Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial
BMJ (Clinical research ed.). 2021;375:n2400
OBJECTIVE To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN Randomised controlled, adaptive, open label clinical trial. SETTING 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m(2). At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION ClinicalTrials.gov NCT04362085.
Randomized trials of therapeutic heparin for COVID-19: A meta-analysis
Research and practice in thrombosis and haemostasis. 2021;5(8):e12638
BACKGROUND Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19. METHODS We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs). RESULTS AND CONCLUSIONS There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (P = .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19.
Restrictive versus Liberal Transfusion in Patients with Diabetes Undergoing Cardiac Surgery: An Open-Label Randomized, Blinded Outcome Evaluation Trial
Diabetes, obesity & metabolism. 2021
AIM: To characterize the association between diabetes and transfusion and clinical outcomes in cardiac surgery, and to evaluate whether restrictive transfusion thresholds are harmful in these patients. MATERIALS AND METHODS The multinational, open-label, randomized controlled TRICS-III trial assessed a restrictive transfusion strategy (hemoglobin [Hb] transfusion threshold <75 g/L) compared to a liberal strategy (Hb <95 g/L for operating room or ICU; or < 85 g/L for ward) in patients undergoing cardiac surgery on cardiopulmonary bypass with a moderate-to-high risk of death (EuroSCORE ≥6). Diabetes status was collected preoperatively. The primary composite outcome was all-cause death, stroke, myocardial infarction, and new-onset renal failure requiring dialysis at 6 months. Secondary outcomes included components of the composite outcome at 6 months, and transfusion and clinical outcomes at 28 days. RESULTS Of the 5092 patients analyzed, 1396 (27.4%) had diabetes (Restrictive: n = 679, Liberal n = 717). Patients with diabetes had more cardiovascular disease than patients without diabetes. Neither the presence of diabetes (OR [95%CI]1.10[0.93-1.31]) or the restrictive strategy increased the risk for the primary composite outcome (diabetes OR [95%CI]1.04[0.68-1.59] vs. no diabetes OR 1.02[0.85-1.22],p(interaction) = 0.92). In patients with versus without diabetes, a restrictive transfusion strategy was more effective at reducing red blood cell transfusion (diabetes OR [95%CI] 0.28[0.21-0.36]; no diabetes OR [95%CI] 0.40[0.35-0.47];p(interaction) = 0.04). CONCLUSIONS The presence of diabetes did not modify the effect of a restrictive transfusion strategy on the primary composite outcome, but improved its efficacy on red cell transfusion. Restrictive transfusion triggers are safe and effective in patients with diabetes undergoing cardiac surgery. This article is protected by copyright. All rights reserved.
Patients with diabetes undergoing cardiac surgery enrolled in the multinational TRICS-III trial (n= 1,396).
Restrictive transfusion threshold strategy (n= 679).
Liberal transfusion threshold strategy (n= 717).
Of the 5,092 patients analysed, 1396 (27.4%) had diabetes. Patients with diabetes had more cardiovascular disease than patients without diabetes. Neither the presence of diabetes nor the restrictive strategy increased the risk for the primary composite outcome vs. no diabetes. In patients with vs. without diabetes, a restrictive transfusion strategy was more effective at reducing red blood cell transfusion.
Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion Among Patients With Spot Sign-Positive Acute Intracerebral Hemorrhage: The SPOTLIGHT and STOP-IT Randomized Clinical Trials
JAMA neurology. 2019
Importance: Intracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion-the computed tomography (CT) angiography spot sign-may identify a subgroup that could benefit from hemostatic therapy. Objective: To investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH. Design, Setting, and Participants: In parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada ("Spot Sign" Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited. Data were collected from November 2010 to May 2016. Data were analyzed from November 2016 to May 2017. Interventions: Eligible patients were randomly assigned 80 mug/kg of intravenous rFVIIa or placebo as soon as possible within 6.5 hours of stroke onset. Main Outcomes and Measures: Head CT at 24 hours assessed parenchymal ICH volume expansion from baseline (primary outcome) and total (ie, parenchymal plus intraventricular) hemorrhage volume expansion (secondary outcome). The pooled analysis compared hemorrhage expansion between groups by analyzing 24-hour volumes in a linear regression model adjusted for baseline volumes, time from stroke onset to treatment, and trial. Results: Of the 69 included patients, 35 (51%) were male, and the median (interquartile range [IQR]) age was 70 (59-80) years. Baseline median (IQR) ICH volumes were 16.3 (9.6-39.2) mL in the rFVIIa group and 20.4 (8.6-32.6) mL in the placebo group. Median (IQR) time from CT to treatment was 71 (57-96) minutes, and the median (IQR) time from stroke onset to treatment was 178 (138-197) minutes. The median (IQR) increase in ICH volume from baseline to 24 hours was small in both the rFVIIa group (2.5 [0-10.2] mL) and placebo group (2.6 [0-6.6] mL). After adjustment, there was no difference between groups on measures of ICH or total hemorrhage expansion. At 90 days, 9 of 30 patients in the rFVIIa group and 13 of 34 in the placebo group had died or were severely disabled (P = .60). Conclusions and Relevance: Among patients with spot sign-positive ICH treated a median of about 3 hours from stroke onset, rFVIIa did not significantly improve radiographic or clinical outcomes. Trial Registration: ClinicalTrials.gov identifier: NCT01359202 and NCT00810888.
Safety of a Restrictive versus Liberal Approach to Red Blood Cell Transfusion on the Outcome of AKI in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial
Journal of the American Society of Nephrology : JASN. 2019
BACKGROUND Safely reducing red blood cell transfusions can prevent transfusion-related adverse effects, conserve the blood supply, and reduce health care costs. Both anemia and red blood cell transfusion are independently associated with AKI, but observational data are insufficient to determine whether a restrictive approach to transfusion can be used without increasing AKI risk. METHODS In a prespecified kidney substudy of a randomized noninferiority trial, we compared a restrictive threshold for red blood cell transfusion (transfuse if hemoglobin<7.5 g/dl, intraoperatively and postoperatively) with a liberal threshold (transfuse if hemoglobin<9.5 g/dl in the operating room or intensive care unit, or if hemoglobin<8.5 g/dl on the nonintensive care ward). We studied 4531 patients undergoing cardiac surgery with cardiopulmonary bypass who had a moderate-to-high risk of perioperative death. The substudy's primary outcome was AKI, defined as a postoperative increase in serum creatinine of ≥0.3 mg/dl within 48 hours of surgery, or ≥50% within 7 days of surgery. RESULTS Patients in the restrictive-threshold group received significantly fewer transfusions than patients in the liberal-threshold group (1.8 versus 2.9 on average, or 38% fewer transfusions in the restricted-threshold group compared with the liberal-threshold group; P<0.001). AKI occurred in 27.7% of patients in the restrictive-threshold group (624 of 2251) and in 27.9% of patients in the liberal-threshold group (636 of 2280). Similarly, among patients with preoperative CKD, AKI occurred in 33.6% of patients in the restrictive-threshold group (258 of 767) and in 32.5% of patients in the liberal-threshold group (252 of 775). CONCLUSIONS Among patients undergoing cardiac surgery, a restrictive transfusion approach resulted in fewer red blood cell transfusions without increasing the risk of AKI.
Restrictive or liberal red-cell transfusion for cardiac surgery
The New England Journal of Medicine. 2017;377((22):):2133-2144
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 .).
Transfusion Requirements in Cardiac Surgery III (TRICS III): study design of a randomized controlled trial
Journal of Cardiothoracic and Vascular Anesthesia. 2017;32((1):):121-129
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.
A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets
BACKGROUND Removal of the plasma supernatant from platelets before transfusion is effective in preventing acute reactions to platelets caused by cytokines. Prestorage WBC reduction of platelets may be even more effective at preventing reactions as the WBCs are removed and WBC-derived cytokines do not accumulate in this component. This study evaluates the effectiveness of plasma removal and two methods of prestorage WBC reduction for preventing acute reactions to platelets. STUDY DESIGN AND METHODS Platelets given to adults with hematologic malignancies were randomly allocated to one of three types: plasma supernatant removed and a platelet storage solution added, whole blood-derived platelets that are prestorage WBC reduced by filtration before storage, and prestorage WBC-reduced apheresis platelets. Patients were monitored before, during, and after transfusion, and the severity of reactions was graded on a Likert scale. RESULTS A total of 129 patients from four centers were given 1190 platelet transfusions. The overall frequency of reactions was 13.6 percent (162 of 1190), 21.3 percent (36 of 169) for the plasma-removed platelets, 11.4 percent (59 of 517) for random donor WBC-reduced platelets, and 13.3 percent (67 of 504) for apheresis WBC-reduced platelets (p=0.384). The overall frequency of severe reactions was 4.1 percent with plasma-removed platelets, 1.7 percent for whole blood-derived, prestorage WBC-reduced platelets, and 1.4 percent for prestorage WBC-reduced apheresis platelets. CONCLUSION The frequency of reactions to plasma-removed platelets and prestorage WBC-reduced platelets was not significantly different; however, the power of the study for this comparison was low. There was no difference in the frequency of reactions to the two types of prestorage WBC-reduced platelets. The frequency of severe reactions to prestorage WBC-reduced platelets is low, occurring in only 1 to 2 percent of transfusions.