Low Molecular Weight Heparin Treatment Research Articles

Low molecular weight heparin treatment of acute moderate and severe pancreatitis: A randomized, controlled,open-label study.

Acute pancreatitis (AP) runs a moderately severe and severe course in 20%-30% of cases. The purpose of the present study was to determine the effect of low molecular weight heparin (LMWH) for the prevention of pancreatic necrosis (PN) in moderately severe and severe AP (MSAP). A total of 100 patients with MSAP were randomized to receive either standard care (SC) or SC plus LMWH. LMWH was administered at 1 mg/kg via subcutaneous injection twice a day between days 1 and 7. The revised Atlanta criteria were used in the diagnosis of MSAP. Patients with a Harmless AP Score of >1 and a Balthazar computed tomography (CT) score of D and E were included in the study. The mean age±SD of the patients (46 male and 54 female) was 52±19 years (range, 17-100). There were 50 patients in each group. On admission, clinical and laboratory parameters and Balthazar CT scores were similar between the groups. Initially, PN was present in one patient in the LMWH group and two in the SC group. Over the course, PN developed in 3 (6.1%) patients in the LMWH group and 11 (22.9%) in the SC group (p<0.05). Local and systemic complications were significantly lower in the LMWH group (p<0.05). No hemorrhagic complication occurred. Mortality was not significantly different between the groups (p=0.056). Low molecular weight heparin treatment is safe and provides better prognosis in MSAP.

Pregnancy success rate and response to heparins and/or aspirin differ in women with antiphospholipid antibodies according to their Global AntiphosPholipid Syndrome Score

BackgroundThe current treatment to prevent pregnancy morbidity (PM) associated with antiphospholipid antibodies (aPL) is based on the use of low dose aspirin and low molecular weight heparin (henceforth defined as standard of care (SoC) treatment). Despite the SoC, up to 30% of women with aPL continue to have pregnancy complications. The global antiphospholipid syndrome (APS) score (GAPSS) is a tool to quantify the risk for the aPL-related clinical manifestations. In this study, we investigated the individual clinical response to SoC in women with aPL after stratifying them according to their GAPSS. MethodsOne-hundred-fourty-three women (352 pregnancies) with aPL ever pregnant treated with SoC therapy were included. The patients GAPSS was then grouped according to the patients’ GAPSS into low risk (< 6), medium risk (6–11), and high risk (≥12). ResultsThe live birth rate was 70.5% (248 out of the 352 pregnancies), 45 patients (31%) experienced at least one event of PM, defined as early or late.Patients were stratified according to GAPSS values, in order to identify a low risk group (GAPSS <6, n = 72), a medium risk group (GAPSS 6–11, n = 66) and a high risk group (GAPSS ≥12, n = 5).When considering patients who ever experienced any PM while treated with SoC, all patients in the high risk group experienced PM, while patients in the medium group had a significant higher rate of PM when compared to the low risk group [29 (43.9%) patients V.s. 11 (15.3%), respectively; p < 0.001]. When analysing the number of pregnancies in the three groups, patients in the high risk group had significantly lower live birth rates, when compared to the other groups [11 (40.7%) live births vs. 100 (62.1%) and 137 (82.5%), respectively; p < 0.05]. Furthermore, patients with medium risk group also had significantly lower live birth rates, when compared to the lower risk group (p < 0.001). ConclusionsGAPSS might be a valuable tool for to identify patients with a higher likelihood of response to SoC.

Pulmonary embolism identified prior to anesthesia induction in a low-risk patient

Introduction: Early detection and treatment of pulmonary embolism (PE) are critical for reducing morbidity and mortality of patients. However, diagnosis can be difficult if the symptoms are not clear. Case Report: A 21-year-old male patient visited the emergency room with multiple fractures, including femur fractures. Three days later, the planned operation was scheduled. On the day of surgery, the operation was canceled due to clinical diagnosis of PE because oxygen saturation on the pulse oximeter was 71–76% without dyspnea. Later, he was diagnosed with PE of the right lower lobe based on computed tomography (CT) pulmonary angiography, and surgery was performed without complications after low-molecular weight heparin treatment. Conclusion: Even if a patient is low risk and does not have symptoms suspicious of PE, careful preoperative patient monitoring and preoperative anesthetic evaluation are important for identifying additional patient risks.

D-Dimer Assay May Guide LMWH Treatment in Repeated Biochemical Pregnancy Losses in Women with Positive Antiphospholipid Antibody.

Do D-dimer levels influence the pregnancy outcomes after treatment with low molecular weight heparin (LMWH) in women of recurrent miscarriage (RM), repeated biochemical pregnancy losses (BPL), and a positive test for antiphospholipid antibodies (aPLs)? This study was a retrospective chart review of 569 RM patients who were identified as having a history of BPL and a positive aPL. These patients were grouped into three groups according to their treatment plan including those who received low dose aspirin (LDA) alone (group A), LDA plus LMWH after ovulation therapy (group B), and LDA plus LMWH after pregnancy confirmation (group C). We hypothesized that the administration of LMWH after ovulation increased the rates of live birth. D-dimer may predict the pregnancy outcome after treatment. The live birth rate of group B and group C is significantly higher than group A (86.96% and 66.80% vs. 52.89%, p < 0.0001, respectively). The live birth rate in group A, B, and C with elevated D-dimer is 36.92%, 90.52%, and 61.60% respectively. However, there is no significant difference in live birth rate among those who had normal baseline D-dimer. These results suggest that LMWH therapy is more effective in improving the live birth rate when given after ovulation than after pregnancy confirmation. The plasma D-dimer assay can possibly guide LMWH treatment appropriately.

Comparative analysis of the impact on pregnancy of low-dose aspirin, low-molecular-weight heparine and combined treatment objectified by values of Doppler velocimetry

Introduction. The fact that thrombophilia is a factor involved in the pathogenesis of preeclampsia is a hypothesis supported bidirectionally by numerous contradictory results; however, it is estimated that approximately 40% of patients with preeclampsia have a thrombophilic substrate. Most valid studies do not support an association between inherited thrombophilia and preeclampsia, intrauterine growth restriction or spontaneous abortion, thus implicitly not supporting the prophylactic anticoagulant treatment with low-molecular-weight heparin (LMWH) for the prevention of the aforementioned conditions. Materials and method. We selected pregnant women with developing or spontaneous discontinued pregnancy undergoing anticoagulant or antiplatelet treatment. In the context where clear protocols for the administration of anticoagulants in pregnancy have not yet been established, we aimed to perform a comparative analysis of the clinical and anamnestic aspects on which the indication of treatment with antiplatelet, anticoagulant or the two combined in pregnancy were based and the impact on placental function by comparative analysis of the values of the Doppler measurements for the uterine, umbilical and average cerebral arteries of the patients included in the three study groups. Results. Spontaneous abortions or intrauterine fetal death in the antecedents was the main criterion for recommending antiplatelet, anticoagulant or combined treatment. In the presence of a personal history of thrombotic events, the combined treatment of LMWH and low-dose aspirin was chosen. We did not obtain a significant difference in the frequency of spontaneous pregnancy loss between the three study groups, the proportion of this condition being similar. Conclusions. The combined treatment of LMWH and low-dose aspirin in pregnancy was significantly correlated with the values of the resistance and pulsatility index of the uterine arteries closest to the normal values, with an average pulsatility index lower than 1, in particular for the left uterine artery, compared to the results obtained for the single treatment with low-dose aspirin or LMWH.

Low molecular weight heparin (nadroparin) improves placental permeability in rats with gestational diabetes mellitus via reduction of tight junction factors.

Placental structural abnormalities and dysfunction in those with gestational diabetes mellitus (GDM) can lead to increased placental permeability, which is in turn related to a poorer maternal and fetal prognosis. The present study sought to assess whether increased placental permeability in rats with GDM was accompanied by alterations in tight junction (TJ) factors and to evaluate the impact of low molecular weight heparin (LMWH) on these factors. The present study was conducted using pregnant female rats that were randomized into control, GDM and GDM + LMWH groups. Diabetes was induced via intraperitoneal administration of streptozotocin to rats in the GDM and GDM + LMWH groups, whereas rats in the GDM + LMWH group received daily subcutaneous LMWH starting on day 5 of pregnancy. On gestational day 16, all rats were sacrificed and Evans Blue (EB) assay was used to gauge vascular permeability based on EB dye leakage. Transmission electron microscopy was further used to assess TJ structures, and the TJ proteins zonular occludens-1 (ZO-1) and occludin (OCLN) were assessed using immunohistochemistry and western blotting. Blood samples were obtained from the abdominal aorta for ELISA measurements of advanced glycation end products (AGEs) concentrations, and placental receptor for AGEs (RAGE) and vascular endothelial growth factor (VEGF) expression was assessed using reverse transcription-quantitative PCR. In addition, western blotting was used to measure placental NF-κB. Compared with in the control group, EB leakage was markedly increased in GDM group rats; this was associated with reduced ZO-1 and OCLN expression. Conversely, LMWH attenuated this increase in placental permeability in rats with GDM and also mediated a partial recovery of ZO-1 and OCLN expression. Blood glucose and serum AGEs concentrations did not differ between the GDM and GDM + LMWH groups. Furthermore, LMWH treatment resulted in decreases in RAGE and VEGF mRNA expression levels, which were upregulated in the GDM group, whereas it had the opposite effect on the expression of NF-κB. In conclusion, GDM was associated with increased placental permeability and this may be linked with changes in TJs. LMWH intervention mediated protection against this GDM-associated shift in placental permeability via the RAGE/NF-κB pathway.

An Ovarian Cancer Patient Presenting Heparin - Induced Thrombocytopenia after use of Low - Molecular - Weight Heparin: A Case Report of Rare Condition

Heparin-induced thrombocytopenia is a rare and life-threatening condition of exposure to heparin. A case of heparin-induced thrombocytopenia due to the low molecular weight heparin was presented. Pulmonary emboli and progressively decreased number of thrombocytes developed during the low molecular weight heparin treatment. For that reason, the heparin-induced thrombocytopenia was diagnosed. The heparin was ceased and fondaparinux treatment initiated. Platelet levels returned to normal limits within six days. The delaying in diagnosis of heparin-induced thrombocytopenia causes serious outcomes. The physician must be careful and keep in mind be developed of this clinical condition in patient under heparin treatment.

Direct Oral Anticoagulants Compared to Low Molecular Weight Heparin in the Treatment of Cancer-Associated Thromboembolism: An Updated Meta-Analysis of Randomized Controlled Trails

Introduction: Cancer patients have approximately 4 times higher risk of developing venous thromboembolism (VTE) compared to the general population. High tendency of bleeding from anticoagulant use in this population makes the treatment of cancer-associated thromboembolism (CAT) very challenging. Low molecular weight heparin (LMWH) is still considered as standard treatment for CAT. Direct oral anticoagulants (DOAC) have emerged as a potential alternative for LMWH due to the ease of administration and predictable pharmacokinetics, but data on DOACs in CAT is limited. Few randomized controlled trials (RCT) published recently have compared the efficacy and safety of DOACs with LMWH in the treatment of CAT. Hence, we conducted an updated meta-analysis of RCTs to determine the relative risk of recurrent VTE and bleeding complications associated with DOACs compared to LMWH in the treatment of thromboembolism in patients with cancer, and to evaluate if the risk estimates have changed since prior report (Li et al.). Methods: We performed a systemic search using Embase, Medline, and the meeting abstracts with appropriate keywords through 06/30/19, to find all RCTs comparing a DOAC with LMWH in treatment of patients with CAT. The search strategy, study selection, data extraction and analysis were performed in accordance with the Preferred Reporting Items for Meta-Analyses (PRISMA) guidelines. We pooled the point estimates in form of risk ratios (RR) with respective 95% confidence intervals (CI), using the random effects model (Mantel-Haenszel method) of Der Simonian and Laird. Heterogeneity of effect size across studies was quantified using I2 statistic and Cochran's Q. Publication bias was assessed by the Egger's regression test. All the statistical analyses were performed with the RevMan 5.3 software. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2014. Results: Overall a total of 1,739 patients with CAT (870 in the DOAC arms and 869 in LMWH arms) from three RCTs were included in the final analysis. Characteristics of studies included in the analysis are summarized in table 1. Different DOACs (Select-D: rivaroxaban, Hokusai VTE cancer: edoxaban and ADAM VTE: apixaban) were used to compare with dalteparin in included trials. Duration of anticoagulation was 6 to 12 months in these studies. Use of DOAC was associated with a significantly lower risk of recurrent VTE in comparison with LMWH [pooled RR 0.48, 95%CI: 0.26-0.87, p = 0.02, I2 = 56%, figure 1]. In addition, there was no statistically significant increase in the risk of major bleeding in patients on the DOAC arms, as compared to those on LMWH arms [ pooled RR 1.55 ,95%CI: 0.79-3.04, p = 0.20, I2 = 29%, figure 2]. Criteria for major bleeding in the studies were defined by the International Society on Thrombosis and Hemostasis. The pooled RR for clinically relevant non major bleeding (CRNMB) was 1.80 [95%CI: 0.96-3.38, p = 0.07, I2 = 60%, figure 3], thus suggesting no significant difference in risk of CRNMB between DOAC and LMWH groups. Moderate heterogeneity was noted across trials. We found no publication bias among studies included in the analysis. Conclusion: In our meta-analysis, use of DOACs for the treatment of CAT was associated with a significantly decreased risk of recurrent VTE compared to LMWH. There was no significant difference in the incidence of major or non-major bleeding events between DOAC and LMWH groups. These study results provide additional evidence for potential use of DOAC as a safe and effective alternative to LMWH for the treatment of thromboembolism in patients with cancer. Disclosures No relevant conflicts of interest to declare.

Effectiveness and Safety of Direct Oral Anticoagulants Vs. Low Molecular Weight Heparin As Anticoagulant Therapy in Patients with Active Cancer Therapy and Non Valvular Atrial Fibrillation

BACKGROUND Non Valvular Atrial Fibrillation (NVAF) is the most common cardiac arrhythmia among patients with cancer. Anticoagulation in this setting is associated with a higher rate of clinically relevant major and non-major bleeding and therefore, can be especially challenging. Due to concerns about drug interactions in patients receiving chemo-immunoterapy, Low Molecular Weight Heparin (LMWH) has been the most commonly prescribed anticoagulant for stroke prevention as a substitute for vitamin K antagonists. Direct Oral Anticoagulants (DOAC) are an increasing alternative for anticoagulant therapy for stroke prevention in NVAF, but there are are still limited data regarding it's effectiveness and safety for cancer patients receiving active treatment. AIMS To assess the effectiveness and safety according to DOAC or LMWH treatment, and to determine the rate of anticoagulant-associated clinically relevant bleeding-free survival in a cohort of cancer patients with NVAF receiving active treatment. METHODS From April 2016 to December 2018 we consecutively included NVAF patients with active cancer therapy treated with DOAC or LMWH in a prospective multicenter registry. Patients with prosthetic valves or a life expectancy of less than one month were excluded from this study. Active cancer therapy was defined as evidence of neoplasm with ongoing antineoplastic therapy (chemo-immunotherapy or hormonal treatment). Pharmacological interactions check-up was performed prior election of treatment. Demographic, laboratory, cancer diagnosis, and antineoplastic therapy data were collected. Patients had a minimum follow-up (FU) of 6 months. In patients who received antineoplastic therapy with a potential DOAC interaction, plasma drug concentrations were measured during the FU using the Direct Thrombin Inhibitor Assay from IL (Bedford-MA-USA) for Dabigatran and the Technoclone anti-Xa assay from Technoclone (Vienna-Austria) for Rivaroxaban. Bleeding events were classified according to ISTH criteria. RESULTS A total of 302 patients with NVAF and active cancer therapy were included. Among all patients, 192 (63.5%) were treated with DOAC (20 dabigatran, 24 rivaroxaban, 80 apixaban and 68 edoxaban) and 110 with LMWH. Mean FU was 14.8 and 12.5 months (DOAC vs LMWH; p:0.53). Demographic characteristics and cancer subtypes and drugs are summarised in table 1 and 2, respectively. In LMWH group, 81.8% (n=90) of patients received full-dose of LMWH, 13.6% (n=15) intermediate dose and only a 4.5% patients received prophylactic doses. Plasma concentrations were measured in 2 patients receiving dabigatran 110 mg twice daily and enzalutamide. Trough level of our patients was 132.4 and 126.8 ng/mL (12 hours after the last dose). Rivaroxaban plasma samples were collected in 3 patients who received doxorubicin as part of chemotherapy regimen. Plasma rivaroxaban levels, determined 4 hours and 24 hours of the last dose, ranged from 112.4 to 432.3 ng/ml and 49.8 to 216 ng/ml, respectively. Considering these results, DOACs were maintained during antineoplastic treatment. Stroke or systemic embolism occurred in three patients in the DOAC group (1.04 %/year) and seven patients in the LMWH group (7.2 %/year) [DOAC vs LMWH; p&amp;lt;0.05]. Major bleeding occurred in eight patients in the DOAC group (4.1%/year) and seven patients in the LMWH group (6.5%/year). All reported mortality was disease related. The bleeding-free survival rates were not statistically different between DOAC vs LMWH. CONCLUSIONS In our cohort, the stroke and systemic embolism rate was higher in the LMWH group without significant differences in relation to major bleeding events. Further investigations on the optimal management of cancer patients with active therapy and NVAF treated with DOAC are needed. Meanwhile, determining DOAC plasma concentrations could be of profit to personalize anticoagulant therapy for patients with unpredictable drug interactions. Anticoagulation units play a crucial role in offering the best personalised therapy. Disclosures Sierra: Novartis: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria.

Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free Pediatric-Inspired ALL Regimen with Imatinib

Background: Venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL) receiving asparaginase (ASNase) based therapy. The MD Anderson Cancer Centre reported an overall VTE incidence of 29% (14/49) in patients with Philadelphia positive ALL (Ph+ ALL) treated with Hyper-CVAD and in the absence of ASNase (Vu et al. Cancer Medicine. 2015;4(1):27-35. doi:10.1002/cam4.332). The VTE incidence in adult Ph+ ALL patients treated with tyrosine kinase inhibitor plus the pediatric-inspired regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol remains unclear. We have previously compared the incidence of VTE in adults with Ph+ ALL treated with or without ASNase during the intensification phase of the modified DFCI treatment. This study suggested that patients with Ph+ve ALL experience high incidence of VTE, even in the absence of ASNase, and that this risk is not restricted to the intensification phase. As ASNase was omitted from the protocol due to toxicity since 2008, in this report, we provide further insight into the risk of VTE in adults with Ph+ ALL during the entire ASNase-free DFCI treatment course. Methods: A single-institution retrospective review of sequential Ph+ ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008-2018 with an imatinib-containing DFCI protocol-based regimen that omitted ASNase. VTE events were recorded from the time of diagnosis to the end of modified DFCI treatment, including at the time of allogenic bone marrow transplantation. Co-variants of age, sex, weight, BMI, Padua score, white blood cell count, and platelet count were also collected. Statistical analyses were performed using the 2-tailed t test. Results: Overall, 130 patients were included for analysis; none received prophylactic anticoagulation. Among the 130 Ph+ ALL patients treated with the modified DFCI protocol, 28 (21.5%) patients had at least 1 VTE events from diagnosis to the end of treatment. The mean age of patients with and without VTE were 56.8 and 49.0 years, respectively (p=0.014) (Table 1). The majority of the VTE events occurred during active treatment, with 9 (7.0%), 11 (8.5%), and 4 (3.1%) occurring during induction, intensification, and maintenance, respectively (Figure 1). Only four patients (3.1%) presented with VTE at the time of diagnosis. Of all VTE events, 14 (50%) were DVT and/or PE, 12 (43%) were line-related, and 2 (7%) involved a cardiac thrombus (Table 2). The average Padua score for these patients was 5.4 with a range of 3-10. All VTE events were treated with low weight molecular heparin (LMWH), with 2 patients experiencing a recurrent episode within a year while on LMWH treatment. Bleeding following anticoagulation was rare. One patient experienced a major bleeding into the psoas muscle while on LMWH plus platelet transfusion for a right atrial clot during the induction phase in ICU. No other significant bleeding event was observed. Conclusion: VTE was observed in more than 20% of adults with Ph+ ALL patients treated with imatinib plus a modified DFCI pediatric ALL protocol. The majority of VTE events occurred during active treatment (induction and intensification), and DVT/PE incidence was similar to that of line-related thrombosis. The high observed VTE incidence suggests that prophylactic anticoagulation should be considered for adult patients with Ph+ ALL even in ASNase-free regimens, especially if additional thromboembolic risk factors are present. Disclosures Maze: Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chan:Celgene: Honoraria, Research Funding; Agios: Honoraria; AbbVie Pharmaceuticals: Research Funding. Gupta:Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Yee:Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Schimmer:Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy. Schuh:Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees. McNamara:Novartis Pharmaceutical Canada Inc.: Consultancy.

Concurrent Treatment of VEGFR Tyrosine Kinase Inhibitors (TKIs) and Factor Xa Inhibitors Is Associated with Increased Bleeding Risks

ABSTRACT Background: Some cancer patients with thromboembolism require dual treatment of VEGFR TKIs and factor Xa inhibitors (direct or indirect), which may contribute to increased bleeding risks. However, the safety of such combination treatment has not been well characterized in the literature or national guidelines. Methods: This is a single center retrospective study, where we identified metastatic cancer patients (renal cancer, colorectal cancer, sarcoma, etc) who received concurrent VEGFR TKIs (pazopanib, sunitinib, sorafenib, axitinib, regorafenib, vandetanib, lenvatinib or cabozantinib) and Xa inhibitors (low-molecular weight heparin [LMWH] or direct oral anticoagulants [DOACs] including rivaroxaban or apixaban) at the Ohio State University Medical Center. We assessed bleeding risks of dual therapies vs. factor Xa inhibitors alone, using the same patients as self controls. We reviewed medical charts of all identified patients for clinically significant bleeding events (defined as combined major bleeding and clinically relevant non-major bleeding by the International Society of Thrombosis and Haemostasis criteria). The Cox proportional hazard model was used to compare the differences of time to first clinically significant bleeding event between the groups of concurrent use and anticoagulant use only. Results: A total of 86 patients (26 females and 60 males) were included: 78 Caucasians, 6 African Americans, and 2 others. 81 patients had concurrent TKI and LMWH treatment; 20 patients had concurrent TKI and DOACs; and 85 patients have had been on factor Xa inhibitor alone (LMWH or DOACs) at some point. Some patients had been on both LMWH and DOACs at different time periods. Overall, there were 29 clinically significant bleeding events (including 8 major bleeding) during concurrent treatment and 17 events (4 major bleeding) during factor Xa inhibitor alone over a median follow up of 63 days (52 days for concurrent treatment and 99 days for Xa inhibitor alone). In this self-control study, concurrent treatment was associated with a statistically higher risk of clinically significant bleeding events (HR, 2.84; 95% CI, 1.43-5.64, P &amp;lt; 0.01), which reached 37% patient population in the first 3 months, while the bleeding associated with factor Xa inhibitor alone seemed spaced out at the entire length of anticoagulation (8% by 6 months). Similar trend was found in the analysis of patient group of concurrent TKI and LMWH vs. LMWH alone (HR, 1.96; 95% CI, 0.95-4.02, P = 0.067), although significance was not reached likely due to insufficient power. Sample size was inadequate for meaningful comparison between concurrent VEGFR TKI and DOAC vs. DOAC alone. Conclusions: Concurrent treatment of VEGFR TKI and factor Xa inhibitors is associated with a significantly increased bleeding risks when compared with factor Xa inhibitors alone in patients with metastatic cancer. Disclosures No relevant conflicts of interest to declare.

The efficacy of low molecular weight heparin in severe acute pancreatitis: A systematic review and meta-analysis of randomized controlled trials.

The effects of low molecular weight heparin (LMWH) on severe acute pancreatitis (SAP) have been controversial. We aimed to evaluate the efficacy of LMWH on prognosis of SAP by systematic review and meta-analysis. We searched relevant studies published up to March 2019 in five databases (MEDLINE/PubMed, EMBASE, the Cochrane Central Register of Controlled Trials in Cochrane Library, China National Knowledge Infrastructure, and the Chinese Journal of Science and Technology of VIP database). Sixteen randomized controlled trials with 1625 patients were included in the final analysis. Most studies were from China. In analysis of laboratory parameters and clinical scores, SAP patients receiving LMWH treatment had lower white blood cell counts, C-reactive protein level, Acute Physiology and Chronic Health Evaluation II score, and computed tomography severity index. In clinical outcomes, SAP patients who received LMWH treatment had shorter hospital stay (pooled mean difference [95% confidence interval; CI] -8.79 [-11.18, -6.40], P < .01), lower mortality (pooled risk ratio [RR] [95% CI] 0.33 [0.24-0.44], P < .01), lower incidences of multiple organ failure (pooled RR [95% CI] 0.34 [0.23-0.52], P < .01), pancreatic pseudocyst (pooled RR [95% CI] 0.49 [0.27-0.90], P = .02), and operation rate (pooled RR [95% CI] 0.39 [0.31-0.50], P < .01). LMWH could improve the prognosis of SAP, and has a potential role in reducing hospital stay, mortality, incidences of multiple organ failure, pancreatic pseudocyst, and operation rate.

Low-molecular-weight-heparin increases Th1- and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomised controlled trial

Low-molecular-weight heparin (LMWH) is widely used to treat recurrent pregnancy loss (RPL) because of its anti-coagulant effects. Although in vitro studies have suggested additional immunological effects, these are debated. We therefore investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomised controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analysed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. Mixed linear models test on LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p < 0.001) and the Th17-associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Subsequent Student’s t-test showed significantly higher plasma levels of CXCL10 and CXCL11 in treated than untreated women at gw 28 and 34. The consistent increase in the two Th1-associated chemokines suggests a potential proinflammatory and unfavourable effect of LMWH treatment during later stages of pregnancy, when Th1 immunity is known to disrupt immunological tolerance.

Low-molecular-weight heparin adherence and effects on survival within a randomised phase III lung cancer trial (RASTEN)

BackgroundCoagulation activation is a hallmark of cancer, and anticoagulants have shown tumour-inhibiting properties. However, recent trials have failed to demonstrate improved survival with low-molecular-weight heparin (LMWH) in cancer populations. This has raised the question of suboptimal adherence as a possible explanation for the lack of benefit. Still, there is no standardised method to directly monitor LMWH in patient plasma. Here, we directly determine LMWH levels in patients using the Heparin Red assay to objectively assess adherence and how this associates with the patient outcome in the RASTEN trial. MethodsRASTEN is a multicentre, randomised phase III trial investigating if the addition of LMWH to standard therapy can improve survival in small-cell lung cancer. LMWH was measured in plasma (N = 258) by the Heparin Red assay and compared with the anti–factor Xa (anti-FXa) activity assay. ResultsBoth methods could differentiate patients in the LMWH arm from the control arm and patients receiving therapeutic LMWH owing to thrombosis. Receiver Operating Characteristic (ROC) analysis yielded adherence rates of 85% for anti-FXa and 68% for Heparin Red. No survival benefits were found in the adherent subgroup compared with the control arm (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 0.95–1.67; P = 0.105 and HR: 1.19; 95% CI: 0.89–1.60; P = 0.248 for anti-FXa and Heparin Red, respectively). Heparin Red could define patients with high probability of adherence to LMWH treatment, which warrants prospective studies for further validation. Our finding that the LMWH-adherent subpopulation did not show improved survival excludes that the negative outcome of RASTEN was due to poor adherence.

Abstract 3367: Treatment patterns in patients with cancer-associated venous thromboembolism in the US: A real world retrospective database analysis

Abstract Background: Cancer patients have higher risk of venous thromboembolism (VTE) due to the cancer-induced hypercoagulable state or activation of the coagulation cascade by chemotherapy. The 2018 National Comprehensive Cancer Network guidelines recommend low molecular weight heparin (LMWH) to treat cancer-associated VTE and direct oral anticoagulants (DOACs) in some circumstances. This study aimed to understand VTE treatment patterns in a cancer-associated VTE population during hospitalization and post-discharge. Methods: Patients with cancer-associated VTE and their respective treatments were identified in IQVIA’s hospital Charge Data Master database from 7/1/15 to 4/30/18. Patients were followed for 1 month after VTE hospitalization. Post-discharge therapy was obtained from outpatient medical and pharmacy claims data. Results: A total of 5,920 cancer patients hospitalized for VTE (54% female; mean age 65.9 [SD=13.0] years) were included. Lung (20%) and breast (13%) cancers were the most common cancer types. Average length of stay was 5.3 days (SD=4.1). 5,366 (91%) patients were treated during the hospital stay; LMWH (51%), DOACs (15%) and warfarin (12%) were the most common inpatient treatments. Within 30 days after discharge, the most common treatments were DOACs (26%) and LMWH (16%); 2,858 (48%) had no observed treatment in the outpatient setting. After discharge, 1,272 (21%) patients remained on the same therapy and 1,436 (24%) switched to a new treatment. Among those patients initiating DOACs (N=865) during hospitalization, 46% remained on DOACs after discharge. Conclusions: In US hospital and outpatient settings, this real world study showed that LMWH treatment and treatment with DOACs were the most common initial inpatient therapies for cancer-associated VTE. DOACs were the most common post discharge treatment. Further investigation of patients without continued treatment within 30 days of discharge is warranted. Distribution of post-discharge VTE therapy by initial VTE observed during index hospitalizationInitial VTE therapy during hospitalization(n=5,920)Post-Discharge VTE TherapyLMWH(n=918)Heparin(n=12)Warfarin(n=560)DOAC(n=1,561)Thrombolytic Agent (n=11)No post-discharge VTE treatment(n=2,858)LMWH n=3,040; 51.4%648 (21.3%)6 (0.2%)213 (7.0%)678 (22.3%)6 (0.2%)1,489 (49.0%)Heparin n=566; 9.6%48 (8.5%)2 (0.4%)34 (6.0%)166 (29.3%)1 (0.2%)315 (55.7%)Warfarin n=685; 11.6%80 (11.7%)2 (0.3%)242 (35.3%)86 (12.6%)2 (0.3%)273 (39.9%)DOAC n=865; 14.6%25 (2.9%)0 (0.0%)13 (1.5%)400 (46.2%)1 (0.1%)426 (49.2%)Thrombolytic agent n=210; 3.5%36 (17.1%)1 (0.5%)13 (6.2%)50 (23.8%)1 (0.5%)109 (51.9%)No initial VTE treatment n=554; 9.4%81 (14.6%)1 (0.2%)45 (8.1%)181 (32.7%)0 (0.0%)246 (44.4%)* Patients with no treatment within 30 days after hospital discharge were censored at 30-days post-dishcarge Citation Format: Jennifer D. Guo, Patrick Hlavacek, Tayla Poretta, Gail Wygant, Daniel C. Lane, Magdaliz Gorritz, Xin Wang, Chi-Chang Chen, Xianying Pan, Lisa Rosenblatt. Treatment patterns in patients with cancer-associated venous thromboembolism in the US: A real world retrospective database analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3367.

Uterine Radial Artery Resistance Index Predicts Reproductive Outcome in Women with Recurrent Pregnancy Losses and Thrombophilia.

Uterine radial artery resistance index (URa-RI) by Doppler ultrasound may reflect the changes in the uteroplacental circulation and be associated with adverse events in early pregnancy. Recurrent pregnancy losses (RPL) are associated with thrombophilia, and anticoagulation treatment with low molecular weight heparin improves pregnancy outcome in women with RPL and thrombophilia. A retrospective cohort study was conducted in 139 pregnant women with 3 or more RPL and thrombophilia. The relationship between pregnancy outcome and dynamic changes of URa-RI was analyzed in 116 women who delivered a liveborn infant and 23 who miscarried the index pregnancy. Patients were on preconception low molecular weight heparin, low-dose aspirin (81mg per day), and prednisone treatment. URa-RI was measured during periovulation time, at the time of positive pregnancy test, and then repeated every two weeks until 32-week gestation or the time of miscarriage. The URa-RI at 8-week gestation was significantly higher in women who miscarried the index pregnancy than those who delivered alive born infant (0.51±0.08 vs. 0.42±0.03, P<0.001). Receiver operating characteristic curve analysis demonstrated that URa-RI of 8 wk gestation effectively distinguished women who miscarried from those who had a live birth with an area under the curve of 82.6% (95% CI 69.01-97.17). After adjusting for covariates including age, BMI, and number of miscarriages, multiple logistic regression models showed that each 0.1 unit increase of URa-RI of 8 wk gestation was associated with 18.70-point increase in the risk of miscarriage (OR19.70, 95%CI 4.26-91.1, P<0.001), and women with an URa-RI≥0.45 had an OR of 49.48 (95% CI 8.01-307.95; P<0.001) for miscarriage compared to those who had URa-RI<0.45. In women with RPL and inherited thrombophilia, increased URa-RI at 8-week gestation was associated with spontaneous abortion independent of other risk factors while they were on anticoagulation treatment.

Extended treatment with non-vitamin K antagonist oral anticoagulants versus low-molecular-weight heparins in cancer patients following venous thromboembolism. A pilot study

BackgroundLow-molecular-weight heparins (LMWH) are the drug of choice for treatment of cancer-associated thrombosis (CAT), however non-vitamin K antagonist oral anticoagulants (NOAC) seem to be a reasonable alternative. We investigated the safety and efficacy of NOAC versus LMWH in patients with a history of CAT. MethodsIn a prospective cohort study 128 consecutive patients with active cancer who experienced CAT were enrolled following LMWH treatment for ≥3 months. Symptomatic recurrent venous thromboembolism (VTE), bleeding and death were recorded during follow-up. Results65 (50.8%) patients were switched to NOAC and 63 (49.2%) continued with LMWH. During a median follow-up of 17 (interquartile range, 15–21) months, recurrent VTE was observed in 6 (9.2%) patients on NOAC and in 12 (19.0%) on LMWH (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.16–1.16). The rate of major bleeding was 9.2% and 4.8%, respectively (HR 2.00, 95% CI 0.50–8.00). The median time to bleeding was shorter in patients on NOAC (3 [2.25–5.5] months) versus on LMWH (9 [6.5–13.0] months). The mortality rates were similar in both groups (15.4% versus 15.9%, respectively, HR 0.76, 95% CI 0.32–1.84). ConclusionsIn patients following CAT, extended treatment with NOAC, compared with LMWH, appears to be associated with similar effectiveness and safety.

Clinical utility of thrombophilia, anticoagulant treatment, and maternal variables as predictors of placenta-mediated pregnancy complications: an extensive analysis

Objective: The objective of this study is to analyze the usefulness of thrombophilia and antithrombotic drugs in combination with materno-fetal characteristics to generate a predictive model of placenta-mediated pregnancy complications (PMPC) for counseling treatment.Methods: A retrospective analysis was performed in women with singleton pregnancy that required a thrombophilia study, including 222 patients with unknown cause PMPC and 151 women with no complications at current pregnancy in Hospital Clínico Universitario, Lozano, Blesa, Zaragoza, Spain. Chi-squared and Mann–Whitney test were applied to analyze univariate risk factors. Multivariate analysis was performed using logistic regression model with candidate variables: maternal characteristics, obstetric history, thrombophilia, and treatment with low-molecular-weight heparin (LMWH) and/or with acid acetylsalicylic (ASA). The calibration, discrimination, and best cutoff point for the clinical application of the model was analyzed.Results: Maternal characteristics showed differences in median body mass index (BMI), odds ratio (OR): 0.4, smoking habit, OR: 8.5, and hypertension, OR: 11.4, appearing all of them as risk factors. In our study, a prior pregnancy that ended in a child alive was a protective factor OR: 0.02–0.4, and having a previous preterm child was a strong risk factor OR: 4.2. Thrombophilia was not a risk factor. Patients under LMWH treatment (15%) and/or ASA (6.2%) had better pregnancy outcomes, showing both as protective factors: ASA OR: 0.32 and LMWH OR: 0.16. The model has an AUC value of 0.847, with good calibration. A nomogram and an app is provided for this adjusted model with high discrimination ability in internal validation (AUC = 0.833). Our clinical utility analysis guide us to choose 40% as the best threshold probability.Conclusions: We found risk and protective factors associated with PMPC, but our data were not conclusive to demonstrate its relation with maternal thrombophilia. However, the challenger finding is the clinical utility of antithrombotic drugs as a protective factors in PMPC prevention. It is possible to identify patients with high risk of PMPC through a combined predictive model, for counseling treatment.

Factors influencing patient's perception of long-term treatment with low-molecular-weight heparins for cancer-associated thrombosis: an updated analysis of TROPIQUE, a prospective observational study.

Our objective was to compare patient's expectations to their experience and to identify factors predictive of patient's perception of long-term LMWH for the treatment of cancer-associated thrombosis (CAT). Results from the validated Perception Anticoagulant Treatment Questionnaires (PACTQ) completed before inclusion (PACTQ1 for expectations) and at the end (PACTQ2 for convenience and satisfaction) of the 6-month TROPIQUE study were studied with principal component analysis. Possible predictive factors of improved perception of LMWH treatment were analyzed with the Kruskall-Wallis test. Among 409 included patients treated with LMWH, 269 PACT-Q1 and 139 PACT-Q2 were evaluable for treatment perception. Patients had high expectations (A1-A7 score of 26.7 ± 3.5, max = 35). Treatment cost (A7 = 1.90 ± 1.31) and concern about a mistake in anticoagulation (A5 = 1.93 ± 1.12) had little importance while LMWH treatment was considered easy to use (A4 = 4.20 ± 0.93). Six-month treatment with LMWH was associated with a high rate of convenience (B1-B11, C1-C2 = 55.1 ± 8.38, max = 65) and a high satisfaction score (D1-D7 = 25.1 ± 4.32, max = 35). Patients' confidence in treatment and perception of possible LMWH side effects were moderate while perception of autonomy and independence significantly improved at the end of the study compared to inclusion. PACT-Q2 satisfaction score was low in patients who experienced bleeding (PACT-Q2 24.1 ± 3.3 vs. 25.1 ± 4.3). LMWH twice daily tended to be found less convenient compared than once daily (53.3 ± 7.2 vs. 55.0 ±8.3). CAT patients had a good perception of the 6-month LMWH treatment when comparing expectations and experience. Using a quantitative scale validated in the general population for VTE and subcutaneous injection and including a large number of patients, bleeding complications and LMWH twice daily were associated with a nonsignificant trend towards a worsen perception.

Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants.

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.