Randomized trials of therapeutic heparin for COVID-19: A meta-analysis
Sholzberg M, da Costa BR, Tang GH, Rahhal H, AlHamzah M, Baumann Kreuziger L, Ní Áinle F, Almarshoodi MO, James PD, Lillicrap D, et al
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.
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
Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Áinle FN, Alomran F, Alayed K, Alsheef M, AlSumait F, et al
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.
The effectiveness of junctional tourniquets: a systematic review and meta-analysis
Smith S, White J, Wanis KN, Beckett A, McAlister VC, Hilsden R
The journal of trauma and acute care surgery. 2018
BACKGROUND Junctional tourniquets have been incorporated into tactical combat casualty care for junctional vascular trauma. They apply external compression to stop blood flow in the groin and axilla. OBJECTIVES The primary outcome was effectiveness in achieving arterial occlusion. Secondary outcomes included time to application and pain scores. DATA SOURCES Medline and EMBASE databases were searched. STUDY APPRAISAL AND SYNTHESIS METHODS A random effects meta-analysis was conducted to estimate the average effectiveness and time to effective application for each device. RESULTS Eight studies reported the effectiveness of junctional tourniquets in healthy volunteers. The average effectiveness was 52% (95% CI: 15-87%) for the abdominal application of the Abdominal Aortic and Junctional Tourniquet (AAJT), 83% (95% CI: 73 to 89%, I: 26%) for the Junctional Emergency Treatment Tool (JETT), 87% (95% CI: 79 to 92%, I: 15%) for the SAM Junctional Tourniquet (SJT), and 95% (95% CI: 90-98%) for the Combat Ready Clamp (CRoC). The groin application of the AAJT was studied in two papers with 100% in both studies. The average time to application was 101 seconds for the SJT (95% CI: 50-152 seconds) and the CRoC (95% CI: 63-139 seconds), while it was 130 seconds (95% CI: 85 to 176 seconds) for the JETT. The abdominal application of AAJT had a time to application of 92 and 171 seconds in two studies. LIMITATIONS All studies were conducted in healthy volunteers. CONCLUSIONS AND IMPLICATIONS Junctional tourniquets may meet a medical need in combat, and in the civilian environment, to control hemorrhage from these difficult injuries. All four FDA-approved devices demonstrate the ability to achieve vascular occlusion in healthy volunteers; however, effectiveness in patient transport has not been evaluated, and outcomes of their use in the field needs to be captured and reported. LEVEL OF EVIDENCE Systematic review, level III.
Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial
Nascimento B, Callum J, Tien H, Peng H, Rizoli S, Karanicolas P, Alam A, Xiong W, Selby R, Garzon AM, et al
British Journal of Anaesthesia. 2016;117((6)):775-782.
BACKGROUND Decreased plasma fibrinogen concentration shortly after injury is associated with higher blood transfusion needs and mortality. In North America and the UK, cryoprecipitate transfusion is the standard-of-care for fibrinogen supplementation during acute haemorrhage, which often occurs late during trauma resuscitation. Alternatively, fibrinogen concentrate (FC) can be beneficial in trauma resuscitation. However, the feasibility of its early infusion, efficacy and safety remain undetermined. The objective of this trial was to evaluate the feasibility, effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma. METHODS Fifty hypotensive (systolic arterial pressure ≤100 mm Hg) adult patients requiring blood transfusion were randomly assigned to either 6 g of FC or placebo, between Oct 2014 and Nov 2015 at a tertiary trauma centre. The primary outcome, feasibility, was assessed by the proportion of patients receiving the intervention (FC or placebo) within one h of hospital arrival. Plasma fibrinogen concentration was measured, and 28-day mortality and incidence of thromboembolic events were assessed. RESULTS Overall, 96% (43/45) [95% CI 86-99%] of patients received the intervention within one h; 95% and 96% in the FC and placebo groups, respectively (P=1.00). Plasma fibrinogen concentrations remained higher in the FC group up to 12 h after admission with the largest difference at three h (2.9 mg dL - 1 vs. 1.8 mg dL - 1; P<0.01). The 28-day mortality and thromboembolic complications were similar between groups. CONCLUSIONS Early infusion of FC is feasible and increases plasma fibrinogen concentration during trauma resuscitation. Larger trials are justified.