Low Molecular Weight Heparin Dalteparin Research Articles

Structured benefit-risk assessment for enoxaparin, in the context of its label extension, for the extended treatment of deep vein thrombosis and pulmonary embolism, and prevention of its recurrence in patients with active cancer.

Guidelines recommend low-molecular-weight heparins (LMWHs) for patients with cancer-associated thrombosis. However, until recently, only dalteparin and tinzaparin were approved in the European Economic Area (EEA) for these patients. This study compares the benefit-risk profile of enoxaparin with dalteparin and tinzaparin for the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrence in adult patients with active cancer. A semi-quantitative structured benefit-risk assessment was conducted for the label-extension application of enoxaparin based on the benefit-risk action team descriptive framework: define decision context; determine key benefit and risk outcomes; identify data sources; extract data; interpret results. The key benefits were defined as reduced all-cause mortality and venous thromboembolism (VTE) recurrence (including symptomatic DVT, fatal PE or non-fatal PE); the key risks were major and non-major bleeding of clinical significance, and heparin-induced thrombocytopenia (HIT). Enoxaparin demonstrated comparable effects for the reduction of VTE recurrence and all-cause mortality versus other EEA-approved LMWHs (dalteparin, tinzaparin). There was no evidence of a significant difference between enoxaparin and the comparator groups with regard to incidence of major and non-major bleeding. The data on HIT were too limited to assess the difference between the two groups. The assessment demonstrated a favourable benefit-risk profile for enoxaparin similar to that of other EEA-approved LMWHs for the treatment of DVT and PE and the prevention of recurrence in patients with active cancer and thus supported the label-extension approval.

The Role of Direct Oral Anticoagulants in the Treatment of Cancer-Associated Venous Thromboembolism: Review by Middle East and North African Experts.

Venous thromboembolism is a leading cause of morbidity and mortality in patients with active cancer who require anticoagulation treatment. Choice of anticoagulant is based on careful balancing of the risks and benefits of available classes of treatment: vitamin K antagonists, low-molecular-weight heparin (LMWH), and direct oral anticoagulants (DOACs). Results from randomized controlled trials have shown the consistent efficacy of DOACs versus LMWH in the treatment of cancer-associated venous thromboembolism (VTE). However, increased major gastrointestinal bleeding was observed for edoxaban and rivaroxaban, but not apixaban, compared with LMWH dalteparin. Most guidelines recommend DOACs for the treatment of cancer-associated VTE in patients without gastrointestinal or genitourinary cancer, and with considerations for renal impairment and drug-drug interactions. These updates represent a major paradigm shift for clinicians in the Middle East and North Africa. The decision to prescribe a DOAC for a patient with cancer is not always straightforward, particularly in challenging subgroups of patients with an increased risk of bleeding. In patients with gastrointestinal malignancies who are at high risk of major gastrointestinal bleeds, apixaban may be the preferred DOAC; however, caution should be exercised if patients have upper or unresected lower gastrointestinal tumors. In patients with gastrointestinal malignancies and upper or unresected lower gastrointestinal tumors, LMWH may be preferred. Vitamin K antagonists should be used only when DOACs and LMWH are unavailable or unsuitable. In this review, we discuss the overall evidence for DOACs in the treatment of cancer-associated VTE and provide treatment suggestions for challenging subgroups of patients with cancer associated VTE.

Abstract 12787: Efficacy and Safety of Apixaban versus Low Molecular Weight Heparin for the Treatment of Venous Thromboembolism in Cancer Patients: A Systematic Review and Meta-Analysis

Introduction: Current guidelines recommend the use of low molecular weight heparin (LMWH) for the management of venous thromboembolism (VTE) in cancer patients. However, direct oral anticoagulants (DOACs) have emerged as promising alternative for reducing VTE events. Moreover, apixaban shows a higher safety profile among DOACs. Hypothesis: This study aims to compare the efficacy and safety of apixaban versus LMWH (Enoxaparin or Dalteparin) in the treatment of venous thromboembolism in cancer patients. Methods: A systematic search was conducted in electronic databases (Pubmed, Embase, Scopus, and Cochrane libraries) from inception until June 2023, using appropriate Mesh terms for ‘apixaban’, ‘LMWH’, and ‘VTE’. Pooled risk ratios (RR) with their corresponding 95% confidence intervals (CI) were calculated using random effects models. A p-value of <0.005 was considered statistically significant. Results: Five randomized trials involving 2311 patients (apixaban: 1088 and LMWH: 1223) with mean ages of 64.5±11.45 and 64.2±10.8, respectively, were included in the analysis. At a median follow-up of six months, the occurrence of clinically relevant non-major bleeding (CRNMB) (OR, 1.04, 95% CI: 0.66 - 1.64, I2=37.72%, p=0.87), composite of major and CRNMB (OR, 1.11, 95% CI: 0.84 - 1.46, I2=0.00%, p=0.47), were higher with apixaban treatment. However, the rates of recurrent VTE (OR, 0.72, 95% CI: 0.50 - 1.04, I2=3.91%, p=0.08), major bleeding (OR, 0.83, 95% CI: 0.55 - 1.25, I2=0.00%, p=0.38), and mortality (OR, 0.91, 95% CI: 0.79 - 1.05, I2=0.00%, p=0.19) were lower with apixaban compared to LMWH treatment. However, none of the observed differences reached statistical significance. Conclusions: In cancer patients with VTE, apixaban demonstrates non-inferior efficacy and a comparable safety profile to LMWH. Further randomized trials are warranted to confirm these findings.

Venous Thromboembolism Prophylaxis in Major Orthopedic Surgeries and Factor XIa Inhibitors.

Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep vein thrombosis (DVT), poses a significant risk during and after hospitalization, particularly for surgical patients. Among various patient groups, those undergoing major orthopedic surgeries are considered to have a higher susceptibility to PE and DVT. Major lower-extremity orthopedic procedures carry a higher risk of symptomatic VTE compared to most other surgeries, with an estimated incidence of ~4%. The greatest risk period occurs within the first 7-14 days following surgery. Major bleeding is also more prevalent in these surgeries compared to others, with rates estimated between 2% and 4%. For patients undergoing major lower-extremity orthopedic surgery who have a low bleeding risk, it is recommended to use pharmacological thromboprophylaxis with or without mechanical devices. The choice of the initial agent depends on the specific surgery and patient comorbidities. First-line options include low-molecular-weight heparins (LMWHs), direct oral anticoagulants, and aspirin. Second-line options consist of unfractionated heparin (UFH), fondaparinux, and warfarin. For most patients undergoing knee or hip arthroplasty, the initial agents recommended for the early perioperative period are LMWHs (enoxaparin or dalteparin) or direct oral anticoagulants (rivaroxaban or apixaban). In the case of hip fracture surgery, LMWH is recommended as the preferred agent for the entire duration of prophylaxis. However, emerging factor XI(a) inhibitors, as revealed by a recent meta-analysis, have shown a substantial decrease in the occurrence of VTE and bleeding events among patients undergoing major orthopedic surgery. This discovery poses a challenge to the existing paradigm of anticoagulant therapy in this specific patient population and indicates that factor XI(a) inhibitors hold great promise as a potential strategy to be taken into serious consideration.

Bleeding risk with concomitant administration of VEGF-TKIs and anticoagulant agents

Anti-cancer treatment is considered an independent risk factor for emergent bleeding during anticoagulant treatment in patients with cancer-associated thrombosis. This increased bleeding risk is perceived as major concern particularly when tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial derived growth factor receptor (VEGFR-TKIs) are co-administered with anticoagulants. We evaluated the effects of the combined administration of a VEGF-TKI and the oral direct anticoagulant (apixaban) or the low-molecular weight-heparin dalteparin in a sub-analysis of the Caravaggio study in patients with a diagnosis of cancer patients with venous thromboembolism. The rate of major bleeding was 4.2% in the 668 patients who received any type of anti-cancer treatment and 3.5% in the 487 patients who did not receive any anti-cancer treatment. The relative risk for patients treated with a VEGF-TKI was 1.58 (95% CI: 0.69-3.68), compared to patients treated with anticancer agents other than a VEGF-TKI and 1.73 (95% CI: 0.73-4.07) compared to patients who did not receive any anticancer treatment. The administration of a VGEF-TKI did not have any impact on the recurrence rate of venous thromboembolism. We observed a numerically not statistically significant increase in major bleeding events in patients on concurrent VEGF-TKI and therapeutic anticoagulation with no excess in those who received apixaban. Further prospective well-designed studies are needed to evaluate whether the concomitant administration of VGEF-TKI and anticoagulant agents may result in an increase of bleeding in patients with a diagnosis of cancer treated for venous thromboembolism.

THE EFFECTS OF DNASE I AND LOW-MOLECULAR-WEIGHT HEPARIN IN A MURINE MODEL OF POLYMICROBIAL ABDOMINAL SEPSIS.

Introduction: Cell-free DNA (CFDNA) has emerged as a prognostic biomarker in patients with sepsis. Circulating CFDNA is hypothesized to be associated with histones in the form of nucleosomes. In vitro, DNA activates coagulation and inhibits fibrinolysis, whereas histones activate platelets and are cytotoxic to endothelial cells. Previous studies have targeted CFDNA or histones in animal models of sepsis using DNase I or heparins, respectively, which has reduced inflammatory and thrombosis markers, thereby improving survival. In this study, we explored the possibility that the combination of DNase I and a low-molecular weight heparin (LMWH) may be a better therapeutic approach than monotherapy in a murine model of abdominal sepsis. Methods: C57Bl/6 mice (8-12 weeks old, both sexes) were subjected to either cecal ligation and puncture or sham surgery. Mice were given antibiotics, fluids, and either saline, DNase I (intraperitoneally, 20 mg/kg/8 h), LMWH (dalteparin, subcutaneously 500 IU/kg/12 h), or a combination of both (n = 12-31). Mice were monitored over 72 h for survival. Organs and blood were harvested for analysis. Levels of LMWH, CFDNA, IL-6, citrullinated histone-H3, thrombin-antithrombin complexes, and protein C were measured in plasma. Results: Administration of either DNase I (81.8%) or LMWH (83.3%, prophylactic range of 0.12 ± 0.07 IU/mL achieved) improved the survival of septic mice compared with saline- (38.7%) and combination-treated mice (48.8%, P < 0.05). Combination-treated mice also showed a small but insignificant improvement in survival compared with saline-treated cecal ligation and puncture mice. Monotherapies may be improving survival by reducing blood bacterial loads, citrullinated histone-H3, and thrombin-antithrombin complexes, and improving protein C levels. Conclusions: Compared with saline- and combination-treated mice, administration of monotherapies to septic mice improved survival. These findings suggest that there may be a negative drug-drug interaction between DNase I and LMWH when DNase I is administered intraperitoneally in a murine model of polymicrobial abdominal sepsis.

Quality control and product differentiation of LMWHs marketed in China using 1H NMR spectroscopy and chemometric tools

Low molecular weight heparins (LMWHs) are heterogeneous mixtures of glycosaminoglycan chains composed of mixture of different lengths and substitution patterns. Structural characterization and quality control of LMWHs have always been challenging. The Chinese drug regulatory authorities have been committed to improve the supervision standards of LMWHs to better regulate the quality and safety of LMWHs in current Chinese market. In the present paper, 80 batches of three types LMWHs (dalteparin, enoxaparin and naldroparin) marketed in China from different manufacturers were studied by 1H NMR experiments and chemometric analysis. The method can be used not only to monitor impurities and contaminants, but also to check the batch-to-batch consistency of each manufacture. Moreover, for the biosimilar LMWHs from different manufactures, they can be differentiated and clustered according to their slightly different structural compositions originated from production process. By using this method, the quality and safety of LMWHs marketed in China were initially assessed.

How I treat and prevent venous thrombotic complications in patients with lymphoma

AbstractVenous thromboembolism (VTE) is a common complication occurring in 5% to 10% of patients with lymphoma. As the complexity of lymphoma management has increased with novel therapies, so too has the treatment of VTE. Therapeutic options for the treatment of cancer-associated VTE have expanded from only warfarin and low-molecular-weight heparins (LMWHs) to include the direct oral anticoagulants (DOACs) apixaban, edoxaban and rivaroxaban. There have been no head-to-head trials comparing different DOACs in this setting, and randomized trials comparing a DOAC with LMWH dalteparin differ in trial design and results. Drug–drug interactions, drug-specific side effects, and patient selection are important considerations when prescribing anticoagulant therapy. In all patients, the relative risks of thrombosis and bleeding, the availability of the anticoagulant, and the life expectancy of the patient are vital elements in selecting the most appropriate anticoagulant (which can vary over time) for the individual patient. We describe the intricacies and challenges of treating thrombotic complications in patients with lymphoma with an emphasis on evidence and guideline-based care.

Treatment of venous thromboembolism in patients with cancer: from clinical trials to real life

Approximately one-fifth of all cases of venous thromboembolism (VTE) are related to cancer. VTE complications may have a substantial impact on prognosis, quality of life and care in patients with cancer. Patients with cancer-related VTE are at increased risk of developing recurrent VTE compared to patients without cancer, but also have a higher risk of major bleeding. In the last years, direct oral anticoagulants (DOACs) have been evaluated in a head-to-head comparison with low molecular weight heparin (LMWH) in two randomized trials for the long-term treatment of VTE in patients with advanced cancer. The results of these trials show that DOACs have a similar efficacy profile, but probably higher risk of bleeding, compared to LMWH dalteparin. Because DOACs offer a simple oral treatment regimen without the need for anticoagulation monitoring, they could be attractive alternatives to LMWHs in these setting. The American Society of Clinical Oncology guidelines, published in August 2019, recommend LMWH, edoxaban and rivaroxaban as first-choice therapies for long-term anticoagulation in cancer patients with VTE. However, several practical issues should be considered concerning the long-term use of DOAC treatment in patients with cancer. Major concerns have been highlighted about the gastrointestinal bleeding risk in patients with gastrointestinal cancers and the potential drug-drug interactions in combination for some specific anticancer therapies. Several studies comparing DOACs with LMWH are currently ongoing to refine our knowledge concerning treatment with DOACs in patients with cancer-associated VTE.

A retrospective single-center evaluation of the safety and efficacy of direct oral anticoagulants versus low molecular weight heparin in patients with cancer-associated thrombosis.

e24102 Background: Over the past decade, there has been an increase in the use of direct oral anticoagulants (DOACs) in the cancer population despite limited data comparing its use against low molecular weight heparin (LMWH), the standard of care in cancer patients. Increasing data supporting DOACs in cancer-associated thrombosis has emerged over the past few years. Nonetheless, this study will evaluate the relative safety and efficacy of DOACs versus LMWH in cancer-associated thrombosis within an urban setting associated with low socioeconomic status. Methods: This is a retrospective chart review of medical records from patients treated at an urban academic medical center from October 2010 through October 2018. Patients met study inclusion if they had a diagnosis of venous thromboembolism occurring after the date of diagnosis of active cancer and were prescribed a direct oral anticoagulant (rivaroxaban, apixaban, dabigatran, edoxaban) or a low molecular weight heparin (dalteparin, enoxaparin, or fondaparinux) as monotherapy for the treatment of venous thromboembolic disease. Patients were excluded if they had less than 6 months of follow up data for reasons other than death. The primary outcomes were recurrent venous thromboembolism, major bleeding and death. Results: Of the 914 patients who met inclusion criteria, 286 were excluded due to lack of follow up data. The remaining patients included 472 in the LMWH arm and 156 in the DOAC arm. At 6 months, recurrent thromboembolism occurred in 5 of the 472 patients (1.1%) in the LMWH group as compared with 4 of the 156 patients (2.6%) in the DOAC group (p = 0.170). Major bleeding occurred in 36 patients (7.6%) in the LMWH group and 11 patients (7.0%) in the DOAC group (p = 0.813). Death within 6 months of starting anticoagulation occurred in 76 patients (16.1%) in the LMWH group and 16 patients (9.6%) in the DOAC group (p = 0.046). Discontinuation before 6 months of treatment occurred in 241 patients (51.2%) in the LMWH group and 46 patients (29.5%) in the DOAC group. Conclusions: The LMWH and DOAC groups had similar rates of recurrent thromboembolism and major bleeding. The mortality rate within 6 months of starting anticoagulation was significantly higher in the LMWH group and this difference requires further evaluation. These results help support the continued use of DOACs for the treatment of cancer-associated thrombosis and demonstrate that DOACs are as safe and effective as LMWH in this patient population.

Evaluation of the anticoagulant effect of low-molecular-weight heparins based on the anti-Xa level during haemodialysis.

Evaluate the relationship between anti-Xa activity and anticoagulant effect, and ascertain whether accumulation of low-molecular-weight heparins (LMWH) occurs during haemodialysis. There was an observational, single-centre study among participants who received the LMWH dalteparin, enoxaparin or nadroparin. A standard haemodialysis session lasted 4 hours. All included participants had anti-Xa activity measures at 0.5 and 4 hours. Extracorporeal circuit (ECC) clotting was evaluated by visual inspection of the haemodialyser and bubble trap after each haemodialysis session. The same person was tested at three consecutive haemodialysis sessions. Overall, 90 participants were enrolled and 259 haemodialysis sessions assessed. There was no significant difference in the mean anti-Xa activity at 0.5 and 4 hours for three consecutive sessions, so LMWH accumulation did not occur. There were 69 (26.6%) sessions in which, ECC clotting was visible. Compared with the group where circuit clotting did not occur, the LMWH dose and anti-Xa activity in the group where circuit clotting occurred were significantly lower. At 0.5 hour, anti-Xa <0.88 IU/mL had significantly higher odds of ECC clotting than that at ≥0.88 IU/mL. At 4 hours, anti-Xa <0.35 IU/mL had significantly higher odds of ECC clotting than that at ≥0.35 IU/mL. We found that over three haemodialysis sessions, no significant accumulation of LMWH was evident in subjects receiving a LMWH dose of between 2000 and 5000 IU for regular. Anti-Xa activity measurement can be used to adjust the dosage of LMWH and predict the anticoagulant effect during haemodialysis.

The antithrombin binding regions of heparin mediate fetal growth and reduced placental damage in the RUPP model of preeclampsia†.

Preeclampsia is a serious hypertensive disorder of pregnancy, which is only cured with delivery of the placenta, thereby commonly necessitating preterm birth of the fetus. Low-molecular-weight heparin (LMWH) has demonstrated potential to reduce the incidence of preeclampsia in high-risk pregnant women, although the underlying mechanism by which LMWH protects against preeclampsia is unknown. Given the complex structure and biologic actions of heparin, we tested the hypothesis that heparin can mediate preeclampsia prevention via nonanticoagulant pathways. We compared the effects of a nonanticoagulant, glycol-split LMWH (gsHep)—rendered nonanticoagulant through disruption of the antithrombin binding regions—with the LMWH dalteparin in the rat reduced uterine perfusion pressure (RUPP) surgical model of preeclampsia. Although RUPP animals exhibit significantly elevated blood pressure and reduced plasma levels of placental growth factor (PGF) compared to sham, neither dalteparin nor gsHep treatment significantly impacted these parameters. However, the observed positive correlation between PGF levels and number of viable fetuses in RUPP-induced animals suggests that reduced PGF levels were predominately due to placental loss. Daily subcutaneous injections of low-dose dalteparin but not gsHep significantly restored fetal growth that was impaired by RUPP surgery. Placentas from RUPP animals exhibited an abnormal labyrinth structure, characterized by expanded sinusoidal blood spaces, relative to sham-operated animals. Morphometric analysis demonstrated that dalteparin but not gsHep treatment normalized development of the labyrinth in RUPP-exposed conceptuses. These data suggest that the antithrombin-binding regions of LMWH are required to confer its protective effects on fetal growth and placental development.

Deep venous thrombosis induced by intravenous thrombogenic drugs

Background: Deep vein thrombosis (DVT) is a major preventable cause of morbidity and mortality worldwide with the potential to cause a dreaded pulmonary embolism (PE). Disease and patient-specific considerations are preferably incorporated into therapeutic options for effective management. Materials and methods: Sixty-eight cases of acute deep vein thrombosis were treated within a period of 3 years from January 2016. All the cases were subjected to routine investigations with the Doppler study of the affected limb. Low molecular weight heparin (dalteparin) was administered in all the cases for a period of 15 days and the Doppler study was repeated at the end of the drug therapy. After the course of low molecular weight heparin, the patients were given acenocoumarol 2mg daily. Estimation of partial thromboplastin time and prothrombin time were performed before starting and during the treatment of the low molecular weight heparin and acenocoumarol regularly. A venogram was done only when the repeated Doppler study revealed unsatisfactory response to low molecular weight heparin therapy. Eight cases underwent thrombectomy and the postoperative period was uneventful. Results: Age group of 21-30 years was most affected (80.8%) with right lower limb being the commonest affected site of injection and associated lesions. Conclusion: DVT in the young population remains a challenge to the evaluating clinician. A variety of disease states can alter the anticoagulant factors. Urgent diagnosis and appropriate intervention carry paramount importance.

Low-molecular-weight-heparin versus a coumarin for the prevention of recurrent venous thromboembolism in high- and low-risk patients with active cancer: a post hoc analysis of the CLOT Study

In patients with active cancer and acute venous thromboembolism (VTE), the low-molecular-weight-heparin (LMWH) dalteparin is more effective than vitamin K antagonist (VKA) in reducing the risk of recurrent venous thromboembolism (rVTE) without increasing the risk of bleeding. However, the relative benefit of LMWH versus VKA in patients with active cancer at high or low risk of rVTE and bleeding is unclear. This post hoc analysis used data from the CLOT study to explore the efficacy and safety of LMWH versus VKA in preventing recurrent thrombosis in high- and low-risk patients with active cancer. High-risk patients were defined by metastatic disease and/or antineoplastic treatment at baseline; low-risk patients presented with neither. Among high-risk patients, rVTE occurred in 25/318 (8%) (LMWH) versus 53/314 (17%) (VKA) (hazard ratio, 0.44; p = 0.001). No significant difference was detected in the rate of major or any bleeding. The 6-month mortality rate was 40% (LMWH) versus 41% (VKA). In low-risk patients, 2/20 (10%) (LMWH) had rVTE versus 0/24 (0%) (VKA) (hazard ratio, not estimable; p = 0.998). No significant difference was detected in the rate of major or any bleeding. The 6-month mortality rate was 20% (LMWH) versus 29% (VKA). In patients with cancer-associated thrombosis at high risk of rVTE and bleeding, the LMWH dalteparin was more effective than VKA in reducing the risk of rVTE without increasing the risk of bleeding. No difference in rate of rVTE or bleeding was observed between LMWH and VKA among low-risk patients.

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia.

Low molecular weight heparin (LMWH) is being investigated as a potential preventative therapy against preeclampsia. There is evidence suggesting that LMWH may prevent preeclampsia through anticoagulation-independent mechanisms. In this study, we compared the in vitro placental, endothelial, and anti-inflammatory effects of an LMWH (dalteparin) with a nonanticoagulant, glycol-split heparin derivative (gsHep). In contrast with dalteparin, gsHep did not interact with antithrombin III, possess significant anti-Factor Xa activity, or significantly prolong in vitro plasma clotting time. However, dalteparin and gsHep were otherwise mechanistically similar, both interacting with soluble fms-like tyrosine kinase-1 (sFlt1) and promoting release of the pro-angiogenic protein placental growth factor, but not the antiangiogenic sFlt1, from healthy placental villous explants. Placental explant media pretreated with dalteparin or gsHep significantly stimulated endothelial cell tube formation compared to untreated explants. Lastly, dalteparin and gsHep both significantly suppressed inflammation by inhibiting complement activation and leukocyte adhesion to endothelial cells that were activated using serum from preeclamptic women. Our data suggest that nonanticoagulant heparin derivatives may be utilized as a tool to distinguish the anticoagulation-independent mechanisms of LMWH, and provide insight into the role of anticoagulation in the prevention of preeclampsia.

Low molecular weight heparin versus rivaroxaban in the treatment of venous thromboembolism in gastrointestinal malignancies

: Due to their ease of use, the direct oral anticoagulants (DOACs) are an attractive treatment option for cancer-associated venous thromboembolism (VTE) and have been readily adopted by many clinicians. A recent published study comparing a DOAC (edoxaban) to the current standard-of-care low molecular weight heparin dalteparin for the treatment of cancer-associated thrombosis showed that edoxaban was noninferior to dalteparin for recurrent VTE, but the risk of major bleeding was higher. We present three patients with high-risk gastrointestinal malignancies complicated by cancer-associated VTE with progression of thrombosis while treated with the oral direct Xa inhibitor rivaroxaban. Upon switching therapy to low molecular weight heparin, we found that these patients had clinical and radiologic improvement of VTE. More studies are needed to evaluate the efficacy of rivaroxaban in high-risk gastrointestinal-VTE. We suggest that in some patients, DOACs may not be sufficient for the treatment of VTEs related to high-risk gastrointestinal malignancies.

Sequencing the oligosaccharide pool in the low molecular weight heparin dalteparin with offline HPLC and ESI–MS/MS

Low molecular weight heparins (LMWHs) are widely used anticoagulant drugs. The composition and sequence of LMWH oligosaccharides determine their safety and efficacy. The short oligosaccharide pool in LMWHs undergoes more depolymerization reactions than the longer chains and is the most sensitive indicator of the manufacturing process. Electrospray ionization tandem mass spectrometry (ESI–MS/MS) has been demonstrated as a powerful tool to sequence synthetic heparin oligosaccharide but never been applied to analyze complicated mixture like LMWHs. We established an offline strong anion exchange (SAX)-high performance liquid chromatography (HPLC) and ESI–MS/MS approach to sequence the short oligosaccharides of dalteparin sodium. With the help of in-house developed MS/MS interpretation software, the sequences of 18 representative species ranging from tetrasaccharide to octasaccharide were obtained. Interestingly, we found a novel 2,3-disulfated hexauronic acid structure and reconfirmed it by complementary heparinase digestion and LC–MS/MS analysis. This approach provides straightforward and in-depth insight to the structure of LMWHs and the reaction mechanism of heparin depolymerization.

Phase I Study of Dalteparin in Combination With Sunitinib in Patients With Metastatic Clear Cell Renal Carcinoma.

Based on the tumor-driven concomitant activation of angiogenesis and coagulation we conducted a phase I combination study of sunitinib with the low molecular weight heparin dalteparin in patients with metastatic clear cell renal cell carcinoma (ccRCC). Patients received standard treatment with sunitinib (50 mg daily, 4 weeks on, 2 weeks off). During the second week of no sunitinib in the first cycle (week 6) patients received dalteparin monotherapy (in escalating doses). Combination therapy of the 2 agents was administered from the second cycle onward. Seventeen patients were enrolled at 3 dose levels of dalteparin. Diarrhea and fatigue were the most frequent reported drug-related toxicities (41%). One dose-limiting toxicity (grade 3 anemia) was observed at the highest dose level of dalteparin. There were 4 partial responses (24%) and the median progression-free survival in this study was 14 months (95% confidence interval, 8.0-23.4). Anti-factor Xa levels were increased during combination therapy compared with dalteparin monotherapy. Combination therapy of sunitinib with therapeutic doses of dalteparin is safe and well tolerated. The increased anti-factor Xa levels during combination treatment suggest that sunitinib might increase the anticoagulation activity of dalteparin. The positive safety profile warrants prospective evaluation of the clinical benefit of this combination strategy in patients with ccRCC.

Structural Characterization of the Low-Molecular-Weight Heparin Dalteparin by Combining Different Analytical Strategies.

A number of low molecular weight heparin (LMWH) products are available for clinical use and although all share a similar mechanism of action, they are classified as distinct drugs because of the different depolymerisation processes of the native heparin resulting in substantial pharmacokinetic and pharmacodynamics differences. While enoxaparin has been extensively investigated, little information is available regarding the LMWH dalteparin. The present study is focused on the detailed structural characterization of Fragmin® by LC-MS and NMR applied both to the whole drug and to its enzymatic products. For a more in-depth approach, size homogeneous octasaccharide and decasaccharide components together with their fractions endowed with high or no affinity toward antithrombin were also isolated and their structural profiles characterized. The combination of different analytical strategies here described represents a useful tool for the assessment of batch-to-batch structural variability and for comparative evaluation of structural features of biosimilar products.

Venous Thromboembolism Prophylaxis with Rivaroxaban in Elective Foot and Ankle Surgery

Category: Other Introduction/Purpose: Oral application for prophylaxis of venous thromboembolism (VTE) after total hip and knee arthroplasty has high acceptance among patients due to its non-invasive nature, when compared to traditional subcutaneous application of low- molecular-weight heparin (LMWH). Approximately 10% of the patients in our clinic receive oral thrombosis prophylaxis (rivaroxaban), the remaining patients receive subcutaneous prophylaxis with LMWH (dalteparin). However, no clinical data exists describing the use of oral prophylaxis in elective orthopedic foot and ankle surgery. The aims of this study where: 1. To assess the incidence of VTE after oral prophylaxis after elective foot and ankle procedures. 2. To identify risk factors for VTE after oral prophylaxis after elective foot and ankle procedures. Methods: A retrospective chart review of patients undergoing elective foot and ankle surgery between January 2010 and 2013 was performed. The type of medicamentous thrombosis prophylaxis was noted. All patients receiving oral antithrombotic medication (rivaroxaban, Xarelto©, Bayer, Germany) were included in the study. Location, length and type of surgery and tourniquet time were assessed. Co-morbidities (e.g. diabetes, coagulopathy, ASA classification) were noted. Patients previously treated with phenprocoumon or clopidrogel were excluded. A phone interview was performed and patients were asked whether a thromboembolic incident occurred or not. If an incidence was confirmed, the report of the diagnostic findings was obtained from the general practitioner. Results: 450 patients were included. Two thromboembolic incidents occurred (0.4%; deep venous thrombosis confirmed by ultrasound). Both patients had a history of previous deep venous thrombosis and a positive family history for VTE. Due to the low percentage of patients with VTE, a multivariate analysis could not be performed. Conclusion: The incidence of VTE after oral thrombosis prophylaxis with rivaroxaban is low and comparable with the incidence after subcutaneous application of LMWH.