Heparin Thromboprophylaxis Research Articles

Challenging management dogma where evidence is non-existent, weak, or outdated: part II.

Many dogmas influence daily clinical practice, and critical care medicine is no exception. We previously highlighted the weak, questionable, and often contrary evidence base underpinning four established medical managements-loop diuretics for acute heart failure, routine use of heparin thromboprophylaxis, rate of sodium correction for hyponatremia, and 'every hour counts' for treating bacterial meningitis. We now provide four further examples in this "Dogma II" piece (a week's course of antibiotics, diabetic ketoacidosis algorithms, sodium bicarbonate to improve ventricular contractility during severe metabolic acidosis, and phosphate replacement for hypophosphatemia) where routine practice warrants re-appraisal.

Aspirin versus low-molecular-weight heparin for thromboprophylaxis after orthopaedic surgery: a systematic review and meta-analysis.

The article aimed to compare the efficiency and safety of aspirin with low-molecular-weight heparin (LMWH) for thromboprophylaxis in orthopaedic surgery patients. According to the inclusion and exclusion criteria, PubMed, Embase and Cochrane Library database were searched for studies comparing aspirin and LMWH in venous thromboembolism (VTE) prophylaxis until 25 April 2023. The outcome measures included deep venous thrombosis(DVT)/Pulmonary embolism(PE) events, major bleeding events, wound complications, wound infection and death. Six studies met the requirements of our meta-analysis, including 12 470 patients in the aspirin group and 10 857 patients in the LMWH group. The meta-analysis showed that results showed that LMWH was superior to aspirin in preventing VTE events (odds ratio (OR) 1.44, 95% CI 1.24-1.68, P < 0.00001), whereas there was no significant difference between them in bleeding events (OR 0.95, 95% CI 0.86-1.05, P = 0.33), wound complication (OR 0.58, 95% CI 0.28-1.17, P = 0.13), wound infection (OR 1.12, 95% CI 0.86-1.47, P = 0.39) and mortality (OR 1.04, 95% CI 0.70-1.55, P = 0.83). In addition, subgroup analysis showed that compared with aspirin, LMWH was more likely to reduce the incidence of DVT events in orthopaedic surgery patients (OR 1.59, 95% CI 1.33-1.91, P < 0.00001), whereas there was no advantage in reducing the incidence of PE events (OR 1.22, 95% CI 0.62-2.40, P = 0.56). Despite the similar safety profiles, this meta-analysis showed that LMWH was significantly superior to aspirin in thromboprophylaxis after orthopaedic surgery. LMWH was still the first-line drug for thrombosis prevention in patients who underwent major orthopaedic surgeries.

Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin for thromboprophylaxis after cancer surgery: a systematic review and meta-analysis.

Direct oral anticoagulants (DOACs) used as an alternative to low-molecular-weight heparin (LMWH) for thromboprophylaxis after cancer surgery for venous thromboembolic events (VTE) remains unclear. This study aimed to investigate the efficacy and safety of DOACs versus LMWH in these patients. A search of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science was carried out and included all randomized controlled trials (RCTs) and observational studies that directly compared DOACs with LMWH for thromboprophylaxis in patients after cancer surgery through July 25, 2023. The primary efficacy and safety outcomes were VTE, major bleeding, and clinically relevant non-major bleeding (CRNMB) within 30days of surgery. The risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB2) tool for RCTs and ROBINS-I tool for non-randomized studies. This study was registered in PROSPERO (CRD42023445386). We retrieved 5149articles, selected 27 for eligibility, and included 10 studies (three RCTs and seven observational studies) encompassing 3054 patients who underwent postoperative thromboprophylaxis with DOACs (41%) or LMWH (59%). Compared to LMWH thromboprophylaxis, DOACs had a comparable risk of VTE (RR:0.69[95% CI:0.46-1.02], I2 = 0%), major bleeding (RR:1.55 [95% CI:0.82-2.93], I2 = 2%), and CRNMB (RR, 0.89 [95% CI, 0.4-1.98], I2 = 31%) during the 30-day postoperative period. Subgroup analysis of VTE and major bleeding suggested no differences according to study type, extended thromboprophylaxis, tumor types, or different types of DOAC. DOACs are potentially effective alternatives to LMWH for thromboprophylaxis in patients undergoing cancer surgery, without increasing the risk of major bleeding events.

Intermediate-dose Versus Low-dose Low–molecular-weight Heparin in Pregnant and Postpartum Women With a History of Venous Thromboembolism (Highleow study): An Open-label, Multicenter, Randomized, Controlled Trial

(Lancet. 2022;400:1777–1787) Venous thromboembolism (VTE) and subsequent major bleeding are leading causes of maternal morbidity and mortality worldwide, and the risk for recurrence increases for women with a history of VTE. Despite this, evidence-based research on thromboprophylaxis strategies is lacking and the optimal dose of low–molecular-weight heparin (LMWH) thromboprophylaxis during the peripartum and postpartum periods is uncertain. This study aimed to assess the safety and efficacy of low-dose compared to intermediate-dose LMWH for pregnant women with past occurrences of VTE.

Delivering Evidence to Prevent Recurrent Venous Thromboembolism in Pregnancy

(Lancet. 2022;400:1743–1745) Pregnant and postpartum women have an increased risk for venous thromboembolism (VTE) (0 to 1%) with a history of VTE increasing the likelihood (2% to 10%). Hypercoagulability, endothelial damage, and venous stasis are contributing factors. Low–molecular-weight heparin (LMWH) thromboprophylaxis during pregnancy to 6 weeks postpartum is the recommended treatment for women with history of VTE, yet evidence-based dosage recommendations are lacking, causing dosage variation between countries and practices.

Effect of therapeutic-dose heparin on severe acute kidney injury and death in noncritically ill patients hospitalized for COVID-19: a prespecified secondary analysis of the ACTIV4a and ATTACC randomized trial

BackgroundAcute kidney injury (AKI) in patients with COVID-19 is partly mediated by thromboinflammation. In noncritically ill patients with COVID-19, therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support. ObjectivesWe investigated whether therapeutic-dose heparin reduces the incidence of AKI or death in noncritically ill patients hospitalized for COVID-19. MethodsWe report a prespecified secondary analysis of the ACTIV4a and ATTACC open-label, multiplatform randomized trial of therapeutic-dose heparin vs usual-care pharmacologic thromboprophylaxis on the incidence of severe AKI (≥2-fold increase in serum creatinine or initiation of kidney replacement therapy (KDIGO stage 2 or 3) or all-cause mortality in noncritically ill patients hospitalized for COVID-19. Bayesian statistical models were adjusted for age, sex, D-dimer, enrollment period, country, site, and platform. ResultsAmong 1922 enrolled, 23 were excluded due to pre-existing end stage kidney disease and 205 were missing baseline or follow-up creatinine measurements. Severe AKI or death occurred in 4.4% participants assigned to therapeutic-dose heparin and 5.5% assigned to thromboprophylaxis (adjusted relative risk [aRR]: 0.72; 95% credible interval (CrI): 0.47, 1.10); the posterior probability of superiority for therapeutic-dose heparin (relative risk < 1.0) was 93.6%. Therapeutic-dose heparin was associated with a 97.7% probability of superiority to reduce the composite of stage 3 AKI or death (3.1% vs 4.6%; aRR: 0.64; 95% CrI: 0.40, 0.99) compared to thromboprophylaxis. ConclusionTherapeutic-dose heparin was associated with a high probability of superiority to reduce the incidence of in-hospital severe AKI or death in patients hospitalized for COVID-19.

Integral assays of hemostasis in hospitalized patients with COVID-19 on admission and during heparin thromboprophylaxis.

Blood coagulation abnormalities play a major role in COVID-19 pathophysiology. However, the specific details of hypercoagulation and anticoagulation treatment require investigation. The aim of this study was to investigate the status of the coagulation system by means of integral and local clotting assays in COVID-19 patients on admission to the hospital and in hospitalized COVID-19 patients receiving heparin thromboprophylaxis. Thrombodynamics (TD), thromboelastography (TEG), and standard clotting assays were performed in 153 COVID-19 patients observed in a hospital setting. All patients receiving treatment, except extracorporeal membrane oxygenation (ECMO) patients (n = 108), were administered therapeutic doses of low molecular weight heparin (LMWH) depending on body weight. The ECMO patients (n = 15) were administered unfractionated heparin (UFH). On admission, the patients (n = 30) had extreme hypercoagulation by all integral assays: TD showed hypercoagulation in ~75% of patients, while TEG showed hypercoagulation in ~50% of patients. The patients receiving treatment showed a significant heparin response based on TD; 77% of measurements were in the hypocoagulation range, 15% were normal, and 8% remained in hypercoagulation. TEG showed less of a response to heparin: 24% of measurements were in the hypocoagulation range, 59% were normal and 17% remained in hypercoagulation. While hypocoagulation is likely due to heparin treatment, remaining in significant hypercoagulation may indicate insufficient anticoagulation for some patients, which is in agreement with our clinical findings. There were 3 study patients with registered thrombosis episodes, and all were outside the target range for TD parameters typical for effective thromboprophylaxis (1 patient was in weak hypocoagulation, atypical for the LMWH dose used, and 2 patients remained in the hypercoagulation range despite therapeutic LMWH doses). Patients with COVID-19 have severe hypercoagulation, which persists in some patients receiving anticoagulation treatment, while significant hypocoagulation is observed in others. The data suggest critical issues of hemostasis balance in these patients and indicate the potential importance of integral assays in its control.

Trauma

The June 2023 Trauma Roundup360 looks at: Aspirin or low-molecular-weight heparin for thromboprophylaxis?; Lateral plating or retrograde nailing for distal femur fractures?; Sciatic nerve palsy after acetabular fixation: what about patient position?; How reliable is the new OTA/AO classification for trochanteric hip fractures?; Young hip fractures: is a medial buttress the answer?; When is the best time to ‘flap’ an open fracture?; The mortality burden of nonoperatively managed hip fractures.

Unchanged Characteristics and Survival among Critically Ill COVID-19 Patients during First, Second, and Third Waves: A Prospective Observational Cohort

Background: This study was carried out to compare characteristics and outcomes in patients with acute respiratory failure related to COVID-19 during first, second, and third waves. Methods: We included consecutive adults admitted to the intensive care unit between March 2020 and July 2021. We compared three groups defined by the epidemic intake phase: waves 1 (W1), 2 (W2), and 3 (W3). Results: We included 289 patients. Two hundred and eight (72%) patients were men with a median age of 63 years (IQR: 54–72), of whom 68 (23.6%) died in hospital. High-flow nasal oxygen (HFNO) was inversely associated with the need for invasive mechanical ventilation (MV) in multivariate analysis (p = 0.003) but not dexamethasone (p = 0.25). The day-90 mortality rate did not vary from W1 (27.4%) to W2 (23.9%) and W3 (22%), p = 0.67. By multivariate analysis, older age (odds ratio [OR]: 0.94/year, p < 0.001), immunodeficiency (OR: 0.33, p = 0.04), acute kidney injury (OR: 0.26, p < 0.001), and invasive MV (OR: 0.13, p < 0.001) were inversely associated with higher day-90 survival as opposed to the use of intermediate heparin thromboprophylaxis dose (OR: 3.21, p = 0.006). HFNO use and dexamethasone were not associated with higher day-90 survival (p = 0.24 and p = 0.56, respectively). Conclusions: In patients with acute respiratory failure due to COVID-19, survival did not change between first, second, and third waves while the use of invasive MV decreased. HFNO or intravenous steroids were not associated with better outcomes, whereas the use of intermediate dose of heparin for thromboprophylaxis was associated with higher day-90 survival. Larger multicentric studies are needed to confirm our findings.

PD31-08 HEPARIN THROMBOPROPHYLAXIS IN SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF OBSERVATIONAL STUDIES

You have accessJournal of UrologyCME1 Apr 2023PD31-08 HEPARIN THROMBOPROPHYLAXIS IN SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF OBSERVATIONAL STUDIES Erica Ai-Li, Kaveh Farrohki, Max Zhang, Juliano Offerni, Patrick Luke, and Alp Sener Erica Ai-LiErica Ai-Li More articles by this author , Kaveh FarrohkiKaveh Farrohki More articles by this author , Max ZhangMax Zhang More articles by this author , Juliano OfferniJuliano Offerni More articles by this author , Patrick LukePatrick Luke More articles by this author , and Alp SenerAlp Sener More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003324.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Thrombosis is a leading causes of pancreas graft loss after simultaneous pancreas kidney (SPK), pancreas after kidney (PAK), and pancreas transplant alone (PTA). There remains no standardized thromboprophylaxis protocol. The aim of this systematic review and meta-analysis is to evaluate the impact of heparin thromboprophylaxis on the incidence of pancreas thrombosis, pancreas graft loss, bleeding, and secondary outcomes in SPK, PAK, and PTA. METHODS: Following PRISMA guidelines, we systematically searched BIOSIS®, PubMed®, Cochrane Library®, EMBASE®, MEDLINE®, and Web of Science® on April 21, 2021. Primary peer-reviewed studies that met inclusion criteria were included. Two methods of quantitative synthesis were performed to account for comparative and non-comparative studies. RESULTS: We included 11 studies, comprising of 1122 patients in the heparin group and 236 patients in the no-heparin group. When compared to the no-heparin control, prophylactic heparinization significantly decreased the risk of early pancreas thrombosis and pancreas loss for SPK, PAK and PTA without increasing the incidence of bleeding or acute return to the operating room. CONCLUSIONS: This study is the first to highlight that heparin thromboprophylaxis yields an approximate two-fold reduction in both pancreas thrombosis and pancreas loss for SPK, PAK and PTA. We report the dosage, frequency, and duration of heparin administration to consolidate the available evidence. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e903 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Erica Ai-Li More articles by this author Kaveh Farrohki More articles by this author Max Zhang More articles by this author Juliano Offerni More articles by this author Patrick Luke More articles by this author Alp Sener More articles by this author Expand All Advertisement PDF downloadLoading ...

Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19

Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Organ support-free days, assigning a value of -1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support-free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support-free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589.

Low-Dose Low-Molecular-Weight Heparin for Thromboprophylaxis During Pregnancy

According to this study: In women who have a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and postpartum periods didn't reduce the risk of recurrence compared with fixed low-dose low-molecular-weight heparin.Further study is needed to determine whether intermediate-dose low-molecular-weight heparin may be more effective than low-dose low-molecular-weight heparin during the postpartum period.

Heparin Thromboprophylaxis in Simultaneous Pancreas-Kidney Transplantation: A Systematic Review and Meta-Analysis of Observational Studies.

Thrombosis is a leading causes of pancreas graft loss after simultaneous pancreas kidney (SPK), pancreas after kidney (PAK), and pancreas transplant alone (PTA). There remains no standardized thromboprophylaxis protocol. The aim of this systematic review and meta-analysis is to evaluate the impact of heparin thromboprophylaxis on the incidence of pancreas thrombosis, pancreas graft loss, bleeding, and secondary outcomes in SPK, PAK, and PTA. Following PRISMA guidelines, we systematically searched BIOSIS®, PubMed®, Cochrane Library®, EMBASE®, MEDLINE®, and Web of Science® on April 21, 2021. Primary peer-reviewed studies that met inclusion criteria were included. Two methods of quantitative synthesis were performed to account for comparative and non-comparative studies. We included 11 studies, comprising of 1,122 patients in the heparin group and 236 patients in the no-heparin group. When compared to the no-heparin control, prophylactic heparinization significantly decreased the risk of early pancreas thrombosis and pancreas loss for SPK, PAK and PTA without increasing the incidence of bleeding or acute return to the operating room. Heparin thromboprophylaxis yields an approximate two-fold reduction in both pancreas thrombosis and pancreas loss for SPK, PAK and PTA. We report the dosage, frequency, and duration of heparin administration to consolidate the available evidence.

Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture

BackgroundClinical guidelines recommend low-molecular-weight heparin for thromboprophylaxis in patients with fractures, but trials of its effectiveness as compared with aspirin are lacking.MethodsIn this pragmatic, multicenter, randomized, noninferiority trial, we enrolled patients 18 years of age or older who had a fracture of an extremity (anywhere from hip to midfoot or shoulder to wrist) that had been treated operatively or who had any pelvic or acetabular fracture. Patients were randomly assigned to receive low-molecular-weight heparin (enoxaparin) at a dose of 30 mg twice daily or aspirin at a dose of 81 mg twice daily while they were in the hospital. After hospital discharge, the patients continued to receive thromboprophylaxis according to the clinical protocols of each hospital. The primary outcome was death from any cause at 90 days. Secondary outcomes were nonfatal pulmonary embolism, deep-vein thrombosis, and bleeding complications.ResultsA total of 12,211 patients were randomly assigned to receive aspirin (6101 patients) or low-molecular-weight heparin (6110 patients). Patients had a mean (±SD) age of 44.6±17.8 years, 0.7% had a history of venous thromboembolism, and 2.5% had a history of cancer. Patients received a mean of 8.8±10.6 in-hospital thromboprophylaxis doses and were prescribed a median 21-day supply of thromboprophylaxis at discharge. Death occurred in 47 patients (0.78%) in the aspirin group and in 45 patients (0.73%) in the low-molecular-weight–heparin group (difference, 0.05 percentage points; 96.2% confidence interval, −0.27 to 0.38; P<0.001 for a noninferiority margin of 0.75 percentage points). Deep-vein thrombosis occurred in 2.51% of patients in the aspirin group and 1.71% in the low-molecular-weight–heparin group (difference, 0.80 percentage points; 95% CI, 0.28 to 1.31). The incidence of pulmonary embolism (1.49% in each group), bleeding complications, and other serious adverse events were similar in the two groups.ConclusionsIn patients with extremity fractures that had been treated operatively or with any pelvic or acetabular fracture, thromboprophylaxis with aspirin was noninferior to low-molecular-weight heparin in preventing death and was associated with low incidences of deep-vein thrombosis and pulmonary embolism and low 90-day mortality. (Funded by the Patient-Centered Outcomes Research Institute; PREVENT CLOT ClinicalTrials.gov number, NCT02984384.)

The Effectiveness of the Intermediate and Therapeutic Doses of Enoxaparin in COVID-19 Patients: A Comparative Study of Factor Xa Inhibition

Background: Management of anticoagulant therapy in COVID-19 patients is critical. Low-molecular-weight heparin (LMWH) thromboprophylaxis is already recommended, and anti-Factor Xa (anti-FXa) monitoring has been used to titrate LMWH doses. Methods: Through a cross-sectional study, we evaluated anti-FXa activity in patients admitted to the ICU, receiving intermediate dose (30, 40, 50 mg, subcutaneously [SC], twice daily) or therapeutic dose (1 mg/kg, SC, Q12h) of enoxaparin to find whether the patients in these two groups achieved anti-FXa levels in the accepted thromboprophylaxis range. Results: The occurrence of deep vein thrombosis was 26% in the therapeutic-dose group and 17% in the intermediate-dose group. D-dimer values were nearly 3.5-fold higher in those who received a therapeutic dose of anticoagulants than in those who received intermediate-dose thromboprophylaxis. Patients in the therapeutic-dose group had significantly higher IL-6 levels (p ≤ 0.001). More than one-third of the patients in the therapeutic-dose group (n = 8; 42.18%) and approximately half of the patients in the intermediate-dose group (n = 12; 52.2%) achieved the target range level of anti-FXa. Patients who received therapeutic doses were more likely to have anti-FXa levels above the expected range (47.4 vs 13% in the intermediate-dose group; p < 0.05). Conclusion: Therapeutic dose of enoxaparin in critically ill COVID-19-infected patients did not reduce the incidence of thromboembolic events and, on the other hand, may predispose these patients to increased risk of bleeding by increasing anti-FXa activity above the desired level. Administration of intermediate-dose thromboprophylaxis is suggested to achieve anti-FXa levels in the accepted thromboprophylaxis range.

Anticoagulation Strategies in Non–Critically Ill Patients with Covid-19

BackgroundOptimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain.MethodsIn an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints.ResultsBetween February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation.ConclusionsIn hospitalized non–critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

Anticoagulation and Antiplatelet Strategies in Non-Critically Ill Patients with Covid-19

Background Optimal thromboprophylaxis for hospitalized patients with Covid-19 is uncertain. Most published clinical trials comparing different anticoagulation protocols in hospitalized patients with Covid-19 have recruited patients in high-income countries (HIC) and results may not be generalizable to patients in low and middle-income countries (LMIC). Furthermore, the incidence of VTE varies by ethnic background with higher rates reported amongst Caucasian compared to diverse Asian populations. We report the results of an international (incorporating both HIC and LMIC regions) adaptive platform randomized trial in hospitalized non-critically ill patients with Covid-19 comparing the effectiveness of low-dose, intermediate-dose, therapeutic-dose anticoagulation, and low-dose plus aspirin on survival and need for organ support. Methods The Australasian COVID-19 Trial (ASCOT) is an investigator-initiated, open-label, pragmatic adaptive platform randomized clinical trial of therapeutics (anticoagulation, antiviral, and therapeutic antibody domains) for non-critically ill patients hospitalized with Covid-19. In our anticoagulation trial, we initially randomly assigned patients to low-dose low-molecular-weight heparin (LMWH) thromboprophylaxis, intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary endpoint was death or the requirement for new organ support by day-28, analyzed with a Bayesian logistic model. Enrolment was closed due to operational constraints. Results Between February 2021 and April 2022, we screened 2,203 patients in 32 hospitals (15 in Australia, 4 in New Zealand, 11 in India, and 2 in Nepal) and enrolled 1574 into the anticoagulation domain (619 assigned to low-dose, 620 to intermediate-dose, 285 to low dose plus aspirin, and 50 to therapeutic-dose). Eighteen participants withdrew consent and 30 were lost to follow-up leaving 1526 included in the primary analysis population (1273 from India, 138 from Australia and New Zealand, 115 from Nepal). The median age of participants was 49 years, 633 (41%) were female, 1291 (83%) were Indian, 480 (31%) were vaccinated against SARS-CoV-2, and 629 (40%) had one or more comorbidities. Adherence to the trial protocol was 98% in the low-dose, 98% in the intermediate-dose, 97% in the low-dose plus aspirin and 92% in the therapeutic-dose anticoagulation arms. All participants received enoxaparin except for one participant in the intermediate group who received tinzaparin. At 28 days after randomization, 35/596 (5.9%) participants assigned to low-dose, 25/601 (4.2%) intermediate-dose, 20/279 (7.2%) low-dose plus aspirin, and 7/50 (14%) therapeutic-dose anticoagulation had died or required organ support. Compared to low-dose thromboprophylaxis, the median adjusted odds ratio (aOR) for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI] 0.43 to 1.27, posterior probability of effectiveness [aOR < 1] [Pr] 86%), for low-dose plus aspirin 0.88 (95% CrI 0.47 to 1.64, Pr 65%) and for therapeutic-dose 2.22 (95% CrI 0.77 to 6.20, Pr 7%). The results were consistent in a number of sensitivity analyses including when restricting the analysis populations to concurrent randomizations. The results were also broadly consistent across the predefined subgroups, with the posterior probability of effectiveness for intermediate-dose compared to low-dose ranging from 56% (corticosteroid exposure) to 94% (>7 days of symptom onset to hospitalization). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. Conclusions In hospitalized adults with Covid-19, compared to low-dose, there was an 86% posterior probability that intermediate-dose, and 7% posterior probability that therapeutic-dose, reduced the odds of death or requirement for organ support by day 28. No treatment strategy met pre-specified statistical stopping criteria prior to trial closure. Trial registration number: NCT04483960

Abstract 14850: Effect of Therapeutic-Dose Heparin on Acute Kidney Injury in Non-Critically Ill Hospitalized Patients With Covid-19: The Activ4a and Attac Randomized Trial

Background: Acute kidney injury (AKI) is common in patients with COVID-19 and mediated, in part, by thromboinflammation. In non-critically ill patients with COVID-19, therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support. We investigated whether therapeutic-dose heparin reduces the incidence of AKI or death in non-critically ill patients hospitalized for COVID-19. Methods: Non-critically ill patients hospitalized for COVID-19 were enrolled in an open-label, multiplatform randomized trial of therapeutic-dose heparin versus usual-care pharmacologic thromboprophylaxis. The primary endpoint of this analysis was in-hospital diagnosis of AKI or death. AKI was defined as Kidney Disease Improving Global Outcomes stage 2 or 3 AKI (≥2-fold increase in serum creatinine or initiation of renal replacement therapy). A Bayesian statistical model estimated the risk of AKI or death between those randomized to therapeutic-dose anticoagulation versus usual-care thromboprophylaxis, adjusted for age, sex, D-dimer, time epoch, country, site, and platform. Results: Among 1922 enrolled from ACTIV4a and ATTACC, 23 were excluded due to ESRD at enrollment. Baseline or follow-up creatinine was missing for 205 individuals. Among 1694 participants analyzed, median age was 60, 58% were men, and median baseline creatinine was 0.9 mg/dL. The primary endpoint occurred in 83 participants (4.9%); 4.4% assigned to therapeutic-dose heparin and 5.5% assigned to thromboprophylaxis (adjusted relative risk [aRR] 0.72, 95% CrI 0.47-1.10; posterior probability of superiority [defined as relative risk &lt; 1.0] was 93.6%). Therapeutic-dose anticoagulation was associated with a 97.7% probability of superiority to reduce the composite of stage 3 AKI or death (3.1% vs. 4.6%; aRR 0.64, 95% CrI 0.40-0.99) compared to usual-care thromboprophylaxis. Conclusions: Therapeutic-dose anticoagulation with heparin was associated with a high probability of superiority to reduce the incidence of in-hospital stage 3 AKI or death in non-critically ill patients hospitalized for COVID-19, compared with usual-care thromboprophylaxis.

Acute Limb Ischemia among COVID-19 Patients in Hospital Kuala Lumpur

BACKGROUND: Acute arterial thromboembolism among the novel coronavirus 2019 (COVID-19) patients is worrying as it can result in significant thrombotic events.&#x0D; AIM: The research aimed to determine the clinical results of COVID-19 infected patients who had ALI (acute limb ischaemia) during the COVID-19 epidemic.&#x0D; METHODS: ALI patients who had a positive COVID-19 were included in the observational cohort study, which was conducted at a single centre. The primary outcomes were 30 days mortality, limb salvage, and successful revascularization.&#x0D; RESULTS: From May to October 2021, data from 21 ALI subjects who had positive COVID-19 were analysed. Of the 21 included subjects, 10 were males (48%). Their mean age was 65±5 years. In nine subjects (42%), revascularization was done. Four (19%) of the 21 persons died while they were hospitalized. Twelve patients underwent major amputation and among them, one patient died after a month of hospitalization for COVID-19-related pneumonia. Among the 12 patients that underwent amputation, 10 of them presented with ALI during the first week of COVID-19 illness. Only one patient developed acute limb ischaemia despite being on heparin thromboprophylaxis.&#x0D; CONCLUSION: Despite attempts at revascularization, ALI-associated with COVID-19 has high mortality and high rates of limb loss. In our experience, major amputation is required in up to a third of patients. This poor result appears to confirm that these infected individuals have a marked hypercoagulable condition. However, adhering to the treatment protocol of heparin thromboprophylaxis confers a benefit in this patient group.

Thromboprophylaxis with standard-dose vs. flexible-dose heparin for hospitalized COVID-19 patients: a target trial emulation

ObjectivesTo compare mortality of hospitalized COVID-19 patients under two low–molecular weight heparin (LMWH) thromboprophylaxis strategies: standard dose and variable dose (standard dose increased to intermediate dose in the presence of laboratory abnormalities indicating an increased thrombosis risk). Study Design and SettingTarget trial emulation using observational data from 2,613 adults admitted with a COVID-19 diagnosis in Madrid, Spain between March 16 and April 15, 2020. ResultsA total of 1,284 patients were eligible. Among 503 patients without increased baseline thrombotic risk, 28-day mortality risk (95% confidence interval [CI]) was 9.0% (6.6, 11.7) under the standard dose strategy and 5.6% (3.3, 8.3) under the variable dose strategy; risk difference 3.4% (95% CI: −0.24, 6.9); mortality hazard ratio 1.61 (95% CI: 0.97, 2.89). Among 781 patients with increased baseline thrombotic risk, the 28-day mortality risk was 25.8% (22.7, 29.0) under the standard dose strategy and 18.1% (9.3, 28.9) under the intermediate dose strategy; risk difference 7.7% (95% CI: −3.5, 17.2); mortality hazard ratio 1.45 (95% CI: 0.81, 3.17). Major bleeding and LMWH-induced coagulopathy were rare under all strategies. ConclusionEscalating anticoagulation intensity after signs of thrombosis risk may increase the survival of hospitalized COVID-19 patients. However, effect estimates were imprecise and additional studies are warranted.