Reduction In Venous Thromboembolism Research Articles

Thromboprophylaxis for outpatients with COVID-19: a Systematic Review and Meta-analysis.

Patients with COVID-19 develop an increased risk of thromboembolism. Thromboprophylaxis is recommended for hospitalized COVID-19 patients, but the role of thromboprophylaxis in outpatients with COVID-19 is less well defined. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of thromboprophylaxis among outpatients with COVID-19. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from inception to August 2023. The outcomes of interest were venous thromboembolic events including deep venous thrombosis and pulmonary embolism, all-cause mortality, cardiovascular events, hospitalization, major bleeding events, and non-major bleeding events. We included 6 trials comprising 3352 patients. Patients who received thromboprophylaxis had an approximately 70% reduction in venous thromboembolism (RR, 0.28 [95% CI, 0.08 to 0.93]) compared to patients who did not receive thromboprophylaxis. The risk of mortality (RR, 0.79 [95% CI, 0.35 to 1.77]), cardiovascular events (RR, 0.91 [95% CI, 0.30 to 2.73]), and hospitalization (RR, 1.09 [95% CI, 0.81 to 1.47]) were similar between the two groups. Patients who received thromboprophylaxis had a higher risk of non-major bleeding (RR, 3.48 [95% CI, 1.72 to 7.05) compared to patients who did not receive thromboprophylaxis. Thromboprophylaxis reduced the risk of venous thromboembolism but not mortality, cardiovascular events, or hospitalization among outpatients with COVID-19.

Prophylactic-dose direct oral anticoagulants for non-hospitalised people with COVID-19: A meta-analysis of randomised controlled trials.

Several reviews have been conducted on thromboprophylaxis in non-hospitalised patients with coronavirus disease 2019 (COVID-19). In this systematic review and meta-analysis, we sought to investigate the impact of prophylactic-dose direct oral anticoagulants (DOACs) in this population. We searched PubMed, Web of Science, EMBASE and Cochrane Library for randomised controlled trials (RCTs) comparing prophylactic-dose DOACs with placebo or no treatment in non-hospitalised patients with COVID-19 until September 2023. The primary efficacy outcome was a composite of all-cause mortality and thromboembolic events, while major bleeding events were the primary safety outcome. We expressed continuous outcome data as mean differences (MDs) with 95% confidence intervals (CIs) and dichotomous outcome data as risk ratios (RRs) with 95% CIs. We included six RCTs involving 4307 patients. Prophylactic-dose DOAC therapy compared with placebo or no treatment was associated with significantly decreased risks of the composite outcome of all-cause mortality and thromboembolic events (1.43% vs 2.67% (RR = 0.53; 95% CI = 0.34-0.82, P = 0.004, I2 = 3%)). Major bleeding events were infrequent, and we detected no significant differences between patients assigned to prophylactic-dose DOACs vs placebo or no treatment (0.19% vs 0.05% (RR = 2.50; 95% CI = 0.49-12.87, P = 0.27, I2 = 0%)). The use of prophylactic-dose DOACs was also associated with a reduction in venous thromboembolism, with no difference in all-cause mortality, arterial thromboembolism, hospitalisations, and clinically relevant nonmajor bleeding between two groups. Sensitivity analyses with the leave-one-out method for the primary efficacy and safety outcome did not change the effect estimate substantially. We found that prophylaxis-dose DOACs could significantly improve clinical outcomes and reduce venous thrombotic events without increasing the risk of major bleeding events compared with placebo or no treatment in non-hospitalised patients with COVID-19. PROSPERO: CRD42023466889.

The effect of obligatory Padua prediction scoring in hospitalized medically ill patients: A retrospective cohort study.

Venous thromboembolism (VTE) is considered a preventable cause of mortality. The evidence for the benefit of VTE prophylaxis in acute medical patients is non-conclusive. Meta-analysis of RCTs failed to demonstrate reduction of all-cause mortality, while showing higher risk of bleeding. The Israeli Ministry of Health has instructed to assess all acute medical patients for the risk for VTE using the Padua Prediction Score, without mandating prophylaxis. To evaluate the effect of filling the Padua score on clinical outcomes and VTE prophylaxis rates. Retrospective Study was performed in Israel during the years 2014-2017. The participants were divided to Padua compliance vs non-compliance group. Primary outcome: 30-day mortality. Secondary outcomes: 90-day incidence of VTE and suspected major bleeding. A propensity-weighted logistic multiple regression was performed. 18,890 patients were included in the study. The fulfillment of the Padua score was associated with an increased use of VTE prophylaxis, OR 1.66 (95% CI 1.49-1.84). However, there was no reduction of mortality or VTE events, OR 1.13 (95% CI 0.97-1.31) and OR 1.22 (95% CI 0.79-1.8) respectively. Hospitalizations related to hemoglobin decrease were not statistically different between the two groups. Padua score for the assessment of VTE risk in medical wards was associated with higher administration of pharmacological prophylaxis without reduction in VTE or mortality rate. Its usage should be reassessed as a performance measure.

Weight-based enoxaparin thromboprophylaxis in young trauma patients: analysis of the CLOTT-1 registry

IntroductionOptimal venous thromboembolism (VTE) enoxaparin prophylaxis dosing remains elusive. Weight-based (WB) dosing safely increases anti-factor Xa levels without the need for routine monitoring but it is unclear if it leads...

Updated Meta-Analysis of Randomized Controlled Trials on Primary Outpatient Thromboprophylaxis (POTP) in Patients with Lung Cancer Receiving Chemotherapy

Introduction Lung cancer (LC) is the leading cause of cancer mortality in the USA. Thrombosis is the second leading cause of death in cancer patients and in recent years, several studies have been conducted to determine beneficial effect of POTP in reduction of VTE (venous thromboembolism) rate in solid cancer patients with the aim to improve the overall survival. We performed an updated meta- analysis of randomized control trials (RCTs) to determine the benefit and risk of POTP with low-molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in patients with LC receiving chemotherapy. Methods We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2023. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results A total of 5,434 patients with LC from five RCTs and subgroups of another five RCTs were included in our meta-analysis. The prophylactic doses of bemiparin, certoparin, dalteparin, nadroparin, semuloparin and tinzaparin, intermediate dose of enoxaparin and prophylactic dose of rivaroxaban and apixaban were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I 2 statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 114 (4.12%) in PATP group and 207 (7.8%) in control group with a RR of 0.53 (95% CI: 0.43 to 0.67, P < 0.00001). The absolute RD in VTE was -0.04 (95% CI: -0.05 to -0.02, P < 0.00001) with an estimate of the number needed to treat (NNT) of 25 to prevent one VTE event. In subgroup analysis of PATP trials treated with LMWHs in study arm, VTE events were reported in 112 (4.2%) in PATP group and 202 (7.9%) in control group with a RR of 0.54 (95% CI: 0.43 to 0.67, P < 0.00001). The absolute RD in VTE was -0.04 (95% CI: -0.05 to -0.02, P < 0.00001). In subgroup analysis of PATP trials treated with DOACs in study arm, VTE events were reported in 2 (2.2%) in PATP group and 5 (5%) in control group with a RR of 0.46 (95% CI: 0.09 to 2.31, P=0.35). The absolute RD in VTE was -0.03 (95% CI: -0.08 to -0.03, P=0.36). Major bleeding (MB) events were reported in 34 (1.6%) patients in POTP group compared to 17 (0.86%) in control group according to an analysis of 7 RCTs. The pooled relative risk for MB was statistically significant at 1.84 (95% CI: 1.06 to 3.22, P = 0.03). Conclusions Our analysis showed that the relative risk reduction is 47% with a NNT of 25 to prevent one VTE with statistically significant increase in MB events in ambulatory patients with LC by providing POTP. In our subgroup meta-analysis of POTP with DOACs, there was no statistically significant difference in reduction of VTE in LC patients with Khorana Score ≥2. Hence, the selection of appropriate patients who are high risk for VTE is crucial and further studies are required to define high risk subsets of LC patients receiving chemotherapy who may benefit from POTP.

Addition of aspirin to venous thromboembolism chemoprophylaxis safely decreases venous thromboembolism rates in trauma patients

BackgroundTrauma patients exhibit a multifactorial hypercoagulable state and have increased risk of venous thromboembolism (VTE). Despite early and aggressive chemoprophylaxis (CP) with various heparin compounds (“standard” CP; sCP), VTE rates...

Systematic Reviews and Meta-analyses of the Procedure-specific Risks of Thrombosis and Bleeding in General Abdominal, Colorectal, Upper Gastrointestinal, and Hepatopancreatobiliary Surgery.

To provide procedure-specific estimates of symptomatic venous thromboembolism (VTE) and major bleeding after abdominal surgery. The use of pharmacological thromboprophylaxis represents a trade-off that depends on VTE and bleeding risks that vary between procedures; their magnitude remains uncertain. We identified observational studies reporting procedure-specific risks of symptomatic VTE or major bleeding after abdominal surgery, adjusted the reported estimates for thromboprophylaxis and length of follow-up, and estimated cumulative incidence at 4 weeks postsurgery, stratified by VTE risk groups, and rated evidence certainty. After eligibility screening, 285 studies (8,048,635 patients) reporting on 40 general abdominal, 36 colorectal, 15 upper gastrointestinal, and 24 hepatopancreatobiliary surgery procedures proved eligible. Evidence certainty proved generally moderate or low for VTE and low or very low for bleeding requiring reintervention. The risk of VTE varied substantially among procedures: in general abdominal surgery from a median of <0.1% in laparoscopic cholecystectomy to a median of 3.7% in open small bowel resection, in colorectal from 0.3% in minimally invasive sigmoid colectomy to 10.0% in emergency open total proctocolectomy, and in upper gastrointestinal/hepatopancreatobiliary from 0.2% in laparoscopic sleeve gastrectomy to 6.8% in open distal pancreatectomy for cancer. VTE thromboprophylaxis provides net benefit through VTE reduction with a small increase in bleeding in some procedures (eg, open colectomy and open pancreaticoduodenectomy), whereas the opposite is true in others (eg, laparoscopic cholecystectomy and elective groin hernia repairs). In many procedures, thromboembolism and bleeding risks are similar, and decisions depend on individual risk prediction and values and preferences regarding VTE and bleeding.

Updated meta-analysis of randomized controlled trials on primary outpatient thromboprophylaxis in patients with gastric and gastroesophageal junction cancers receiving chemotherapy

Advanced gastric cancer is a highly thrombogenic cancer per Khorana score. Recent clinical practice guidelines suggest primary outpatient thromboprophylaxis (POTP) for patients with a Khorana score ≥2. We performed an updated meta-analysis to evaluate the benefit of POTP in patients with gastric cancer and gastroesophageal junction cancers receiving chemotherapy. Randomized controlled trials with reduction in venous thromboembolism (VTE) as a primary or secondary endpoint were incorporated. A total of 631 patients from subgroups of three randomized controlled trials were included. The VTE incidence was 1.6% and 5.1% in POTP and control groups, respectively (risk ratio 0.31; confidence interval 0.11 to 0.83; P = 0.02), with a number needed to treat of 29 to prevent one VTE event. Even though the recent clinical practice guidelines suggest POTP in patients with gastric cancer and gastroesophageal junction cancers, our meta-analysis findings do not support the routine use of POTP in those patients.

Incidence of Thromboembolic Complications Following Kidney Transplantation with Short and Extended Aspirin Prophylaxis: A Retrospective Single-Center Study.

BACKGROUND Aspirin prophylaxis has been associated with reduced graft-related thrombosis following kidney transplantation. Aspirin cessation, however, can increase risk of venous thromboembolic complications, including pulmonary thromboembolism and deep venous thrombosis. This single-center, retrospective, pre-post interventional study from Brisbane, Australia, aimed to compare the rate of thrombotic complications in 1208 adult kidney transplant recipients receiving postoperative aspirin for 5 days or >6 weeks. MATERIAL AND METHODS We enrolled1208 kidney transplant recipients who received 100 mg aspirin for 5 days (n=571) or >6 weeks (n=637) postoperatively. The primary outcome was venous thromboembolism (VTE) in the first 6 weeks after transplant, examined by multivariable logistic regression analysis. Secondary outcomes were renal vein/artery thrombosis, 1-month serum creatinine, rejection, myocardial infarction, stroke, blood transfusion, dialysis at day 5 and day 28, and mortality. RESULTS Sixteen (1.3%) patients experienced VTE (5-day n=8, 1.4%; >6-week n=8, 1.3%; P=0.8). Extended aspirin duration was not independently associated with a reduction in VTE (OR 0.91, 95% CI 0.32-2.57; P=0.9). Graft thrombosis was rare (n=3, 0.25%). Aspirin duration was not associated with cardiovascular events, blood transfusion, graft thrombosis, graft dysfunction, rejection, or mortality. VTE was independently associated with older age (OR 1.09, 95% CI 1.04-1.16; P=0.002), smoking (OR 3.59, 95% CI 1.20-13.2; P=0.032), younger donor age (OR 0.96, 95% CI 0.93-1.00; P=0.036), and thymoglobulin use (OR 10.5, 95% CI 3.09-32.1; P≥0.001). CONCLUSIONS Extended-duration aspirin use did not significantly reduce the incidence of VTE in the first 6 weeks following kidney transplantation. An association was identified between anti-human thymocyte immunoglobulin and VTE, which requires further assessment.

Effect of extended duration of thromboprophylaxis for medically ill patients

BackgroundThere are knowledge gaps regarding the comparative efficacy and safety of various venous thromboprophylaxis regimens with extended timing in patients hospitalized for acute medical illnesses. This study aims to investigate the optimal regimen for the prevention of venous thromboembolism in these patients. MethodsWe conducted a Bayesian network meta-analysis of randomized controlled trials (RCTs) comparing different venous thromboprophylaxis regimens for acutely ill medical patients. Outcomes included venous thromboembolism, major bleeding, and all-cause mortality. Risk ratios (RR) and associated 95% credible interval (CrI) were estimated. In addition, we assessed the most effective interventions in a subgroup of patients with stroke. ResultsWe identified five RCTs involving 40,124 patients. Extended thromboprophylaxis with direct oral anticoagulant (DOAC) (RR 0.78, 95% CrI 0.68 to 0.89) and low molecular weight heparin (LMWH) (RR 0.62, 95% CrI 0.45 to 0.84) were superior to standard therapy in the prevention of venous thromboembolism. However, both of them (DOAC: RR 1.99, 95% CrI 1.38 to 2.92; LMWH: RR 2.56, 95% CrI 1.26 to 5.68) lead to a significant increase in major bleeding). Moreover, both LMWH (RR 0.76, 95% CrI 0.57 to 1.00) and DOAC (RR 0.86, 95% CrI 0.76 to 0.98) with extended thromboprophylaxis showed favorable net clinical benefit compared to standard therapy. ConclusionsExtended thromboprophylaxis, especially with LMWH, showed better efficacy in venous thromboembolism reduction with increased risk of major bleeding. The beneficial effect of LMWH with extended timing has also been shown in stroke patients. Overall, extended thromboprophylaxis is associated with a positive net clinical benefit.

Thromboembolic Events During Weightbearing vs Nonweightbearing Accelerated Rehabilitation Protocols for Complete Achilles Tendon Ruptures.

Achilles tendon rupture can be treated nonoperatively with functional rehabilitation. However, prolonged immobilization has associated risk of venous thromboembolism (VTE). Early weightbearing may reduce VTE risk, and this was introduced to our rehabilitation protocol. We investigated the prevalence of symptomatic VTE events before and after the introduction of the early weightbearing protocol. Adults with ultrasonography-confirmed complete tendo-Achilles ruptures between January 2017 and June 2020 were included. Preprotocol, patients were instructed to not weightbear for 4 weeks. In 2018, immediate weightbearing was introduced to the treatment protocol. All patients in both cohorts were given low-molecular-weight heparin for 4 weeks. Patients with symptomatic VTE events were investigated with duplex ultrasonographic scan or chest computed tomography. Two independent anonymized examiners collected data from electronic records. Rates of symptomatic VTEs were compared. A total of 296 patients were included. Sixty-nine patients were managed with the nonweightbearing protocol, and 227 patients were managed with the early-weightbearing protocol. Two patients in each group developed deep vein thrombosis and 1 developed pulmonary embolism in the early-weightbearing group. Rates of VTEs were lower in the early-weightbearing group (1.3% vs 2.9%) but did not reach statistical significance (P = .33). In this cohort we found that symptomatic VTE after nonoperatively treated Achilles tendon rupture was uncommon. We did not demonstrate a reduction in symptomatic VTE between our early weightbearing and nonweightbearing rehabilitation protocols. We believe a larger study may help clarify whether early weightbearing is beneficial in VTE reduction. Level III, retrospective cohort study.

Hydroxychloroquine Use and Cardiovascular Events Among Patients With Systemic Lupus Erythematosus and Rheumatoid Arthritis.

We evaluated the potential temporal association between hydroxychloroquine (HCQ) use and cardiovascular (CV) events among patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). We conducted a nested case-control study within inception cohorts of SLE and RA patients using administrative health databases including the entire population of British Columbia, Canada. We identified cases with incident CV events, including myocardial infarction (MI), stroke, or venous thromboembolism (VTE). We matched each case with up to 3 controls on age, sex, and rheumatic disease. HCQ exposure was categorized by the time between the last HCQ prescription date covered and the index date as current use, recent use, remote use, or never used. We used conditional logistic regression to assess the association between HCQ exposure and CV events, using remote use as the reference group. We identified 10,268 cases and 29,969 controls. Adjusted conditional odd ratios (cORs) and 95% confidence intervals (95% CIs) for current HCQ use relative to remote use were 0.86 (0.77-0.97) for combined CV events, 0.88 (0.74-1.05) for MI, 0.87 (0.74-1.03) for stroke, and 0.74 (0.59-0.94) for VTE. Recent HCQ users and nonusers had similar odds of combined CV events as remote users (cORs 0.93, 95% CI 0.77-1.13 and 0.96, 95% CI 0.88-1.04, respectively). In this nested case-control study of patients with SLE and RA, we found a reduced risk of overall CV events associated with current HCQ use, including reductions in VTE and trends toward reductions in MI and stroke. These findings suggest a possible cardiovascular preventative benefit of HCQ use.

Just What the Doctor Ordered: Missed Ordering of Venous Thromboembolism Chemoprophylaxis Is Associated With Increased VTE Events in High-risk General Surgery Patients.

To define the impact of missed ordering of venous thromboembolism (VTE) chemoprophylaxis in high-risk general surgery populations. The primary cause of preventable death in surgical patients is VTE. Although guidelines and validated risk calculators assist in dosing recommendations, there remains considerable variability in ordering and adherence to recommended dosing. All adult inpatients who underwent a general surgery procedure between 2016 and 2019 and were entered into Atrium Health National Surgical Quality Improvement Program registry were identified. Patients at high risk for VTE (2010 Caprini score ≥5) and without bleeding history and/or acute renal failure were included. Primary outcome was 30-day postoperative VTE. Electronic medical record identified compliance with "perfect" VTE chemoprophylaxis orders (pVTE): no missed orders and no inadequate dose ordering. Multivariable analysis examined association between pVTE and 30-day VTE events. A total of 19,578 patients were identified of which 4252 were high-risk inpatients. Hospital compliance of pVTE was present in 32.4%. pVTE was associated with shorter postoperative length of stay and lower perioperative red blood cell transfusions. There was 50% reduced odds of 30-day VTE event with pVTE (odds ratio: 0.50; 95% CI, 0.30-0.80) and 55% reduction in VTE event/mortality (odds ratio: 0.45; 95% CI, 0.31-0.63). After controlling for relevant covariates, pVTE remained significantly associated with decreased odds of VTE event and VTE event/mortality. pVTE ordering in high-risk general surgery patients was associated with 42% reduction in odds of postoperative 30-day VTE. Comprehending factors contributing to missed or suboptimal ordering and development of quality improvement strategies to reduce them are critical to improving outcomes.

Approaches for optimizing venous thromboembolism prevention in injured patients: Findings from the consensus conference to implement optimal venous thromboembolism prophylaxis in trauma.

Venous thromboembolism (VTE) is a major issue in trauma patients. Without prophylaxis, the rate of deep venous thrombosis approaches 60% and even with chemoprophylaxis may be nearly 30%. Advances in VTE reduction are imperative to reduce the burden of this issue in the trauma population. Novel approaches in VTE prevention may include new medications, dosing regimens, and extending prophylaxis to the postdischarge phase of care. Standard dosing regimens of low-molecular-weight heparin are insufficient in trauma, shifting our focus toward alternative dosing strategies to improve prophylaxis. Mixed data suggest that anti-Xa-guided dosage, weight-based dosing, and thromboelastography are among these potential strategies. The concern for VTE in trauma does not end upon discharge, however. The risk for VTE in this population extends well beyond hospitalization. Variable extended thromboprophylaxis regimens using aspirin, low-molecular-weight heparin, and direct oral anticoagulants have been suggested to mitigate this prolonged VTE risk, but the ideal approach for outpatient VTE prevention is still unclear. As part of the 2022 Consensus Conference to Implement Optimal Venous Thromboembolism Prophylaxis in Trauma, a multidisciplinary array of participants, including physicians from multiple specialties, pharmacists, nurses, advanced practice providers, and patients met to attack these issues. This paper aims to review the current literature on novel approaches for optimizing VTE prevention in injured patients and identify research gaps that should be investigated to improve VTE rates in trauma.

Updated Meta-Analysis of Randomized Controlled Trials on Primary Outpatient Thromboprophylaxis (POTP) in Patients with Advanced Pancreatic Cancer (APC) Receiving Chemotherapy

Introduction: APC is as a highly thrombogenic cancer where the score of 2 is assigned per Khorana score (KS). POTP is currently suggested to patients with KS of 2 and above by recent clinical practice guidelines. We conducted an updated meta-analysis to demonstrate the benefit of POTP with low-molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) in patients with APC receiving chemotherapy. Methods: Comprehensive literature across MEDLINE and EMBASE databases were searched from inception through June 30, 2022, using search terms 'thromboprophylaxis’ OR 'anticoagulation’ OR 'low-molecular-weight heparin’ OR 'direct oral anticoagulants’ AND 'pancreas cancer'. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in venous thromboembolism (VTE) as a primary or secondary endpoint were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). I2 statistic and Cochran's Q- statistic were used to assess heterogeneity among the studies. Results: Two RCTs and a subgroup of another four RCTs including 1,091 patients with APC were included. The prophylactic, intermediate and therapeutic doses of LMWH and prophylactic doses of DOAC (rivaroxaban and apixaban) were used in the trials. The duration of anticoagulation ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2 statistic for heterogeneity was 35, suggesting some heterogeneity among RCTs. The VTE incidence was 30 (5.4%) in ATP group and 71 (13.2%) in control group with a RR of 0.42 (95% CI: 0.23 to 0.74, P = 0.003). The absolute RD was -0.08 (95% CI: -0.11 to -0.04, P < 0.0001) with an estimate of the number needed to treat (NNT) of 13 to prevent one VTE event. In a subset of patients treated with LMWH (n= 740, 4 studies), the pooled RR was significant at 0.32 (95% CI: 0.15 to 0.69, P = 0.003) whereas in patients who received DOACs (n=351, 2 studies), RR was statistically non-significant at 0.66 (95% CI: 0.36 to 1.22, P = 0.19). Conclusions: Although POTP in APC statistically significantly decreases VTE events (approximately with relative risk reduction of 59% and a NNT of 13), the VTE reduction seemed only statistically significantly observed in patients who had received "LMWH vs control” compared to patients who were treated with "DOAC vs control". One hypothesis could be that in the trials with LMWH, higher doses (therapeutic dose in FRAGEM and intermediate dose in CONKO-004) were utilized compared to the studies with DOAC where only prophylactic doses were utilized. Another possibility is that the compliance rates were poor in the CASSINI trial. More randomized trials are required to further define the high-risk subsets who may benefit from POTP as well as the optimal dosing and types of anticoagulation in such population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thrombin Generation Is Differentially Affected By Anticoagulants in Patients with Acute Lymphoblastic Leukemia - an Ex-Vivo Study

Background: Venous thromboembolism (VTE) is a frequent complication in patients with acute lymphoblastic leukemia (ALL). Low molecular weight heparin (LMWH) reduces the risk of VTE in ALL, but is not well tolerated in children. VTE rates remain unacceptably high in adults despite LMWH prophylaxis. Thus, novel strategies for VTE prevention are warranted. In the primary analysis of the PREVAPIX-ALL trial there was no statistically significant reduction in VTE among children treated with the oral factor Xa inhibitor, apixaban, compared to no anticoagulation (AC). Comparative data on activity of different anticoagulants are needed to guide planning of VTE prophylaxis trials. Aims: To characterize and compare the ex-vivo effect of LMWH (enoxaparin), oral direct factor Xa inhibitors (apixaban, rivaroxaban) and oral direct thrombin inhibitor (dabigatran etexilate) in ALL patients' samples using thrombin generation (TG). Methods: A prospective observational cohort study of 46 children with newly-diagnosed ALL, treated with the L-asparaginase (ASP)-based BFM protocol, at a tertiary medical center. Patients on therapeutic-dose AC at baseline were excluded. Blood samples were drawn before ASP treatment (ALL-Day0) and 7 days after (ALL-Day7). Normal pooled plasma (NP) was collected from healthy adult volunteers. Samples were spiked ex-vivo with enoxaparin [0.2 U/mL], apixaban [39 ng/mL], rivaroxaban [39 ng/mL] and dabigatran [150 ng/mL] or vehicle (i.e., control). AC concentrations chosen based on 50% peak reduction (for Xa inhibitors) or 200% LT prolongation (for dabigatran) in NP. Subsequently, TG was performed initiated using 5 pM tissue factor in the presence of 4 µM phospholipids using Calibrated Automated Thrombogram method in these samples. Results are expressed as peak height (PH) and lag time (LT) and relative reduction or prolongation (% difference in PH or LT, respectively) in plasma samples spiked with anticoagulants compared to control. Reduction in PH reflects enoxaparin, apixaban and rivaroxaban activity, while LT prolongation indicates dabigatran activity. This report focuses on measures reflecting the activity of each drug. Descriptive statistics were used to show the median [interquartile range (IQR)] for continuous variables and percentages for categorical data. T-Test / Mann-Whitney U test and paired T-test / Wilcoxon test used to compare between paired and non-paired samples, respectively. Results: Selected sample characteristics are as follows: median age, 7.75 years [IQR 3.73-11.93]; 19 (41%) females; median BMI, 16.8 [IQR 15.5-19.9]; B-cell precursor immunophenotype in 33 (71.7%) and T-cell in 13 (28.3%); prior VTE in 1 (2%). Median PH [IQR] in control samples (without AC) was 256.6 [252.6-265.3] nmol/l, 396.0 [347.2-464.7] nmol/l and 354.4 [307.1-407.4] nmol/l in NP, ALL-Day0 and ALL-Day7 respectively. Median LT [IQR] in control samples was 2.7 [2.5-2.83] nmol/l, 1.8 [1.7-2.3] nmol/l and 1.7 [1.6-2] nmol/l in NP, ALL-Day0 and ALL-Day7 respectively. Median % differences in PH and LT between samples spiked with different anticoagulants and controls are shown in Figure 1A and Figure 1B, respectively. Enoxaparin, apixaban and rivaroxaban reduced PH in NP, ALL-Day0 and ALL-Day7 samples (p<0.0005). There was less reduction in PH with enoxaparin, apixaban and rivaroxaban in ALL-Day0 samples than in NP (p=0.029, p<0.0005, p<0.0005 respectively), suggesting reduced anticoagulant activity in ALL patients compared to subjects without ALL. LT was prolonged with dabigatran in NP, ALL-Day0 and ALL-Day7 samples (p<0.05). Dabigatran resulted in a similar LT prolongation in ALL-Day0 and NP (p=0.677), suggesting a preserved AC effect in ALL. There was less LT prolongation in ALL-Day7 (134% [123-175%] than in ALL-Day0 (180% [134-238]; p=0.031). This reflects an ongoing dabigatran effect after ASP, albeit to a lesser degree. Conclusions: Our ex-vivo results suggest limited anticoagulant activity of enoxaparin and lack of anticoagulant activity of apixaban and rivaroxaban (both factor Xa inhibitors) in preventing VTE in ALL, in line with prior clinical data. In contrast, dabigatran etexilate, an oral direct thrombin inhibitor not previously tested in ALL, exhibited preserved anticoagulant activity in ALL patients, even after exposure to ASP. This may suggest that dabigatran should be investigated in clinical studies for the unmet need of VTE prophylaxis in ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Net clinical benefit of DOACs vs. usual anticoagulation treatment in venous thromboembolism and active cancer: systematic review and meta-analysis.

Patients with active cancer are at high risk of recurrent venous thromboembolism (VTE). Usual treatment includes low molecular weight heparin (LMWH), while vitamin K antagonists (VKAs) have also been used as substitutes for LMWH. Direct oral anticoagulants (DOACs) are considered a beneficial alternative to the usual treatment but are accompanied by an increased rate of bleeding compared to LMWH. We conducted a meta-analysis to evaluate the benefits and harms under a common denomination, namely the net clinical benefit (NCB), between DOACs and usual anticoagulation. The primary outcome was NCB-1, defined as non-fatal VTE, major non-fatal bleedings, and all-cause mortality). Co-primary outcomes were 1) NCB-2 (i.e., NCB-1 and clinically relevant non-major bleedings) and 2) NCB-3 (i.e., fatal or non-fatal VTE and major bleedings). A random-effects model was used to calculate outcome risk ratios and 95% confidence intervals (CI). Prospective Register of Systematic Reviews identification number CRD42021284238. We selected 8 studies (n = 4,4461 patients; mean follow-up, 6months). The NCB-1 and -2 were not different between DOACs and usual anticoagulation, while the NCB-3 showed a reduction of 28% (95% CI, 10-42%), favoring DOACs. Recurrent VTE was reduced by 40% (95% CI, 25-53%) with DOACs than the usual treatment. Different bleeding outcomes and all-cause mortality were not different between treatments. All primary outcomes did not differ between DOACs and LMWH, while NCB-2 and NCB-3 were reduced with DOACs than VKAs. The NCB of DOACs was similar or more favorable to usual anticoagulation in patients with active cancer due to a substantial reduction of VTE and no bleeding excess.

Use of anticoagulants in patients with COVID-19: a living systematic review and meta-analysis.

ABSTRACTObjective:To answer questions related to the use of anticoagulants in the treatment of COVID-19 patients. Methods:This was a systematic review and meta-analysis of phase 3 randomized controlled trials comparing the use of anticoagulants in non-hospitalized and hospitalized COVID-19 patients. We searched the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to January 22, 2022. The risk of bias was assessed by the Cochrane risk-of-bias tool, and the quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation system. Results:A total of 401 studies were initially selected. Of those, 9 met the inclusion criteria and were therefore analyzed (a total of 6,004 patients being analyzed). In non-hospitalized COVID-19 patients, no significant difference was found between post-discharge prophylactic anticoagulation and no intervention regarding venous thromboembolism or bleeding at 30 days. In hospitalized COVID-19 patients, full anticoagulation resulted in a slight reduction in thrombotic events at 30 days (risk difference, −0.03; 95% CI, −0.06 to −0.00; p = 0.04; I2 = 78%), the quality of evidence being moderate. However, no significant difference was found between full anticoagulation and no intervention regarding the risk of major bleeding, the quality of evidence being very low. No significant difference was found between intermediate- and standard-dose prophylactic anticoagulation (risk difference, −0.01; 95% CI, −0.07 to 0.06; p = 0.81; I2 = 0%), the quality of evidence being very low. Conclusions:Therapeutic anticoagulation appears to have no effect on mortality in COVID-19 patients, resulting in a slight reduction in venous thromboembolism in hospitalized patients.

Urgent surgery versus anticoagulation for treatment of superficial vein thrombosis in patients with varicose veins.

Background: We performed a prospective observational study to compare the results of surgery and anticoagulation in patients with superficial vein thrombosis (SVT). Patients and methods: A total of 190 patients (195 limbs) with varicose veins and SVT were included and treated by anticoagulation or by surgery. Patients were followed-up during 6 months. The primary outcome for treatment efficacy was the composite rate of SVT extension/recurrence; deep vein thrombosis (DVT) or symptomatic pulmonary embolism (PE). The primary outcome for safety was the rate of wound complications and rate of bleedings. Results: Surgery was performed in 85 (44.7%) patients and 105 patients (5 with bilateral SVT) were treated conservatively. In the whole study cohort the primary outcome for treatment efficacy was registered in 15 (7.6%) cases: 9/85 (10.5%) in surgical group and 6/110 (5.4%) in anticoagulation group. Nine patients treated with surgery were diagnosed with postoperative DVT. In anticoagulation group SVT extension occurred in 3 limbs; SVT recurrence in 2 and DVT in one. There were no cases of PE or death during the follow-up. Time-to-event analysis demonstrated no significant difference between groups (HR 0.48; 95% CI 0.17-1.34). The total length of the thrombus was associated with primary efficacy outcome in surgical group (HR 1.07; 95% CI 1.02-1.11); and duration of anticoagulation (HR 0.91 per day; 95% CI 0.83-0.99) and value of Caprini score (HR 1.86; 95% CI 1.1-3.14) in anticoagulation group. Six (7%) wound complications were registered after surgery and 6 (5.71%) bleedings during anticoagulation. Conclusions: Urgent surgery is not associated with reduction of venous thromboembolism compared to anticoagulation in treatment of patients with SVT and varicose veins during 6-months follow-up. However, in patients with isolated thrombosis of varicose tributaries or with limited involvement of the saphenous trunk surgery is relatively safe.

Relationship between anti-Xa level achieved with prophylactic low-molecular weight heparin and venous thromboembolism in trauma patients: A systematic review and meta-analysis.

Trauma patients have simultaneously high venous thromboembolism (VTE) and bleeding risk. Optimal chemoprophylaxis regimens remain unclear. This study aims to answer three questions for trauma patients. Is there any association between anti-Xa and VTE? Does dose adjustment improve prophylactic anti-Xa rates? Does dose adjustment improve anti-Xa adequacy and VTE compared with standard dosing? Systematic search of MEDLINE, Embase, Scopus, and Web of Science occurred in May 2021. Two author reviews included trauma studies that evaluated low molecular weight heparin chemoprophylaxis, reported anti-Xa level, and evaluated more than one outcome. Data were dually extracted and estimated effects were calculated using RevMan 5.4 applying the Mantel-Haenszel method. Analysis 1 compared patients with peak anti-Xa of 0.2 IU/mL or greater or trough 0.1 IU/mL or greater to those with lower anti-Xa using VTE as the primary outcome. Analysis 2 reported the effect of dose adjustment on anti-Xa. Analysis 3 compared standard dosing to dose adjustment with the primary outcome being anti-Xa adequacy; secondary outcomes were VTE, pulmonary embolism, and bleeding complications. There were 3,401 studies evaluated with 24 being included (19 retrospective studies, 5 prospective studies). In analysis 1, achieving adequate anti-Xa was associated with reduced odds of VTE (4.0% to 3.1%; odds ratio [OR], 0.52; p = 0.03). Analysis 2 demonstrated that 768 (75.3%) patients achieved prophylactic anti-Xa with adjustment protocols. Analysis 3 suggested that dose-adjusted chemoprophylaxis achieves prophylactic anti-Xa more frequently (OR, 4.05; p = 0.007) but without VTE (OR, 0.72; p = 0.15) or pulmonary embolism (OR, 0.48; p = 0.10) differences. In subgroup analysis, anti-Xa dose adjustment also suggested no VTE reduction (OR, 0.68; p = 0.08). Patients with higher anti-Xa levels are less likely to experience VTE, and anti-Xa guided chemoprophylaxis increases anti-Xa adequacy. However, dose adjustment, including anti-Xa guided dosing, may not reduce VTE. Systematic Review Meta-Analysis, Level IV.