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.
Effect of 6% hydroxyethyl starch 130/0.4 on kidney and haemostatic function in cardiac surgical patients: a randomised controlled trial
Whether third-generation hydroxyethyl starch solutions provoke kidney injury or haemostatic abnormalities in patients having cardiac surgery remains unclear. We tested the hypotheses that intra-operative administration of a third-generation starch does not worsen postoperative kidney function or haemostasis in cardiac surgical patients compared with human albumin 5%. This triple-blind, non-inferiority, clinical trial randomly allocated patients aged 40-85 who underwent elective aortic valve replacement, with or without coronary artery bypass grafting, to plasma volume replacement with 6% starch 130/0.4 vs. 5% human albumin. Our primary outcome was postoperative urinary neutrophil gelatinase-associated lipocalin concentrations, a sensitive and early marker of postoperative kidney injury. Secondarily, we evaluated urinary interleukin-18; acute kidney injury using creatinine RIFLE criteria, coagulation measures, platelet count and function. Non-inferiority (delta 15%) was assessed with correction for multiple comparisons. We enrolled 141 patients (69 starch, 72 albumin) as planned. Results of the primary analysis demonstrated that postoperative urine neutrophil gelatinase-associated lipocalin (median (IQR [range])) was slightly lower with hydroxyethyl starch (5 (1-68 [0-996]) ng.ml(-1) ) vs. albumin (5 (2-74 [0-1604]) ng.ml(-1) ), although not non-inferior [ratio of geometric means (95%CI) 0.91 (0.57, 1.44); p = 0.15] due to higher than expected variability. Urine interleukin-18 concentrations were reduced, but interleukin-18 and kidney injury were again not non-inferior. Of 11 individual coagulation measures, platelet count and function, nine were non-inferior to albumin. Two remaining measures, thromboelastographic R value and arachidonic acid-induced platelet aggregation, were clinically similar but with wide confidence intervals. Starch administration during cardiac surgery produced similar observed effects on postoperative kidney function, coagulation, platelet count and platelet function compared with albumin, though greater than expected variability and wide confidence intervals precluded the conclusion of non-inferiority. Long-term mortality and kidney function appeared similar between starch and albumin.
Effect of red blood cell storage duration on major postoperative complications in cardiac surgery: A randomized trial
The Journal of thoracic and cardiovascular surgery. 2019
BACKGROUND Although observational studies suggest an association between transfusion of older red blood cell (RBC) units and increased postoperative risk, randomized trials have not supported this. The objective of this randomized trial was to test the effect of RBC storage age on outcomes after cardiac surgery. METHODS From July 2007 to May 2016, 3835 adults undergoing coronary artery bypass grafting, cardiac valve procedures, or ascending aorta repair, either alone or in combination, were randomized to transfusion of RBCs stored for ≤14 days (younger units) or for ≥20 days (older units) intraoperatively and throughout the postoperative hospitalization. According to protocol, 2448 patients were excluded because they did not receive RBC transfusions. Among the remaining 1387 modified intent-to-treat patients, 701 were randomized to receive younger RBC units (median age, 11 days) and the remaining 686 to receive older units (median age, 25 days). The primary endpoint was composite morbidity and mortality, analyzed using a generalized estimating equation (GEE) model. The trial was discontinued midway owing to enrollment constraints. RESULTS A total of 5470 RBC units were transfused, including 2783 in the younger RBC storage group and 2687 in the older RBC storage group. The GEE average relative-effect odds ratio was 0.77 (95% confidence interval [CI], 0.50-1.19; P = .083) for the composite morbidity and mortality endpoint. In-hospital mortality was lower for the younger RBC storage group (2.1% [n = 15] vs 3.4% [n = 23]), as was occurrence of other adverse events except for atrial fibrillation, although all CIs crossed 1.0. CONCLUSIONS This clinical trial, which was stopped at its midpoint owing to enrollment constraints, supports neither the efficacy nor the futility of transfusing either younger or older RBC units. The effects of transfusing RBCs after even more prolonged storage (35-42 days) remains untested.
Adults undergoing coronary artery bypass grafting, cardiac valve procedures, or ascending aorta repair, either alone or in combination (n=3835).
Younger red blood cell (RBC) units (median age, 11 days), (n=701).
Older units (median age, 25 days), (n=686).
A total of 5470 RBC units were transfused, including 2783 in the younger RBC storage group and 2687 in the older RBC storage group. The generalized estimating equation (GEE) average relative-effect odds ratio was 0.77 for the composite morbidity and mortality endpoint. In-hospital mortality was lower for the younger RBC storage group (2.1% [n = 15] vs 3.4% [n = 23]), as was occurrence of other adverse events except for atrial fibrillation.
Effect of Intraoperative Goal-directed Balanced Crystalloid versus Colloid Administration on Major Postoperative Morbidity: A Randomized Trial
WHAT WE ALREADY KNOW ABOUT THIS TOPIC Crystalloid solutions leave the circulation quickly, whereas colloids remain for hours, thus promoting hemodynamic stability. However, colloids are expensive and promote renal toxicity in critical care patients. Whether goal-directed intraoperative tetrastarch colloid administration reduces complications or promotes renal injury remains unknown. WHAT THIS ARTICLE TELLS US THAT IS NEW In a large randomized trial comparing intraoperative goal-directed 6% hydroxyethyl starch with goal-directed lactated Ringer's solution in patients having major abdominal surgery, 6% hydroxyethyl starch reduced neither a composite of serious complications nor the duration of hospitalization. However, 6% hydroxyethyl starch did not cause acute or long-term renal toxicity. BACKGROUND Crystalloid solutions leave the circulation quickly, whereas colloids remain for hours, thus promoting hemodynamic stability. However, colloids are expensive and promote renal toxicity in critical care patients. This study tested the hypothesis that goal-directed colloid administration during elective abdominal surgery decreases 30-day major complications more than goal-directed crystalloid administration. METHODS In this parallel-arm double-blinded multicenter randomized trial, adults having moderate- to high-risk open and laparoscopically assisted abdominal surgery with general anesthesia were randomly assigned to Doppler-guided intraoperative volume replacement with 6% hydroxyethyl starch 130/0.4 (n = 523) or lactated Ringer's solution (n = 534). The primary outcome was a composite of serious postoperative cardiac, pulmonary, infectious, gastrointestinal, renal, and coagulation complications that were assessed with a generalized estimating equation multivariate model. The primary safety outcome was a change in serum creatinine concentration up to 6 months postoperatively, compared to baseline concentrations. RESULTS A total of 1,057 patients were included in the analysis. Patients assigned to crystalloid received a median [quartile 1, quartile 3] amount of 3.2 l [2.3, 4.4] of crystalloid, and patients assigned to colloid received 1.0 l [0.5, 1.5] of colloid and 1.8 l [1.2, 2.4] of crystalloid. The estimated intention-to-treat common effect relative risk for the primary composite was 0.90 for colloids versus crystalloids (95% CI: 0.65 to 1.23, P = 0.51), and 18% (91 of 523) of colloid patients and 20% (103 of 534) of crystalloid patients incurred at least one component of the primary outcome composite. There was no evidence of renal toxicity at any time. CONCLUSIONS Doppler-guided intraoperative hydroxyethyl starch administration did not significantly reduce a composite of serious complications. However, there was also no indication of renal or other toxicity.
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.
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.
A randomized clinical trial of red blood cell transfusion triggers in cardiac surgery
The Annals of Thoracic Surgery. 2017;104((4):):1243-1250
BACKGROUND Class I evidence supporting a threshold for transfusion in the cardiac surgical setting is scarce. We randomly allocated patients to a transfusion hematocrit trigger of 24% versus 28% to compare morbidity, mortality, and resource use. METHODS From March 2007 to August 2014, two centers randomly assigned 722 adults undergoing coronary artery bypass graft surgery or valve procedures to a 24% hematocrit trigger (n = 363, low group) or 28% trigger (n = 354, high group). One unit of red blood cells was transfused if the hematocrit fell below the designated threshold. The primary endpoint was a composite of postoperative morbidities and mortality. Treatment effect was primarily assessed using an average relative effect generalized estimating equation model. RESULTS At the second planned interim analysis, the a priori futility boundary was crossed, and the study was stopped. There was no detected treatment effect on the composite outcome (average relative effect odds ratio, low versus high, 0.86, 95% confidence interval: 0.29 to 2.54, p = 0.71). However, the low group received fewer red blood cell transfusions than the high group (54% versus 75%, p < 0.001), mostly administered in the operating room (low group, 112 [31%]; high group, 208 [59%]), followed by intensive care unit (low, 105 [31%]; high, 115 [34%]) and floor (low, 41 [12%]; high, 42 [13%]). The low group was exposed to lower hematocrits: median before transfusion, 22% (Q1 = 21%, Q3 = 23%) versus 24% (Q1 = 22%, Q3 = 25%). CONCLUSIONS Negative exposures differed between treatment groups, with lower hematocrit in the 24% trigger group and more red blood cells used in the 28% group, but adverse outcomes did not differ. Because red blood cell use was less with a 24% trigger without adverse effects, our randomized trial results support aggressive blood conservation efforts in cardiac surgery.
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 .).
Thromboelastometry-guided intraoperative haemostatic management reduces bleeding and red cell transfusion after paediatric cardiac surgery
British Journal of Anaesthesia. 2015;114((1):):91-102.
BACKGROUND Thromboelastometric evaluation of coagulation might be useful for prediction and management of bleeding after paediatric cardiac surgery. We tested the hypothesis that the use of a thromboelastometry-guided algorithm for blood product management reduces blood loss and transfusion requirements. METHODS We studied 78 patients undergoing paediatric cardiac surgery with cardiopulmonary bypass (CPB) for the initial 12 h after operation. Stepwise multiple linear regression was used to develop an algorithm to guide blood product transfusions. Thereafter, we randomly assigned 100 patients to conventional or algorithm-guided blood product management, and assessed bleeding and red cell transfusion requirements. RESULTS CPB time, post-bypass rotational thromboelastometry (ROTEM()) EXTEM amplitude at 10 min (A10), and FIBTEM-A10 were independently associated with chest tube drainage volume during the initial 12 h after operation. Discriminative analysis determined cut-off values of 30 mm for EXTEM-A10 and 5 mm for FIBTEM-A10, and estimated optimal intraoperative fresh-frozen plasma and platelet concentrate transfusion volumes. Thromboelastometry-guided post-bypass blood product management significantly reduced postoperative bleeding (9 vs 16 ml kg(-1), P<0.001) and packed red cell transfusion requirement (11 vs 23 ml kg(-1), P=0.005) at 12 h after surgery, and duration of critical care stay (60 vs 71 h, P=0.014). CONCLUSIONS Rotational thromboelastometry-guided early haemostatic intervention by rapid intraoperative correction of EXTEM-A10 and FIBTEM-A10 reduced blood loss and red cell transfusion requirements after CPB, and reduced critical care duration in paediatric cardiac surgical patients. CLINICAL TRIAL REGISTRATION UMIN Clinical Trials Registry UMIN000006832 (December 4, 2011). The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: email@example.com.