Dalteparin Group Research Articles

Efficacy and Safety of a DOAC Compared to Unfractionated Heparin and A Low Molecular Weight Heparin in the Prevention of Thromboembolism in Hematopoietic Stem Cell Transplant Recipients.

Hematopoietic stem cell transplantation (HSCT) patients are at risk of thromboembolic events, making thromboprophylaxis crucial. This study aimed to compare apixaban, a direct factor Xa inhibitor (DOAC), with dalteparin and unfractionated heparin for thromboprophylaxis in HSCT recipients. The safety outcome included the assessment of hemorrhagic events. In this open-label randomized clinical trial, 182 HSCT recipients were divided into three groups: Apixaban (n = 61, 2.5 mg two times a day), dalteparin (n = 59, 5000 IU daily), and unfractionated heparin (n = 62, 5000 IU twice daily). These anticoagulant regimens were administered after central vein catheterization and during hospitalization. The primary clinical outcome was the risk of thrombosis, and the secondary outcome was the rate of bleeding. Relevant laboratory results were analyzed using appropriate statistical tests. Among the 61 patients in the apixaban group, six experienced thrombosis (9.83%), with four (6.65%) of them on anticoagulants. In the dalteparin group, three patients (5%) developed thrombosis, two of whom (3.38%) were on anticoagulants. In the heparin group, all four thrombosis cases (6.4%) occurred in patients on anticoagulants (P = 0.543 overall and P = 0.776 in anticoagulant users). Only two cases of bleeding were reported (1.09% overall), one in the dalteparin group (1.69%) and the other in the apixaban group (1.63%). Apixaban, dalteparin, and heparin demonstrated similar effectiveness in preventing thromboembolism in HSCT recipients. Furthermore, the comparison of bleeding rates across the study groups did not reveal significant differences. Larger studies with higher event rates may yield more precise conclusions.

Evaluation of the Modification Effects of Heparin/Dalteparin on Silk Fibroin Structure and Physical Properties for Skin Wound Healing.

We have developed a functionalized silk fibroin (BSF) that can serve as an improved fundamental material for dressings by specifically capturing growth factors secreted during the healing process and supplying them to cells accumulated in the wound area to enhance the tissue regeneration efficiency. When considering the design of heparin-modified BSF, there is a difficulty with binding to high-molecular-weight polysaccharides without disrupting the hydrophobic crystalline structure of the BSF. In this study, a low-molecular-weight pharmaceutical heparin, dalteparin, was selected and cross-linked with the tyrosine residue presence in the BSF non-crystalline region. When targeting 3D porous applications like nanofiber sheets, as it is crucial not only to enhance biological activity but also to improve handling by maintaining stability in water and mechanical strength, a trade-off between improved cell affinity and reduced mechanical strength depending on crystalline structure was evaluated. The use of dalteparin maintained the mechanical strength better than unfractionated heparin by reducing the effect on disturbing BSF recrystallization. Film surface hydrophilicity and cell proliferation induction were significantly higher in the dalteparin group. For BSF functionalization, using purified heparin was an effective approach that achieved a balance between preserving the mechanical properties and induction of tissue regeneration, offering the potential for various forms in the future.

Early Time Courses of Recurrent Venous Thromboembolism and Bleeding during Apixaban or Dalteparin Therapy for Patients with Cancer.

In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated noninferiority of apixaban to dalteparin for treatment of cancer-associated VTE without an increased risk of major bleeding. We compared the early time course of VTE recurrence and major bleeding events of apixaban compared with dalteparin at 7, 30, and 90 days of treatment in patients with cancer-associated VTE. The study design of the CARAVAGGIO trial has been described. Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed recurrent VTE. The primary safety outcome was major bleeding. In 1,155 patients, recurrent VTE after 7, 30, and 90 days occurred in 6 (1%), 15 (2.6%), and 27 (4.7%) patients in the apixaban arm versus 5 (0.9%), 20 (3.5%), and 36 (6.2%) patients respectively in the dalteparin arm. By day 7, 30, and 90, major bleeding events had occurred in 3 (0.5%), 9 (1.6%), and 16 (2.8%) patients in the apixaban group versus 5 (0.9%), 11 (1.9%), and 17 (2.9%) patients in the dalteparin group. The frequencies of recurrent VTE and major bleeding events at 7, 30, and 90 days of apixaban compared with dalteparin were similar in patients with cancer-associated VTE. This supports the use of apixaban for the initiation and early phase of anticoagulant therapy in cancer-associated VTE.

The effects of three different low-molecular-weight heparins on blood loss after intramedullary nailing of trochanteric fractures.

The purpose of this study was to compare the effects of reviparin, dalteparin and enoxaparin on intraoperative blood loss in patients with trochanteric fracture treated with intramedullary nailing. This retrospective multicenter study included 100 patients with trochanteric fracture who were divided into three groups according to the low-molecular-weight heparin administered. In all cases, a short third generation Gamma nail was used for osteosynthesis. Complete blood count and number of red blood cell transfusions (RBC) were evaluated. The mean value of postoperative haemoglobin level was lower in the enoxaparin group compared to the reviparin group, with significant difference (p = 0.001; 95% CI 4.1-18.87). Patients in the dalteparin group received more RBC transfusions compared to the reviparin and enoxaparin group (p = 0.048). The use of enoxaparin and dalteparin in hip fracture patients can result in lower postoperative haemoglobin levels and more RBC transfusions compared to reviparin.

Comparative analysis of the effects of dalteparin and reviparin on perioperative blood loss in patients with extracapsular hip fractures treated with intramedullary nailing.

Aim To determine differences between reviparin and dalteparin treatment in patients with extracapsular hip fractures treated with intramedullary nailing and their effects on perioperative blood loss and early postoperative recovery. Methods Retrospective comparative study included 68 patients with extracapsular hip fracture who were divided into dalteparin and reviparin group. Medical records were used to obtain demographic data, laboratory parameters, haemoglobin and haematocrit levels, platelet count, mortality rate and medical complications. Results Out of total 68 patients, 31 were in reviparin and 37 in dalteparin group. Mean age of patients was 70.5 (±14.4) and 76.8 (±8.4) years in reviparin and dalteparin group, respectively (p=0.071). Median values of haemoglobin levels on the first postoperative day were lower in dalteparin group compared to reviparin group (p=0.012). On the first postoperative day haematocrit values were also lower in dalteparin than in reviparin group (p=0.015). Both groups showed an increase in platelet count on the first postoperative day, but without significant difference (p=0.084). There was no statistically significant difference in intrahospital mortality between the groups (6.4% vs. 2.7%; p=0.588). One case of pulmonary embolism was detected in the dalteparin group. Conclusion Low-molecular-weight heparin is the drug of choice in patients with hip fractures for thromboprophylaxis. Due to non-antithrombin-mediated actions, reviparin and dalteparin could have different effects on perioperative blood loss. Both dalteparin and reviparin are safe and effective agents for thromboprophylaxis in patients with proximal femur fractures.

The Effects of Three Different Low-molecular-weight Heparins on Blood Loss After Intramedullary Nailing of Trochanteric Fractures.

The three most commonly used low-molecular-weight heparins (LMWH) in Bosnia and Herzegovina for thromboprophylaxis in patients with hip fracture are reviparin, dalteparin and enoxaparin. The purpose of this study was to compare the effects of reviparin, dalteparin and enoxaparin on intraoperative blood loss in patients with trochanteric fracture treated with intramedullary nailing. This retrospective multicenter study included 100 patients with trochanteric fracture who were divided into three groups according to the low-molecular-weight heparin administered. In all cases, a short third generation Gamma-nail was used for osteosynthesis. Complete blood count and number of red blood cell transfusions (RBC) were evaluated. Results: The mean value of postoperative hemoglobin level was lower in the enoxaparin group compared to the reviparin group, with significant difference (p=0.001; 95% CI: 4.1-18.87). Patients in the dalteparin group received more RBC transfusions compared to the reviparin and enoxaparin group (p=0.048). The use of enoxaparin and dalteparin in hip fracture patients can result in lower postoperative haemoglobin levels and more RBC transfusions compared to reviparin.

Early Time Courses of Recurrent Thromboembolism and Bleeding during Apixaban or Dalteparin Therapy for Patients with Cancer

Introduction The CARAVAGGIO trial was a multinational, randomised, investigator initiated, open-label with blind outcome assessment, noninferiority trial which demonstrated noninferiority of apixaban to dalteparin for treatment of cancer related venous thromboembolism (VTE) without an increased risk of major bleeding. In patients with acute VTE, the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation (1). We sought to evaluate the efficacy and safety of apixaban during the initial high-risk phase of treatment in patients with cancer associated VTE. Specifically, we performed a pre-specified sub-analysis of the time courses of recurrence and bleeding, with the aim to determine the incidence after 7, 30 and 90 days of treatment with apixaban compared with dalteparin. Methods The study design and methods of the CARAVAGGIO trial (CARAVAGGIO; NCT03045406; https://clinicaltrials.gov/ct2/show/NCT03045406) have been described (2). Briefly, CARAVAGGIO compared the efficacy and safety of apixaban with dalteparin in consenting patients who had active cancer and a newly diagnosed symptomatic or incidental proximal lower-limb deep-vein thrombosis (DVT) or pulmonary embolism (PE). Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed VTE. The primary safety outcome was major and clinically relevant non-major (CRNM) bleeding. Results The CARAVAGGIO study enrolled 1170 patients from 119 centres in eleven countries from April 2017 through June 2019); 1155 patients were included in the modified intention-to-treat analysis. The demographic and clinical characteristics of the patients were similar in the two treatment groups. Of the 78 recurrent VTE events 11 (14.1%) occurred in the first 7 days, 35 (44.8%) in the first 30 days and 63 (80.7%) in the first 90 days. Recurrent events occurred in 6 (1.0%) in the apixaban group and 5 (0.9%) in the dalteparin group (RR 1.21; 95% CI 0.37-3.93) by day 7, 15 (2.6%) in the apixaban group and 20 (3.5%) in the dalteparin group (RR 0.75; 95% CI 0.39-1.46) by day 30, and in 27 (4.7%) in the apixaban group and 36 (6.2%) in the dalteparin group (RR 0.75; 95% CI 0.46-1.23) by day 90. By 6 months, recurrent events occurred in 32 (5.6%) in the apixaban group and 46 (7.9%) in the dalteparin group (RR 0.70; 95% CI 0.45-1.08). (Table 1). During the six months of treatment, major and CRNM bleeding occurred in 70 patients who received apixaban (12.2%) and in 56 patients who received dalteparin (9.7%) (RR 1.26; 95% CI 0.90-1.75). Of the total 126 bleeding events, 24 (19.0%) occurred during the first 7 days; 58 (46.0%) during the first 30 days, and 89 (70.6%) during the first 90 days. Bleeding events occurred in 14 (2.4%) in the apixaban group and 10 (1.7%) in the dalteparin group (RR 1.40; 95% CI 0.63-3.14) by day 7, 30 (5.2%) in the apixaban group and 28 (4.8%) in the dalteparin group (RR 1.08; 95% CI 0.65-1.78) by day 30, and in 46 (8.0%) in the apixaban group and 43 (7.4%) in the dalteparin group (RR 1.07; 95% CI 0.72-1.60) by day 90. The Kaplan-Meier plot of time to recurrent VTE and major and CRNM bleeding is shown in figure 1. Conclusion The results of this sub-analysis of the CARAVAGGIO trial demonstrate no difference of oral apixaban to subcutaneous dalteparin at all time points. Specifically, there was no increase in recurrent VTE or bleeding events at 7 days, 30 days, 90 days and 6 months. This supports early initiation of oral anticoagulation. Oral versus subcutaneous anticoagulation has the advantage of ease of administration and outpatient delivery which may improve patients’ quality of life - an important consideration in patients with cancer. Reference 1. Raskob GE, Gallus AS, Sanders P, Thompson JR, Agnelli G, Buller HR, et al. Early time courses of recurrent thromboembolism and bleeding during apixaban or enoxaparin/warfarin therapy. A sub-analysis of the AMPLIFY trial. Thrombosis and haemostasis. 2016;115(4):809-16. 2. Agnelli G, Becattini C, Meyer G, Muñoz A, Huisman MV, Connors JM, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. New England Journal of Medicine. 2020;382(17):1599-607. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II Study to Compare the Safety and Efficacy of Direct Oral Anticoagulants versus Subcutaneous Dalteparin for Cancer-Associated Venous Thromboembolism in Patients with Advanced Upper Gastrointestinal, Hepatobiliary and Pancreatic Cancer: PRIORITY.

Simple SummaryThis prospective phase II trial evaluated the safety and efficacy of direct oral anticoagulants (DOACs) versus subcutaneous dalteparin for cancer-associated venous thromboembolism (CA-VTE) in patients with high-risk cancer types and currently active advanced cancers. The clinically relevant bleeding (CRB) as the primary endpoint and major bleeding (MB) more occurred in the DOAC group than in the dalteparin group, and the hazard ratio for CRB and MB was approximately three and four times more in the DOAC group than in the dalteparin group. Cancer involvement at the GI mucosa was also a significant risk factor for CRB. The extra caution is necessary when using DOAC therapy for CA-VTE in patients with advanced upper gastrointestinal (GI) tract, hepatobiliary, or pancreatic cancer.Background: We evaluated the safety and efficacy of direct oral anticoagulants (DOACs) versus subcutaneous dalteparin for cancer-associated venous thromboembolism (CA-VTE) in patients with advanced upper gastrointestinal (GI) tract, hepatobiliary, or pancreatic cancer. Methods: This was a multicenter, randomized, open-label, phase II trial in five centers. Patients randomly received rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily)/apixaban (10 mg twice daily for the first 7 days, then 5 mg twice daily) or dalteparin (200 IU/kg once daily for the first month, then 150 IU/kg once daily). Randomization was stratified by the Eastern Cooperative Oncology Group Performance Status, primary cancer type, active chemotherapy, and participating centers. The primary endpoint was the rates of clinically relevant bleeding (CRB) in the full analysis set (FAS). Results: A total of 90 patients were randomly assigned to the DOAC (n = 44) and dalteparin groups (n = 46) in FAS. CRB and major bleeding (MB) rates were 34.1% and 13.0% (p = 0.018) and 18.2% and 4.3% (p = 0.047) for the DOAC and dalteparin groups, respectively. Time to CRB and MB was higher in the DOAC group than in the dalteparin group (hazard ratio [HR] 2.83; p = 0.031 and HR 4.32; p = 0.064). Cancer involvement at the GI mucosa was also a significant risk factor for CRB. Recurrent CA-VTE occurred in 2.3% and 2.2% of patients given DOAC and dalteparin, respectively (p = 1.000). Conclusion: DOAC therapy further increased the risk of bleeding compared with dalteparin in patients with active advanced upper GI tract, hepatobiliary, or pancreatic cancer, suggesting that extra caution should be taken when selecting anticoagulants for CA-VTE.

Risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer using edoxaban

BackgroundIn the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients. ObjectivesTo evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. Patients/MethodsIn this nested case‐control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4‐week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type. ResultsTwenty‐four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01–12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5–16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1–1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5–3.5). ConclusionAdvanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power.

Rivaroxaban vs Dalteparin in Cancer-Associated Thromboembolism: A Randomized Trial

Direct oral anticoagulants (DOACs) are an alternative to low-molecular-weight heparin for treating cancer-associated VTE. Is rivaroxaban as efficient and safe as dalteparin to treat patients with cancer-associated VTE? In a randomized open-label noninferiority trial, patients with active cancer who had proximal DVT, pulmonary embolism (PE), or both were assigned randomly to therapeutic doses of rivaroxaban or dalteparin for 3months. The primary outcome was the cumulative incidence of recurrent VTE, a composite of symptomatic or incidental DVT or PE, and worsening of pulmonary vascular or venous obstruction at 3months. Of 158 randomized patients, 74 and 84 patients were assigned to receive rivaroxaban and dalteparin, respectively. Mean age was 69.4 years, and 115 patients (76.2%) had metastatic disease. The primary outcome occurred in 4 and 6 patients in the rivaroxaban and dalteparin groups, respectively (both the intention-to-treat and per-protocol populations: cumulative incidence, 6.4%vs10.1%; subdistribution hazard ratio [SHR], 0.75; 95%CI, 0.21-2.66). Major bleeding occurred in 1 and 3 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 1.4%vs3.7%; SHR, 0.36; 95%CI, 0.04-3.43). Major or clinically relevant nonmajor bleeding occurred in 9 and 8 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 12.2%vs9.8%; SHR, 1.27; 95%CI, 0.49-3.26). Overall, 19 patients (25.7%) and 20 patients (23.8%) died in the rivaroxaban and dalteparin groups, respectively (hazard ratio, 1.05; 95%CI, 0.56-1.97). In this trial comparing rivaroxaban and dalteparin in the treatment of cancer-associated VTE, the number of patients was insufficient to reach the predefined criteria for noninferiority, but efficacy and safety results were consistent with those previously reported with DOACs. An updated meta-analysis of randomized trials comparing DOACs with low-molecular-weight heparin in patients with cancer-associated VTE is provided. ClinicalTrials.gov; No.: NCT02746185; URL: www. gov.

Effect of low-molecular-weight heparins on anti-Xa peak levels and adverse reactions in Chinese patients with recurrent spontaneous abortion: a single-center, observational study

ObjectiveTo compare three commonly used low-molecular-weight heparins (LWMHs) in the treatment of recurrent spontaneous abortion (RSA) by evaluating the anti-Xa peak levels and adverse reactions.MethodsIn this single-center, observational study, we enrolled 310 patients with RSA in whom anti-Xa levels were measured during pregnancy. Patients were divided into three groups according to the LMWH they used: the nadroparin group, enoxaparin group and dalteparin group. We compared the peak anti-Xa levels and the coagulation status of each group, and analyzed the incidence of adverse reactions, including local allergy, liver and renal dysfunction, and the impact on platelet.ResultsPatients in the enoxaparin group had a higher anti-Xa peak level than those in the nadroparin group (0.80 ± 0.22 IU/ml vs. 0.61 ± 0.24 IU/ml; P < 0.0001), although most patients in the three groups reached the target concentration of anti-Xa. Furthermore, patients in the enoxaparin group had a more stable anti-Xa levels during pregnancy. In addition, patients in the nadroparin group had a higher rate of local allergy than those in the enoxaparin group (60.5% vs. 42.5%; P = 0.004) and those in the dalteparin group (60.5% vs. 33.3%; P = 0.002). Further examination by the type of local allergy indicated a dramatic difference in pruritus and induration between the nadroparin group and the other two groups. No difference was found in the incidence of liver and renal dysfunction and thrombocytopenia.ConclusionCompared with nadroparin and daltepatin, enoxaparin showed a better performance regarding anti-Xa levels and the incidence of adverse reactions in the treatment of RSA.

The Comparison of Novel Oral Anticoagulants with Conventional Anticoagulants in the Treatment of Cancer-Associated Thrombosis: A Systemic Review

Introduction: Venous thromboembolism (VTE) is one of the major causes of mortality among patients with malignancy. It is estimated that around 4-20% of patients with cancer experience venous thrombosis. Typically, low molecular weight heparin (LMWH) is used as an initial agent of choice in VTE except in patients with renal insufficiency who cannot tolerate LMWH and require alternate therapy. Also, despite adequate therapy, VTE recurrence is common among cancer patients. The novel oral anticoagulants (NOACs) have recently been introduced in the treatment of VTE and have shown promising results. We have performed a systemic review of the literature comparing the safety and efficacy profiles of NOACs with LWMH in cancer patients with VTE. Methods: We performed a comprehensive literature search completed on July 7, 2020, on Pubmed, Cochrane library, and ClinicalTrials.gov. We used the MeSH terms: 'venous thrombosis', 'neoplasms', 'rivaroxaban', 'dabigatran', and 'enoxaparin' with associated entry terms. Our search yielded 46 studies. Following PRISMA guidelines and subsequent screening by three reviewers, we shortlisted 5 completed clinical trials (n=2873) and included data from these studies in our systemic review. Results: EINSTEIN-PE investigators (2013, n=223) reported a net clinical benefit (VTE plus major bleeding) in 83 patients (3.4%) vs 96 patients (4%) in the rivaroxaban arm versus control arm (enoxaparin + warfarin/acenocoumarol arm) respectively (HR 0.85 [95% CI 0.63-1.14], p=0.28). Recurrence occurred in 2.1% vs 1.8% (HR 1.12 [95% CI 0.75-1.68] p=0.003). Major bleed events occurred in 1.1% vs 2.2% (HR 0.49 [95% CI 0.31-0.79] p=0.003). Clinically relevant minor bleed events occurred in 9.5% vs 9.8%. Deaths were lower in rivaroxaban arm (20 vs 23). Hokusai-VTE investigators (2013, n=414) reported edoxaban as non-inferior to warfarin when compared the primary efficacy (defined as recurrence of symptomatic VTE) 3.2% vs 3.5% respectively (HR 0.89 [95% CI 0.70 to 1.13] p&amp;lt;0.001). Recurrence occurred in 3.4% vs 3.3% (HR 1.02 [95% CI 0.75-1.38]). Major bleed events occurred in 1.4% vs 1.6% (HR 0.84 [0.59-1.21] P=0.35). Non-major bleed events were significantly lower in edoxaban arm 7.2% vs 8.9% (HR 0.80 [0.68-0.93] p=0.004). 20 participants died in edoxaban arm vs 21 in control. AMPLIFY study (2015, n=169) reported reduced recurrence rate of 3.7% vs 6.4% in apixaban vs conventional therapy (enoxaparin + warfarin) respectively (RR 0.56 [95% CI 0.13-2.37]). Major bleed events weremore common in controls 2.9% vs 5% (RR 0.45 [95% CI 0.08-2.46]). Non major bleed events occurred in 12.6% vs 22.5% (RR 0.57 [95% CI 0.29-1.12]). Three vs five deaths occurred in apixaban arm vs conventional therapy respectively. MAGELLAN study (2013, n=592) reported a better net clinical benefit (defined as primary efficacy outcome up to 10 days or safety outcome up to 35 days) of 9.4% vs 7.8% in rivaroxaban vs enoxaparin respectively. Recurrence was low in rivaroxaban (4.8% vs 6.4%). Major bleed events occurred more commonly in rivaroxaban arm 2.85% vs 0.95% (RR 2.9 [95% CI 1.60-5.15] p&amp;lt;0.001). Non-major bleed events were more frequent with rivaroxaban 1.25% vs 0.72% (RR 2.5 [1.85- 3.25] p&amp;lt;0.001). Deaths occurred in 2.2% vs 2% in intervention vs control. ADAM VTE (2020, n=300) reported recurrence in 0.7% vs 6.3% in apixaban vs dalteparin respectively (HR 0.099 [95% CI 0.013-0.78] p=0.0281). Major bleed events noted in 0 vs 1.4% (p=0.138) and clinically relevant non-major bleed events noted in 6.2% vs 4.2% patients in the apixaban vs control respectively. Deaths were more common in apixaban group 23 (16%) vs dalteparin group 15 (11%). Conclusion: NOACs have comparable efficacy to conventional LMWH based treatment options and are feasible alternate therapy for VTE in patients with cancer. Apixaban so far has demonstrated better efficacy profile among the NOACs. However, the data at present is conflicting regarding safety profile. Large double-blinded randomized clinical trials are required to confirm the safety profile. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Apixaban role in the treatment of venous thromboembolic complications in patients with active cancer

The relationship of venous thromboembolic complications (VTEC) to cancer is well known. Modern recommendations for the treatment of VTEC in patients with cancer suggest treatment with subcutaneous injections of LMWH in the first 6 months. The emergence of evidence of comparable efficacy and safety of four OACs (dabigatran, rivaroxaban, apixaban and edoxaban) with traditional LMWH treatment and further transition to VKA led to their approval for VTEC treatment. But the efficacy and safety of OACs compared to long-term LMWH treatment in VTEC and cancer patients until recently was limited to single randomized studies (Hokusai VTE Cancer and SELECT-D), in which edoxaban and rivaroxaban were compared to dalteparin. The results were close: the recurrence rate of vTEC in oAC groups was lower than in those receiving dalteparin, but the number of bleedings was higher, mainly due to gastrointestinal bleeding. In March 2020, the results of a prospective randomized open Caravaggio study were published to demonstrate that the results of prescription of oral apixaban in order to prevent relapse of vTEC in patients with cancer-associated vTEC will not be worse than those of subcutaneous LMWH injections, and will not cause an increase in major bleedings. the study results showed that relapses of VTEC in the apixaban group were 5.6% and in the dalteparin group 7.9% (RA 0.63; 95% CI [0.371.07]; P < 0.001 for «not worse»; P = 0.09 for «better»). Heavy bleeding was observed in 3.8% of cases in the apixaban group and in 4.0% of patients receiving dalteparin (RA 0.82; 95% CI [0.40-1.69]; P = 0.60). Large gastrointestinal bleedings during treatment were recorded in 11 patients (1,9%) in the apixaban group and in 10 patients (1,7%) receiving dalteparin. oral apixaban proved to be no worse than subcutaneous dalteparin injections in the treatment of VTEC in cancer patients. Unlike studies with rivaroxaban and edoxaban, there was no increase in risk of large bleeding, including from the gastrointestinal tract, in patients receiving apixaban.

Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer

BackgroundRecent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use.MethodsThis was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding.ResultsRecurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P=0.60).ConclusionsOral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb–Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.)

Dalteparin as a Novel Therapeutic Agent to Prevent Diabetic Encephalopathy by Targeting Oxidative Stress and Inflammation.

Introduction:Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models.Methods:Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200–250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6.Results:The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline.Conclusion:Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes.

Direct Oral Factor Xa Inhibitors for the Treatment of Acute Cancer-Associated Venous Thromboembolism: A Systematic Review and Network Meta-analysis

ObjectiveTo explore the efficacy and safety of direct oral factor Xa inhibitors in the treatment of cancer-associated acute venous thromboembolism (VTE). Patients and MethodsMEDLINE, CENTRAL (Cochrane Central Register of Controlled Trials), and Embase databases were searched for trials comparing direct oral anticoagulants (DOACs) to dalteparin for the management of cancer-associated acute VTE. Databases were searched from inception to September 19, 2018. A network meta-analysis using both frequentist and Bayesian methods was performed to analyze VTE recurrence and major and clinically relevant nonmajor bleeding. ResultsWe identified 3 randomized controlled trials, at low risk of bias, that enrolled 1739 patients with cancer-associated VTE. Direct comparison revealed a lower rate of VTE recurrence in DOAC compared with dalteparin groups (odds ratio [OR], 0.48; 95% CI, 0.24-0.96; I2=46%). Indirect comparison suggested that apixaban had greater reduction in VTE recurrence compared with dalteparin (OR, 0.10; 95% CI, 0.01-0.82) but not rivaroxaban or edoxaban. Apixaban also had the highest probability of being ranked most effective. By direct comparisons, there was an increased likelihood of major bleeding in the DOAC group compared with dalteparin (OR, 1.70; 95% CI, 1.04-2.78). Clinically relevant nonmajor bleeding did not differ. Indirect estimates were imprecise. Subgroup analyses in gastrointestinal cancers suggested that dalteparin may have the lowest risk of bleeding, whereas estimates in urothelial cancer were imprecise. ConclusionDirect oral anticoagulants appear to lower the risk of VTE recurrence compared with dalteparin while increasing major bleeding. Apixaban may be associated with the lowest risk of VTE recurrence compared with the other DOACs.

Extended treatment with edoxaban in cancer patients with venous thromboembolism: A post‐hoc analysis of the Hokusai‐VTE Cancer study

BackgroundPatients with active cancer and venous thromboembolism (VTE) are at high risk of recurrence. Therefore, continued anticoagulant therapy beyond the initial 6 months is suggested in this patient population, but evidence supporting this approach is limited. MethodsThe Hokusai VTE Cancer trial compared edoxaban with dalteparin for VTE treatment in patients with active cancer. This post hoc analysis focused on the follow‐up period from 6 to 12 months. The primary outcome was the composite of adjudicated first recurrent VTE or major bleeding. Secondary outcomes included recurrent VTE, major bleeding, and clinically relevant bleeding. ResultsOf the 522 and 524 patients randomized to edoxaban or dalteparin, 294 (56%) received edoxaban and 273 (52%) received dalteparin for more than 6 months (median duration of 318 and 211 days, respectively). Between 6 and 12 months, the primary outcome during study treatment occurred in seven patients (2.4%) in the edoxaban group and six patients (2.2%) in the dalteparin group (unadjusted hazard ratio 1.05; 95% confidence interval, 0.36‐3.05). Recurrent VTE occurred in two patients (0.7%) in the edoxaban group and in three patients (1.1%) in the dalteparin group, whereas major bleeding occurred in 5 (1.7%) and three patients (1.1%), respectively. ConclusionsThe rates of recurrent VTE or major bleeding are relatively low among patients with active cancer receiving extended anticoagulant therapy beyond 6 months. Extended treatment with oral edoxaban appears as effective and safe as subcutaneous dalteparin.

Direct oral factor Xa inhibitors for the treatment of acute cancer-associated venous thromboembolism: A systematic review and network meta-analysis.

e23156 Background: A direct meta-analysis was performed to explore the efficacy and safety of direct oral factor Xa inhibitors with dalteparin in patients with cancer associated acute venous thromboembolism (VTE). Also, the comparative efficacy and safety of apixaban, rivaroxaban, and edoxaban was assessed with a network meta-analysis. Methods: MEDLINE, CENTRAL, and EMBASE were searched for trials comparing direct oral anticoagulants (DOACs) to dalteparin for the management of cancer associated acute VTE. A network meta-analysis using both frequentist and Bayesian methods was performed to analyze VTE recurrence, major and clinically relevant non-major bleeding (CRNMB). Results: Three randomized control trials, at low risk of bias, enrolled 1,739 patients with cancer associated VTE. Direct comparison showed a lower rate of VTE recurrence in DOAC compared to dalteparin groups (odds Ratio [OR]:0.48, 95% Confidence interval [CI]:0.24-0.96; I2:46%). Indirect comparison suggested that apixaban had greater reduction in VTE recurrence compared to dalteparin (OR: 0.10; 95% CI: 0.01–0.82), but not rivaroxaban or edoxaban. Apixaban also had the highest probability of being ranked most effective. By direct comparisons, there was an increased likelihood of major bleeding in the DOAC group compared to dalteparin (OR: 1.70; 95% CI: 1.04–2.78). CRNMB did not differ. Indirect estimates were imprecise. Subgroup analyses in gastrointestinal cancers suggested that dalteparin may have the lowest risk of bleeding whereas estimates in urothelial cancer were imprecise. Conclusions: DOACs appear to lower the risk of VTE recurrence compared to daltaparin while increasing major bleeding. Apixaban may be associated with the lowest risk of VTE recurrence compared to the other DOACs.

A Retrospective Study on Efficacy and Safety of Rivaroxaban and Dalteparin for Long-Term Treatment of Venous Thromboembolism in Patients with Lung Cancer

Background: Standard therapy for cancer-associated venous thromboembolism (VTE) is low-molecular-weight heparin. The use of direct oral anticoagulants for cancer-associated VTE has increased; however, their efficacy and safety in lung cancer patients remain unclear. Objectives: We examined the efficacy and safety of rivaroxaban compared with dalteparin for cancer-associated VTE in patients with primary lung cancer. Methods: A single-center retrospective study of 204 patients with primary lung cancer who were prescribed rivaroxaban (n = 131) or dalteparin (n = 73) for VTE was performed. The primary endpoint was a composite event including recurrence and major or clinically relevant nonmajor bleeding. Secondary endpoints included the incidence of recurrence, major and clinically relevant nonmajor bleeding, all-cause mortality, and bleeding or pulmonary embolism-related mortality. Results: The composite event occurred in 38 (29.0) and 12 (16.4%) patients in the rivaroxaban and dalteparin (p = 0.045) groups, respectively. The multivariate Cox proportional hazards model for age, Eastern Cooperative Oncology Group performance score, and bleeding risk factors revealed the rivaroxaban group showed a 1.176-fold composite event risk without statistical significance (0.595–2.324, p = 0.641). There was no statistically significant intergroup difference for the incidence of VTE recurrence (5.3% in the rivaroxaban group versus 2.7% in the dalteparin group, p = 0.495) and major or clinically relevant nonmajor bleeding (23.7% in the rivaroxaban group versus 13.7% in the dalteparin group, p = 0.089). There was no significant difference in the all-cause mortality rate (hazard ratio 0.864, 95% CI 0.624–1.196, p = 0.337). Conclusions: There was no difference in the safety and efficacy profile of rivaroxaban compared with dalteparin. Therefore, rivaroxaban may be a valuable treatment option for lung cancer-associated VTE.

Apixaban, Dalteparin, in Active Cancer Associated Venous Thromboembolism, the ADAM VTE Trial

▪Background: Currently, low molecular weight heparin is the guideline endorsed treatment of patients with cancer associated venous thromboembolism (VTE). While apixaban is approved for the treatment of acute VTE, there are limited data supporting its use in cancer patients.Methods: Patients with cancer associated acute VTE were randomly assigned to receive either apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily or subcutaneous dalteparin (200 IU/kg for 1 month followed by 150 IU/kg once daily) for 6 months. The primary outcome was major bleeding. Secondary outcomes included VTE recurrence and a composite of major plus clinically relevant non-major bleeding.Results: Of the 300 patients who underwent randomization, 287 were included in the primary analysis. Of these, metastatic disease was present in 65.5% of subjects and 74% were receiving concurrent systemic cancer therapy. Colorectal, lung, pancreas, and breast cancers were the four most prevalent cancer types. Major bleeding occurred in 0 of the 142 patients (0%) in the apixaban group as compared with 3 of the 145 patients (2.1%) in the dalteparin group (p=0.9956). Recurrent VTE occurred in 5 patients (3.4%) in the apixaban group and 20 patients (14.1%) in the dalteparin group (difference in risk -10.7 percentage points) with a Hazard Ratio (HR) 0.26, (95% CI, 0.09 - 0.80, p = 0.0182). Major plus clinically relevant non-major bleeding were similar at 9% for both groups. There were no mortality differences comparing apixaban (15.9%) and dalteparin (10.6%) groups at 6 months (HR 1.36, 95% CI 0.79 - 2.35). Monthly quality of life surveys favored apixaban therapy for many measures including: concern for excess bruising, stress, irritation, burden of delivery, and overall satisfaction with anticoagulant therapy (p<0.05). Monthly bruising questionnaire favored apixaban at each interval (p<0.002).Conclusions: Oral apixaban therapy was associated with very low rates of bleeding and significantly lower VTE recurrence with superior quality of life outcome measures compared to parenteral dalteparin in the treatment of cancer associated VTE. These data support the clinical utility of apixaban for the acute treatment of VTE in this patient population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.