospital population, there was no significant difference in the rate of death among those who underwent transfusion with the freshest available blood and those who underwent transfusion according to the standard practice of transfusing the oldest available blood. (Funded by the Canadian Institutes of Health Research and others; INFORM Current Controlled Trials number, ISRCTN08118744 .).