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TH Open : Companion Journal To... Jul 2019Direct oral anticoagulants (DOACs) represent an attractive alternative to low-molecular-weight heparins (LMWHs) for the long-term treatment of cancer-associated... (Review)
Review
Direct oral anticoagulants (DOACs) represent an attractive alternative to low-molecular-weight heparins (LMWHs) for the long-term treatment of cancer-associated thrombosis (CT) since they avoid the burden of daily injections. Analyses in subgroups of cancer patients from large randomized trials suggested that DOACs were at least as effective as vitamin K antagonists, while indirect comparisons suggested that DOACs' efficacy and safety profile were comparable to those of LMWHs. In the randomized controlled HOKUSAI-VTE Cancer study, currently the only completed phase III trial on DOACs in CT patients, edoxaban was shown noninferior to dalteparin on the composite primary endpoint of time to first recurrent venous thromboembolism or major bleeding during the 12 months after randomization. Study results suggest that both agents had comparable benefit/risk ratio in patients with CT. Even though this conclusion was valid from a strict statistical viewpoint, it was potentially misleading when interpreting benefit/risk ratios. Besides the obvious heterogeneity of the study population (e.g., 23% of patients no longer had cancer) and significantly different treatment durations between arms, secondary outcomes for efficacy were in favor of edoxaban for recurrent deep-vein thrombosis but not for recurrent pulmonary embolism, and major bleeding episodes were significantly more frequent in the edoxaban group, with an excess of gastrointestinal (GI) bleeding episodes observed mainly but not only in patients with GI cancers. More research is needed regarding specific patients' profiles, cancer types, and treatment period to better clarify the respective roles of DOACs and LMWHs in CT patients.
PubMed: 31535076
DOI: 10.1055/s-0039-1696659 -
Proceedings of the National Academy of... Oct 2022The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell...
The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell motility. This mechanical work is driven by the ATPase activity at the catalytic site in the F-form. For deeper understanding of the actin cellular functions, the reaction mechanism must be elucidated. Here, we show that a single actin molecule is trapped in the F-form by fragmin domain-1 binding and present their crystal structures in the ATP analog-, ADP-Pi-, and ADP-bound forms, at 1.15-Å resolutions. The G-to-F conformational transition shifts the side chains of Gln137 and His161, which relocate four water molecules including W1 (attacking water) and W2 (helping water) to facilitate the hydrolysis. By applying quantum mechanics/molecular mechanics calculations to the structures, we have revealed a consistent and comprehensive reaction path of ATP hydrolysis by the F-form actin. The reaction path consists of four steps: 1) W1 and W2 rotations; 2) P-O bond cleavage; 3) four concomitant events: W1-PO formation, OH and proton cleavage, nucleophilic attack by the OH against P, and the abstracted proton transfer; and 4) proton relocation that stabilizes the ADP-Pi-bound F-form actin. The mechanism explains the slow rate of ATP hydrolysis by actin and the irreversibility of the hydrolysis reaction. While the catalytic strategy of actin ATP hydrolysis is essentially the same as those of motor proteins like myosin, the process after the hydrolysis is distinct and discussed in terms of Pi release, F-form destabilization, and global conformational changes.
Topics: Actins; Adenosine Diphosphate; Adenosine Triphosphate; Dalteparin; Hydrolysis; Myosins; Protons; Water
PubMed: 36252034
DOI: 10.1073/pnas.2122641119 -
Research and Practice in Thrombosis and... May 2022Venous thromboembolism (VTE) is a frequent complication in patients with cancer and a leading cause of morbidity and death.
BACKGROUND
Venous thromboembolism (VTE) is a frequent complication in patients with cancer and a leading cause of morbidity and death.
OBJECTIVES
The objective of the RIETECAT study was to compare the long-term effectiveness and safety of enoxaparin versus dalteparin or tinzaparin for the secondary prevention of VTE in adults with active cancer.
METHODS
We used the data from the multicenter, multinational RIETE registry to compare the rates of VTE recurrences, major bleeding, or death over 6 months in patients with active cancer and acute VTE using full doses of enoxaparin versus dalteparin or tinzaparin, and a multivariable Cox proportional hazard model was used to analyze the primary end point.
RESULTS
From January 2009 to June 2018, 4451 patients with active cancer received full doses of the study drugs: enoxaparin, 3526 patients; and dalteparin or tinzaparin, 925 (754 + 171) patients. There was limited difference in VTE recurrences (2.0% vs 2.5%) and mortality rate (19% vs 17%) between the enoxaparin and dalteparin or tinzaparin subgroups. However, there was a slight numerical increase in major bleeding (3.1% vs 1.9%). Propensity score matching confirmed that there were no differences in the risk for VTE recurrences (adjusted hazard ratio [aHR], 0.81; 95% confidence interval [CI], 0.48-1.38), major bleeding (aHR, 1.40; 95% CI, 0.80-2.46), or death (aHR, 1.07; 95% CI, 0.88-1.30) between subgroups.
CONCLUSIONS
In RIETECAT, in patients with cancer and VTE receiving full-dose enoxaparin or dalteparin or tinzaparin, no statistically significant differences were observed regarding effectiveness and safety outcomes over a 6-month period.
PubMed: 35664535
DOI: 10.1002/rth2.12736 -
Clinical and Applied... 2022Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. On the basis of results from randomized controlled trials, direct... (Review)
Review
Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. On the basis of results from randomized controlled trials, direct oral anticoagulants (DOACs) are now recommended for the treatment of cancer-associated VTE. The decision to use a DOAC requires consideration of bleeding risk, particularly in patients with gastrointestinal (GI) malignancies, the cost-benefit and convenience of oral therapy, and patient preference. While efficacy with apixaban, edoxaban, and rivaroxaban versus dalteparin has been consistent in the treatment of cancer-associated VTE, heterogeneity is evident with respect to major GI bleeding, with an increased risk with edoxaban and rivaroxaban but not apixaban. Although cost and accessibility vary in different countries of Latin America, DOACs should be considered for the long-term treatment of cancer-associated VTE in all patients who are likely to benefit. Apixaban may be the preferred DOAC in patients with GI malignancies and LMWH may be preferred for patients with upper or unresected lower GI tumors. Vitamin K antagonists should only be used for anticoagulation when DOACs and low molecular weight heparin are inaccessible or unsuitable.
Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Humans; Incidence; Latin America; Neoplasms; Venous Thromboembolism
PubMed: 35261295
DOI: 10.1177/10760296221082988 -
Annals of Oncology : Official Journal... Jun 2019Anticoagulation for cancer-associated venous thromboembolism (VTE) can be challenging due to complications-including bleeding and potential drug-drug interactions with... (Review)
Review
Anticoagulation for cancer-associated venous thromboembolism (VTE) can be challenging due to complications-including bleeding and potential drug-drug interactions with chemotherapy-associated with vitamin K antagonists and inconvenience of low-molecular-weight heparin (LMWH). Direct oral anticoagulants (DOACs) could partially overcome these issues, but until recently there were no large clinical trials assessing their efficacy and safety in cancer patients. This review summarizes clinical treatment guidelines, prior clinical and real-world evidence for anticoagulant choice, recent clinical trials assessing DOACs for cancer-associated VTE (i.e. Hokusai-VTE Cancer, SELECT-D, CARAVAGGIO, and ADAM VTE), and special considerations for DOAC use. Based on established data, clinical guidelines recommend patients with cancer-associated VTE receive LMWH treatment of at least 3-6 months. Nevertheless, LMWH is underused and associated with poor compliance and persistence in these patients relative to oral anticoagulants. Clinical data supporting DOAC use in cancer patients are becoming available. In Hokusai-VTE Cancer, edoxaban was noninferior to dalteparin for the composite of recurrent VTE and major bleeding (12.8% versus 13.5%), with numerically lower recurrent VTE (7.9% versus 11.3%) and significantly higher major bleeding (6.9% versus 4.0%); only patients with gastrointestinal cancer had significantly higher risk of bleeding with edoxaban. In SELECT-D, rivaroxaban had numerically lower VTE recurrence (4% versus 11%), comparable major bleeding (6% versus 4%), and numerically higher clinically relevant nonmajor bleeding (13% versus 4%) versus dalteparin. Most bleeding events were gastrointestinal or urologic; patients with esophageal/gastroesophageal cancer had higher rates of major bleeding with rivaroxaban (36% versus 11%). For comparison of apixaban versus dalteparin, CARAVAGGIO is ongoing, and preliminary results from ADAM VTE are favorable. This review concludes that DOACs appear to be reasonable alternatives to LMWH for treatment of cancer-associated VTE. In patients with gastrointestinal cancer, DOAC use should be considered on a case-by-case basis with consideration of the relative risks and benefits.
Topics: Administration, Oral; Anticoagulants; Clinical Trials as Topic; Humans; Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Venous Thromboembolism
PubMed: 30918939
DOI: 10.1093/annonc/mdz111 -
Haematologica Jun 2024Thrombocytopenia occurs frequently in patients with cancer-associated thrombosis (CAT), however prospective evaluation of clinical outcomes following randomization to... (Randomized Controlled Trial)
Randomized Controlled Trial
Thrombocytopenia occurs frequently in patients with cancer-associated thrombosis (CAT), however prospective evaluation of clinical outcomes following randomization to anticoagulants is limited. The HOKUSAI VTE Cancer study was a randomized, open-label, non-inferiority, phase III trial comparing dalteparin with edoxaban in CAT patients. This post hoc analysis of Hokusai VTE Cancer Study was performed to compare outcomes in patients with platelet count ≤100x109/L at one or more specified time points (baseline, 1-month, or 3-month) versus those without thrombocytopenia. Cumulative incidences at 180 days were calculated with death as a competing risk. The primary outcome was major bleeding; secondary outcomes were clinically relevant non-major bleeding (CRNMB), recurrent thrombosis, and survival. The analysis included 1,045 patients with primarily solid tumor malignancies (89%), median age 65 years, and 52% male. The thrombocytopenia group comprised 9.6% (N=101) of the cohort and relative to the non-thrombocytopenia cohort (N=944), experienced significantly higher major bleeding (9.0% vs. 4.0%, sub-distribution hazard ratio [SHR] =2.4; P=0.02) and CRNMB (17.9% vs. 9.6%, SHR=2.0; P=0.01). Thrombocytopenia did not impact recurrent venous thromboembolic event (VTE) (9.8% vs. 7.4%, SHR=1.3; P=0.37) nor overall mortality (21.8% vs. 26.0%, HR=0.9; P=0.48). Major bleeding was higher in patients with thrombocytopenia and gastrointestinal malignancies receiving edoxaban versus dalteparin (16.8% vs. 0; P<0.01) but similar for patients with other malignancies (P=0.30). In patients with hematologic malignances and thrombocytopenia major bleeding was higher for patients receiving dalteparin compared to edoxaban (19.0% vs. 0; P<0.01). Mild thrombocytopenia was associated with a doubling in risk of major hemorrhage in patients receiving anticoagulation for CAT. Bleeding risk for edoxaban and dalteparin varied in gastrointestinal and hematologic malignances in patients with thrombocytopenia (clinicaltrails gov. Identifier: NCT02073682).
Topics: Humans; Male; Female; Thrombocytopenia; Aged; Neoplasms; Hemorrhage; Middle Aged; Thrombosis; Recurrence; Pyridines; Thiazoles; Anticoagulants; Dalteparin
PubMed: 37855029
DOI: 10.3324/haematol.2023.284192 -
The Journal of Pharmacy Technology :... Apr 2016To evaluate the pharmacokinetic, safety, and effectiveness data of dosing low-molecular-weight heparins (LMWHs) for prophylaxis of venous thromboembolic events (VTEs)... (Review)
Review
To evaluate the pharmacokinetic, safety, and effectiveness data of dosing low-molecular-weight heparins (LMWHs) for prophylaxis of venous thromboembolic events (VTEs) in obese people. A PubMed search (1966 to September 2015) was performed of published English articles using the following keywords: low-molecular-weight heparin, prophylaxis, and obesity. In all, a total of 11 articles were included in this review. The search was conducted to identify pharmacokinetic studies, clinical trials (phases I-IV), or retrospective evaluations of the impact of weight and/or obesity on anti-Xa levels as well as the safety and effectiveness of LMWHs used for VTE prophylaxis. The vast majority of the available data focus on enoxaparin. Pharmacokinetic, effectiveness, and safety data all support increased enoxaparin dosing in obese patients. However, the optimal adjustment remains uncertain. For now, we recommend using 40 mg twice daily as the data for effectiveness use this regimen. Dalteparin dosing should not be adjusted in class I-II obese (body mass index 30.0-39.9 kg/m) patients. Data regarding the impact of class III obesity (body mass index ≥40 kg/m) on dalteparin effectiveness is needed. Total body weight dosing of tinzaparin can be used to optimize anti-Xa levels, but safety and effectiveness data are needed before weight-based tinzaparin dosing is routine medical practice for obese patients. The data regarding dosing of LMWHs for VTE prophylaxis are quite limited. High-quality studies are needed to help optimize dosing for obese adults requiring LMWH prophylaxis.
PubMed: 34860988
DOI: 10.1177/8755122515617200 -
Indian Journal of Hematology & Blood... Jul 2018Venous thromboembolism (VTE) is a complication of malignancy that is associated with significant mortality. The CLOT trial showed superiority of dalteparin in comparison...
Venous thromboembolism (VTE) is a complication of malignancy that is associated with significant mortality. The CLOT trial showed superiority of dalteparin in comparison to warfarin in preventing VTE recurrence. Rivaroxaban has been approved for treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). In the absence of large randomized trials in the oncology population, the efficacy and safety of rivaroxaban for the treatment of VTE in cancer patients needs to be assessed. A single-center retrospective chart review was conducted to assess the efficacy and safety of rivaroxaban compared with dalteparin in cancer-associated thrombosis. Out of 671 patients identified, 286 patients (107 in the rivaroxaban group and 179 in the dalteparin group) were eligible for analysis. The rivaroxaban group had a rate of VTE recurrence at 6 months of 4.9 versus 11.1% with dalteparin ( = 0.252). The incidence of recurrent DVT at 6 months was lower in patients treated with rivaroxaban (0%) compared with dalteparin (8.2%) at 6 months ( = 0.025). Incidence of recurrent PE in the rivaroxaban group (5%) versus dalteparin group (3.1%) at 6 months was not statistically significant ( = 0.675). No significant difference was identified between the rivaroxaban group and dalteparin group in the rate of major bleeding (2.8 vs. 1.1%, respectively). Rivaroxaban was comparable to dalteparin in prevention of VTE recurrence while having no significant differences with major or minor bleeding.
PubMed: 30127566
DOI: 10.1007/s12288-017-0895-8 -
Cancers Jan 2022We evaluated the safety and efficacy of direct oral anticoagulants (DOACs) versus subcutaneous dalteparin for cancer-associated venous thromboembolism (CA-VTE) in...
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.
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 ( = 44) and dalteparin groups ( = 46) in FAS. CRB and major bleeding (MB) rates were 34.1% and 13.0% ( = 0.018) and 18.2% and 4.3% ( = 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; = 0.031 and HR 4.32; = 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 ( = 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.
PubMed: 35158827
DOI: 10.3390/cancers14030559 -
Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism.Journal of Clinical Pharmacology Feb 2021This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label...
This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label study was conducted in children who required anticoagulation for the treatment of VTE. The study population included children with and without cancer. The goal was to describe the pharmacokinetics of dalteparin using anti-Xa as a surrogate marker and to determine the dose required to achieve therapeutic anti-Xa levels (0.5-1.0 IU/mL). The anti-Xa data were supplemented with 2 published studies and analyzed using population pharmacokinetic approaches. The pharmacokinetics of dalteparin following subcutaneous injection in pediatric patients was described by a 1-compartment model with linear absorption and elimination. Body weight was added as a covariate on both CL/F and Vd/F as a power function with fixed exponents of 0.75 and 1.0, respectively. The estimates of CL/F and Vd/F in the full model were 929 mL/h and 7180 mL, respectively, for a reference female patient aged 12 years with body weight of 43 kg. Body weight-normalized CL/F decreased with age. Cancer status and sex did not have significant effects on CL/F and Vd/F. Simulations were conducted to select starting doses of dalteparin that would rapidly achieve therapeutic anti-Xa levels. These simulations suggested that the recommended starting doses of dalteparin administered subcutaneously in pediatric patients of different age cohort groups for treatment of VTE were 150 IU/kg every 12 hours (1 month to <2 years), 125 IU/kg every 12 hours (≥2 to <8 years), and 100 IU/kg every 12 hours (≥8 to <19 years).
Topics: Adolescent; Age Factors; Anticoagulants; Biomarkers; Body Weight; Child; Child, Preschool; Dalteparin; Factor Xa Inhibitors; Female; Humans; Infant; Infant, Newborn; Injections, Subcutaneous; Male; Metabolic Clearance Rate; Prospective Studies; Sex Factors; Venous Thromboembolism
PubMed: 32827160
DOI: 10.1002/jcph.1716