Summer Syed

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery

BACKGROUND The effect of a restrictive versus liberal red‐cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS In this multicenter, open‐label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red‐cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red‐cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non‐ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red‐cell transfusion and other clinical outcomes. RESULTS The primary outcome occurred in 11.4% of the patients in the restrictive‐threshold group, as compared with 12.5% of those in the liberal‐threshold group (absolute risk difference, ‐1.11 percentage points; 95% confidence interval [CI], ‐2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive‐threshold group and 3.6% in the liberal‐threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red‐cell transfusion occurred in 52.3% of the patients in the restrictive‐threshold group, as compared with 72.6% of those in the liberal‐threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between‐group differences with regard to the other secondary outcomes. CONCLUSIONS In patients undergoing cardiac surgery who were at moderate‐to‐high risk for death, a restrictive strategy regarding red‐cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898.)

Effect of standardized perioperative dabigatran interruption on the residual anticoagulation effect at the time of surgery or procedure.

Essentials Anticoagulants need to be stopped preprocedure so there is little or no remaining anticoagulant effect. We assessed the residual anticoagulant effect with standardized interruption for patients on dabigatran. With this protocol, 80–86% of patients had no residual anticoagulant effect at the time of a procedure. A standardized perioperative dabigatran protocol appears to be safe, but requires further study.

Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): a randomized controlled trial

Background: Remote ischemic preconditioning is a simple therapy that may reduce cardiac and kidney injury. We undertook a randomized controlled trial to evaluate the effect of this therapy on markers of heart and kidney injury after cardiac surgery. Methods: Patients at high risk of death within 30 days after cardiac surgery were randomly assigned to undergo remote ischemic preconditioning or a sham procedure after induction of anesthesia. The preconditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles. The sham procedure was identical except that ischemia was not induced. The primary outcome was peak creatine kinase–myocardial band (CK-MB) within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation). The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per litre). Patient-important outcomes were assessed up to 6 months after randomization. Results: We randomly assigned 128 patients to remote ischemic preconditioning and 130 to the sham therapy. There were no significant differences in postoperative CK-MB (absolute mean difference 0.15, 95% confidence interval [CI] −0.07 to 0.36) or creatinine (absolute mean difference 0.06, 95% CI −0.10 to 0.23). Other outcomes did not differ significantly for remote ischemic preconditioning relative to the sham therapy: for myocardial infarction, relative risk (RR) 1.35 (95% CI 0.85 to 2.17); for acute kidney injury, RR 1.10 (95% CI 0.68 to 1.78); for stroke, RR 1.02 (95% CI 0.34 to 3.07); and for death, RR 1.47 (95% CI 0.65 to 3.31). Interpretation: Remote ischemic precnditioning did not reduce myocardial or kidney injury during cardiac surgery. This type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery. Trial registration: ClinicalTrials.gov, no. NCT01071265.

Periprocedural Management of Direct Oral Anticoagulants: Comment on the 2015 American Society of Regional Anesthesia and Pain Medicine Guidelines.

An increasing number of patients are receiving a direct oral anticoagulant (DOAC) (ie, dabigatran, rivaroxaban, apixaban, or edoxaban) for stroke prevention in atrial fibrillation and for the treatment of venous thromboembolism. Annually, approximately 10% of such patients will require DOAC interruption for an elective procedure, and many of these patients will require a neuraxial procedure for anesthesia or pain control. In response to the increasing need for managing DOACs in a perioperative setting, several reviews provide clinical guidance regarding the perioperative management of patients on DOACs. More recently, theAmericanSocietyofRegionalAnesthesia (ASRA), in collaboration with other pain medicine societies, issued practice guidelines for the management of DOAC-treated patients who require anticoagulant interruption for interventional spine and pain procedures.Theseguidelines recommend that thepreprocedure interruption interval for the DOACs should be 4 to 6 days for dabigatran, 3 days for rivaroxaban, and 3 to 5 days for apixaban. The interruption intervals allow a period of at least 5 elimination half-lives (but often longer) to elapse between the last DOAC dose and the procedure, corresponding to a residual anticoagulant effect of ~3% (~6% if 4 drug half-lives elapsed). These guidelines also recommend that DOACs are resumed 24 hours after the procedure. It is noteworthy that the guideline authors state that a grading for these recommendations, whether strong or weak, cannot be given because of the lack of evidence. Against this background, the purpose of this communication is 3-fold: (1) to express concern that the 2015 ASRA recommendations pertaining to the periprocedural management of DOACs have been developed prematurely, without the requisite evidence; (2) to share emerging data regarding the effect of DOAC interruption on the residual anticoagulant effect at the time of a procedure that will help inform this discussion; and (3) to sound a call to action for more research in this clinical domain to inform best practices.

The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study for Patients on a Direct Oral Anticoagulant Who Need an Elective Surgery or Procedure: Design and Rationale

Background The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol. Methods PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patients renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group. Conclusion The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.

Tranexamic Acid Administration During On-Pump Cardiac Surgery: A Survey of Current Practices Among Canadian Anesthetists Working in Academic Centers.

BACKGROUND: Tranexamic acid (TXA) is commonly administered during on-pump cardiac surgery to minimize bleeding. However, an optimal dosing regimen has not been described, and recent studies suggest that higher doses may be associated with seizure. Little is known about current practice among cardiac anesthetists. METHODS: We contacted all academic anesthesia departments in Canada to identify cardiac anesthetists, who represent the majority of practitioners. This group constituted our sampling frame. Information regarding participant demographics, TXA dose, and administration details were obtained by electronic survey. Responses were analyzed descriptively. To compare dose, we assumed an 80-kg patient and 3 hours of infusion time. The Kruskal-Wallis test was used to compare average dose across provinces. RESULTS: Among 341 Canadian academic cardiac anesthetists, 234 completed the survey (68.2% response rate). Among respondents, 86.3% administer TXA to all patients; 13.7% administer it to some. Most (68.4%) administer an infusion after a bolus; other modes included infusion (4.7%), single bolus (13.2%), 2 or more boluses (12.0%), or another regimen (1.7%). The mean (standard deviation) dose given was 49 mg/kg (24), with a range from 10 to 100 mg/kg. The mean dose varied across provinces from 23 to 55 mg/kg (P = .001). CONCLUSIONS: TXA is given to nearly all patients undergoing on-pump cardiac surgery at academic hospitals in Canada. However, there is significant heterogeneity in practice between individuals and across provinces. Further research is needed to determine the TXA dose that maximizes efficacy and minimizes side effects.

Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery

Background We reported previously that, in patients undergoing cardiac surgery who were at moderate‐to‐high risk for death, a restrictive transfusion strategy was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis by hospital discharge or 28 days after surgery, whichever came first. We now report the clinical outcomes at 6 months after surgery. Methods We randomly assigned 5243 adults undergoing cardiac surgery to a restrictive red‐cell transfusion strategy (transfusion if the hemoglobin concentration was <7.5 g per deciliter intraoperatively or postoperatively) or a liberal red‐cell transfusion strategy (transfusion if the hemoglobin concentration was <9.5 g per deciliter intraoperatively or postoperatively when the patient was in the intensive care unit [ICU] or was <8.5 g per deciliter when the patient was in the non‐ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis occurring within 6 months after the initial surgery. An expanded secondary composite outcome included all the components of the primary outcome as well as emergency department visit, hospital readmission, or coronary revascularization occurring within 6 months after the index surgery. The secondary outcomes included the individual components of the two composite outcomes. Results At 6 months after surgery, the primary composite outcome had occurred in 402 of 2317 patients (17.4%) in the restrictive‐threshold group and in 402 of 2347 patients (17.1%) in the liberal‐threshold group (absolute risk difference before rounding, 0.22 percentage points; 95% confidence interval [CI], ‐1.95 to 2.39; odds ratio, 1.02; 95% CI, 0.87 to 1.18; P=0.006 for noninferiority). Mortality was 6.2% in the restrictive‐threshold group and 6.4% in the liberal‐threshold group (odds ratio, 0.95; 95% CI, 0.75 to 1.21). There were no significant between‐group differences in the secondary outcomes. Conclusions In patients undergoing cardiac surgery who were at moderate‐to‐high risk for death, a restrictive strategy for red‐cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis at 6 months after surgery. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898.)

Risk of Acute Kidney Injury in Patients Randomized to a Restrictive Versus Liberal Approach to Red Blood Cell Transfusion in Cardiac Surgery: A Substudy Protocol of the Transfusion Requirements in Cardiac Surgery III Noninferiority Trial

Background: When safe to do so, avoiding blood transfusions in cardiac surgery can avoid the risk of transfusion-related infections and other complications while protecting a scarce resource and reducing costs. This protocol describes a kidney substudy of the Transfusion Requirements in Cardiac Surgery III (TRICS-III) trial, a multinational noninferiority randomized controlled trial to determine whether the risk of major clinical outcomes in patients undergoing planned cardiac surgery with cardiopulmonary bypass is no greater with a restrictive versus liberal approach to red blood cell transfusion. Objective: The objective of this substudy is to determine whether the risk of acute kidney injury is no greater with a restrictive versus liberal approach to red blood cell transfusion, and whether this holds true in patients with and without preexisting chronic kidney disease. Design and Setting: Multinational noninferiority randomized controlled trial conducted in 73 centers in 19 countries (2014-2017). Patients: Patients (~4800) undergoing planned cardiac surgery with cardiopulmonary bypass. Measurements: The primary outcome of this substudy is perioperative acute kidney injury, defined as an acute rise in serum creatinine from the preoperative value (obtained in the 30-day period before surgery), where an acute rise is defined as ≥26.5 μmol/L in the first 48 hours after surgery or ≥50% in the first 7 days after surgery. Methods: We will report the absolute risk difference in acute kidney injury and the 95% confidence interval. We will repeat the primary analysis using alternative definitions of acute kidney injury, including staging definitions, and will examine effect modification by preexisting chronic kidney disease (defined as a preoperative estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). Limitations: It is not possible to blind patients or providers to the intervention; however, objective measures will be used to assess outcomes, and outcome assessors will be blinded to the intervention assignment. Results: Substudy results will be reported by the year 2018. Conclusions: This substudy will provide generalizable estimates of the risk of acute kidney injury of a restrictive versus liberal approach to red blood cell transfusion in the presence of anemia during cardiac surgery done with cardiopulmonary bypass. Trial Registration: www.clinicaltrials.gov; clinical trial registration number NCT 02042898.

Transfusion Requirements in Cardiac Surgery III (TRICS III): Study Design of a Randomized Controlled Trial

OBJECTIVES To determine if a restrictive transfusion threshold is noninferior to a higher threshold as measured by a composite outcome of mortality and serious morbidity. DESIGN Transfusion Requirements in Cardiac Surgery (TRICS) III was a multicenter, international, open-label randomized controlled trial of two commonly used transfusion strategies in patients having cardiac surgery using a noninferiority trial design (ClinicalTrials.gov number, NCT02042898). SETTING Eligible patients were randomized prior to surgery in a 1:1 ratio. PARTICIPANTS Potential participants were 18 years or older undergoing planned cardiac surgery using cardiopulmonary bypass (CPB) with a preoperative European System for Cardiac Operative Risk Evaluation (EuroSCORE I) of 6 or more. INTERVENTIONS Five thousand patients; those allocated to a restrictive transfusion group received a red blood cell (RBC) transfusion if the hemoglobin concentration (Hb) was less than 7.5 g/dL intraoperatively and/or postoperatively. Patients allocated to a liberal transfusion strategy received RBC transfusion if the Hb was less than 9.5 g/dL intraoperatively or postoperatively in the intensive care unit or less than 8.5 g/dL on the ward. MEASUREMENTS AND MAIN RESULTS The primary outcome was a composite of all-cause mortality, myocardial infarction, stroke, or new onset renal dysfunction requiring dialysis at hospital discharge or day 28, whichever comes first. The primary outcome was analyzed as a per-protocol analysis. The trial monitored adherence closely as adherence to the transfusion triggers is important in ensuring that measured outcomes reflect the transfusion strategy. CONCLUSION By randomizing prior to surgery, the TRICS III trial captured the most acute reduction in hemoglobin during cardiopulmonary bypass.

Reply to Dr Lessire et al.

To the Editor: We thank Lessire and associates for their interest in our work. We agree with their first point that a normal activated partial thromboplastin time (aPTT) may not exclude a clinically important effect of dabigatran. The aPTT assay we used (Siemens Dade Actin FS, Malvern, Pennsylvania) is considered a more sensitive assay but there is a need for additional study comparing the sensitivity of different aPTT assays to measure dabigatrans anticoagulant effect and we are in the process of doing this. Their second point seems to infer that clinicians should rely on a normal thrombin clotting time to exclude a residual anticoagulant effect of dabigatran. However, the thrombin clotting time can be abnormal in patients who likely have a small, clinically unimportant residual anticoagulant effect of dabigatran. We are concerned that measuring such a test may, if abnormal, lead to unnecessary postponement of a surgery/ procedure or, perhaps, inappropriate use of idarucizumab to reverse this presumed anticoagulant effect. As regard their final 2 points, we agree with the need to use an appropriately calibrated dilute thrombin time assay to measure dabigatrans anticoagulant effect and also agree with their point regarding the interpretation of dabigatran plasma levels when measured using mass spectrometry/high-performance liquid chromatography. Taken together, the comments by Lessire and associates highlight the urgent need for further real-world clinical research to (a) determine and standardize which tests (and which assay types) are best able to reliably measure the residual anticoagulant effect of dabigatran (and other direct oral anticoagulants) after treatment interruption in patients who require a surgery/ procedure, and (b) to determine what residual anticoagulant levels are clinically important—that is, the level that confers an increased risk for bleeding in a variety of perioperative settings.