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1.
Efficacy and Safety of Low-Molecular-Weight Heparin on Prevention of Venous Thromboembolism after Laparoscopic Operation for Gastrointestinal Malignancy in Japanese Patients: A Multicenter, Open-Label, Prospective, Randomized Controlled Trial.
Obitsu, T, Tanaka, N, Oyama, A, Ueno, T, Saito, M, Yamaguchi, T, Takagi, A, Rikiyama, T, Unno, M, Naitoh, T, et al
Journal of the American College of Surgeons. 2020;(5):501-509.e2
Abstract
BACKGROUND The risk of venous thromboembolism (VTE) after surgery for malignancy in Japanese patients is unclear; therefore, standard prevention protocols have not been established, especially for minimally invasive procedures. We aimed to investigate the additional effect of low molecular weight heparin (LMWH) on prevention of VTE after laparoscopic surgery for gastrointestinal malignancy. STUDY DESIGN From February 2013 to January 2017, 400 patients scheduled for laparoscopic surgery were included. Cases were randomly allocated to the physical therapy group (Control group; 201 patients) or to the combination-therapy group (LMWH group; 199 patients), in which enoxaparin sodium (20 mg [= 2000 IU] twice a day) was administered for 1 week postoperatively in addition to the physical therapy. A diagnosis of VTE was made by contrast-enhanced CT or ultrasonography when symptomatic or D-dimer was ≥10 μg/mL. RESULTS VTE was observed in 1.2% and 4.0% of patients in the LMWH and Control groups, respectively (odds ratio [OR] 0.3, 95% confidence interval [CI] 0.03-1.53). Pulmonary embolism was confirmed only in the Control group (1.7%). No major bleeding occurred in either group. Logistic multiple regression analysis revealed that surgical time extension (OR 1.02, 95% CI 1.00-1.04) was a risk factor of VTE, while administration of LMWH (OR 0.21, 95% CI 0.03-0.99), male sex (OR 0.12, 95% CI 0.01-0.60), and early cancer (OR 0.17, 95% CI 0.02-0.82) reduced the risk of VTE. CONCLUSIONS Postoperative LMWH administration is safe. The additional effect of LMWH administration on the physical therapy was not statistically proven in this study. However, it could be useful for the patients with risk factors such as female sex, long operation time, and higher cancer stage.
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2.
Low-Molecular-Weight Heparin for the Treatment of Unexplained Recurrent Miscarriage With Negative Antiphospholipid Antibodies: A Randomized Controlled Trial.
Shaaban, OM, Abbas, AM, Zahran, KM, Fathalla, MM, Anan, MA, Salman, SA
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2017;(6):567-572
Abstract
BACKGROUND Recurrent miscarriage (RM) is one of the most common clinical problems in reproduction with no definite cause in about 50% of the cases. The study aims to evaluate the effect of low-molecular-weight heparin (LMWH) in the treatment of women with RM negatively tested for antiphospholipid antibodies (APAs). METHODS An open-labeled registered randomized controlled study (NCT 01608347) included women who attended the outpatient clinic in Assiut Women Health Hospital and Nag-Hamady Central Hospital, Egypt, with 3 or more unexplained RM. Eligible participants were randomly assigned into 2 groups. The study group included 150 patients receiving LMWH (Tinzaparin sodium 4500 IU) subcutaneous daily injection with 500 µg folic acid once daily orally started once positive pregnancy test till the 20th week of gestation. The control group included 150 patients receiving the same dose of folic acid alone. The primary outcome of the study was the rate of continuation of a viable pregnancy after 20 weeks of gestation. RESULTS There was no significant difference between both groups as regards age, parity, or number of previous miscarriages. There was a significant increase in women who continued their pregnancy beyond 20 weeks in the study group compared to the control group (73.3% vs 48%, respectively; P = .002). The take-home baby rate was also significantly higher in the LMWH group compared to the control group ( P = .001). CONCLUSION Early start of LMWH decreases the incidence of miscarriage in the first 20 weeks of pregnancy in women with unexplained RM negative for APAs.
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3.
Pharmacokinetics of Certoparin During In Vitro and In Vivo Dialysis.
Krieter, DH, Fink, S, Dorsch, O, Harenberg, J, Melzer, N, Wanner, C, Lemke, HD
Artificial organs. 2015;(11):951-9
Abstract
The efficacy and safety of certoparin in the prophylaxis of clotting during hemodialysis have recently been proven. Different to other low-molecular weight heparins (LMWHs), certoparin does not accumulate in maintenance dialysis patients for unknown reasons. The purpose of the present study was to examine the impact of the dialysis procedure on the removal of certoparin. In a subgroup of the MEMBRANE study consisting of 12 patients, the pharmacokinetics of certoparin during hemodialysis was determined by means of the anti-Xa activity. In addition, the elimination of certoparin into continuously collected dialysate was assessed. Further, in vitro experiments with human blood-simulating high-flux hemodialysis and hemofiltration were performed to quantify the elimination and the sieving coefficients SK of the two LMWHs certoparin and enoxaparin compared with unfractionated heparin (UFH). The surrogate marker middle molecules inulin and myoglobin served as reference solutes during the experiments. Finally, the adsorption of (125) iodine-radiolabeled certoparin onto the synthetic dialysis membrane was quantified. The clinical study reconfirmed the absence of bioaccumulation of certoparin with anti-Xa activities between <0.01 and 0.02 IU/mL after 24 h. A short plasma half-life time of 2.0 ± 0.7 h was determined during hemodialysis. Of the total certoparin dose injected intravenously prior to hemodialysis, only 2.7% was eliminated into dialysate. The in vitro experiments further revealed only 6% of certoparin to be adsorbed onto the dialysis membrane. The anti-Xa activities of certoparin and enoxaparin slowly declined during in vitro hemofiltration to 87.3 ± 5.5 and 82.5 ± 9.4% of baseline, respectively, while inulin and myoglobin concentrations rapidly decreased. The anti-Xa activity of UFH remained unchanged. The SK of both LMWH and UFH was very low in hemofiltration and particularly in hemodialysis with values ≤0.1. The elimination kinetics during hemodialysis suggests strong protein-binding of certoparin. Different from LMWH significantly cleared by the kidneys, the relatively short half-life time of certoparin of only 2 h during hemodialysis allows a more reliable control of the anti-coagulatory effects and decreases the risk of bleeding complications. Dialytic removal does not significantly contribute to the clearance of certoparin in maintenance dialysis patients.
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4.
A randomised open-label trial comparing long-term sub-cutaneous low-molecular-weight heparin compared with oral-anticoagulant therapy in the treatment of deep venous thrombosis.
Romera, A, Cairols, MA, Vila-Coll, R, Martí, X, Colomé, E, Bonell, A, Lapiedra, O
European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2009;(3):349-56
Abstract
OBJECTIVE To evaluate whether low-molecular-weight heparin (LMWH) could be equally (or more) effective than oral anti-vitamin-K agents (AVK) in the long-term treatment of deep venous thrombosis (DVT). DESIGN A randomised, open-label trial. MATERIAL AND METHODS In this trial, 241 patients with symptomatic proximal DVT of the lower limbs confirmed by duplex ultrasound scan were included. After initial LMWH, patients received 6 months of treatment with full therapeutic dosage of tinzaparin or acenocoumarol. The primary outcome was the 12-month incidence of symptomatic recurrent venous thrombo-embolism (VTE). Duplex scans were performed at 6 and 12 months. RESULTS During the 12-month period, six patients (5%) of 119 who received LMWH and 13 (10.7%) of 122 who received AVK had recurrent VTE (p=0.11). In patients with cancer, recurrent VTE tended to be lower in the LMWH group (two of 36 [5.5%]) vs. seven of 33 [21.2%]; p=0.06). One major bleeding occurred in the LMWH group and three in the AVK group. Venous re-canalisation increased significantly at 6 months (73.1% vs. 47.5%) and at 12 months (91.5% vs. 69.2%) in the LMWH group. CONCLUSIONS Tinzaparin was more effective than AVK in achieving re-canalisation of leg thrombi. Long-term tinzaparin was at least as efficacious and safe as AVK for preventing recurrent VTE, especially in patients with cancer.
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5.
Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer.
Hull, RD, Pineo, GF, Brant, RF, Mah, AF, Burke, N, Dear, R, Wong, T, Cook, R, Solymoss, S, Poon, MC, et al
The American journal of medicine. 2006;(12):1062-72
Abstract
PURPOSE A substantial clinical need exists for an alternative to vitamin K antagonists for treating deep-vein thrombosis in cancer patients who are at high risk of both recurrent venous thromboembolism and bleeding. Low-molecular-weight heparin, body-weight adjusted, avoids anticoagulant monitoring and has been shown to be more effective than vitamin-K-antagonist therapy. SUBJECTS AND METHODS Subjects were patients with cancer and acute symptomatic proximal-vein thrombosis. We performed a multi-centre randomized, open-label clinical trial using objective outcome measures comparing long-term therapeutic tinzaparin subcutaneously once daily with usual-care long-term vitamin-K-antagonist therapy for 3 months. Outcomes were assessed at 3 and 12 months. RESULTS Of 200 patients, 100 received tinzaparin and 100 received usual care. At 12 months, the usual-care group had an excess of recurrent venous thromboembolism; 16 of 100 (16%) versus 7 of 100 (7%) receiving low-molecular-weight heparin (P=.044; risk ratio=.44; absolute difference -9.0; 95% confidence interval [CI], -21.7 to -0.7). Bleeding, largely minor, occurred in 27 patients (27%) receiving tinzaparin and 24 patients (24%) receiving usual care (absolute difference -3.0; 95% CI, -9.1 to 15.1). In patients without additional risk factors for bleeding at the time of randomization, major bleeding occurred in 0 of 51 patients (0%) receiving tinzaparin and 1 of 48 patients (2.1%) receiving usual care. Mortality at 1 year was high, reflecting the severity of the cancers; 47% in each group died. CONCLUSION Our findings confirm the limited but benchmark data in the literature that long-term low-molecular-weight heparin is more effective than vitamin-K-antagonist therapy for preventing recurrent venous thromboembolism in patients with cancer and proximal venous thrombosis.
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6.
Comparative efficacy of once daily parnaparin and unfractionated heparin in unstable angina pectoris: PRIME CARE study.
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Indian heart journal. 2005;(6):648-54
Abstract
BACKGROUND This study sought to compare the efficacy of low molecular weight heparin, parnaparin and unfractionated heparin in Indian patients presenting with unstable angina pectoris. METHODS AND RESULTS In this randomized, prospective and multicentre trial 897 adult patients of both sexes suffering from unstable angina were included. All patients also received oral aspirin and adequate anti-anginal treatment as per their individual needs. Patients in unfractionated heparin group received unfractionated heparin as an intravenous bolus of 5000 IU followed by an intravenous infusion of 800 to 1000 IU/hour for 48 hours, followed by 5000 IU subcutaneously every 6 hours for 5 days. The patients in the other group were treated with parnaparin sodium 6400 IU subcutaneously once daily for 7 days. In the unfractionated heparin group there were 446 patients (310 males, 136 females) with a mean age of 55.9 + 12.27 years and in parnaparin group 451 patients (312 males, 139 females) with a mean age of 57.6 +/- 11.19 years. Both the groups were similar with respect to age and sex (p = 0.89 and 0.068, respectively). The associated cardiovascular risk factors such as diabetes, hypertension, dyslipidemia, previous myocardial infarction and previous coronary artery bypass grafting/percutaneous transluminal coronary angioplasty were similar in both the groups. At the end of 7 days, the primary end points (death, myocardial infarction, or need for myocardial revascularization) were reported in 33 (7.32%) patients in parnaparin group and 51 (11.43%) patients in unfractionated heparin group. This difference was statistically significant. At the end of 30 days, data from 330 patients from parnaparin group and 334 patients from unfractionated heparin group was available for analysis. The cumulative event rate of primary end points at the end of 30 days was reported in 40 (12.12%) patients in parnaparin group and in 73 (21.86%) patients in unfractionated heparin group. This difference was statistically significant. Two episodes of major bleeding each were reported in both the groups. Minor bleeding was reported by 12 (2.66%) patients in parnaparin group and by 115 (25.8%) patients in unfractionated heparin group. This difference was statistically significant. CONCLUSIONS Addition of parnaparin to the standard treatment of unstable angina significantly reduced the incidence of combined triple end points of death, myocardial infarction and need for revascularization when compared to unfractionated heparin. This benefit was observed at 7 days as well as at 30 days of follow-up. The incidence of minor bleeding was significantly less in patients treated with parnaparin. Thus, once daily administration of parnaparin 6400 IU as a fixed dose is a safe and effective alternative to unfractionated heparin in the treatment of unstable angina.
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7.
An open-label, comparative study of the efficacy and safety of once-daily dose of enoxaparin versus unfractionated heparin in the treatment of proximal lower limb deep-vein thrombosis.
Ramacciotti, E, Araújo, GR, Lastoria, S, Maffei, FH, Karaoglan de Moura, L, Michaelis, W, Sandri, JL, Dietrich-Neto, F, ,
Thrombosis research. 2004;(3):149-53
Abstract
BACKGROUND Treatment of deep-vein thrombosis (DVT) with a once-daily regimen of enoxaparin, rather than a continuous infusion of unfractionated heparin (UFH) is more convenient and allows for home care in some patients. This study was designed to compare the efficacy and safety of these two regimens for the treatment of patients with proximal lower limb DVT. METHODS 201 patients with proximal lower limb DVT from 13 centers in Brazil were randomized in an open manner to receive either enoxaparin [1.5 mg/kg subcutaneous (s.c.) OD] or intravenous (i.v.) UFH (adjusted to aPTT 1.5-2.5 times control) for 5-10 days. All patients also received warfarin (INR 2-3) for at least 3 months. The primary efficacy endpoint was recurrent DVT (confirmed by venography or ultrasonography), and safety endpoints included bleeding and serious adverse events. The rate of pulmonary embolism (PE) was also collected. Hospitalization was at the physician's discretion. RESULTS Baseline patient characteristics were comparable between groups. The duration of hospital stay was significantly shorter with enoxaparin than with UFH (3 versus 7 days). In addition, 36% of patients receiving enoxaparin did not need to be hospitalized, whereas all of the patients receiving UFH were hospitalized. The treatment duration was slightly longer with enoxaparin (8 versus 7 days). There was a nonsignificant trend toward a reduction in the rate of recurrent DVT with enoxaparin versus UFH, and similar safety. CONCLUSIONS A once-daily regimen of enoxaparin 1.5 mg/kg subcutaneous is at least as effective and safe as conventional treatment with a continuous intravenous infusion of UFH. However, the once daily enoxaparin regimen is easier to administer (subcutaneous versus intravenous), does not require aPTT monitoring, and leads to both a reduced number of hospital admissions and an average 4-day-shorter hospital stay.
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8.
A pilot randomized double-blind comparison of a low-molecular-weight heparin, a nonsteroidal anti-inflammatory agent, and placebo in the treatment of superficial vein thrombosis.
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Archives of internal medicine. 2003;(14):1657-63
Abstract
BACKGROUND The efficacy and safety of antithrombotic treatment in patients with superficial vein thrombosis remain to be established in adequately designed trials. METHODS In a double-blind trial, 427 patients older than 18 years, with documented acute symptomatic superficial vein thrombosis of the legs, were randomly assigned to receive subcutaneous enoxaparin sodium, 40 mg; subcutaneous enoxaparin, 1.5 mg/kg; oral tenoxicam; or placebo, once daily for 8 to 12 days. The primary efficacy outcome was deep venous thromboembolism between days 1 and 12, defined as deep vein thrombosis detected by ultrasonography between days 8 and 12 or earlier if clinically indicated, or documented symptomatic pulmonary embolism. For the secondary efficacy outcomes, superficial vein thrombosis recurrence or extension was also considered. RESULTS The incidence of deep venous thromboembolism by day 12 was 3.6% (4 of 111 patients) in the placebo group, 0.9% (1 of 109 patients) in the 40-mg enoxaparin group (P =.37 vs placebo), 1.0% (1 of 102 patients) in the 1.5-mg/kg enoxaparin group (P =.37 vs placebo), and 2.1% (2 of 94 patients) in the tenoxicam group (P =.69 vs placebo). The incidence of deep and superficial venous thromboembolism by day 12 was significantly reduced in all active treatment groups, from 30.6% (34 of 111 patients) in the placebo group to 8.3% (9 of 109 patients), 6.9% (7 of 102 patients), and 14.9% (14 of 94 patients) in the 40-mg enoxaparin (P<.001), 1.5-mg/kg enoxaparin (P<.001), and tenoxicam (P<.01) groups, respectively. No death or major hemorrhage occurred during the study. CONCLUSION Treatment with a low-molecular-weight heparin or with an oral nonsteroidal anti-inflammatory agent should be evaluated further in the prevention of thromboembolic complications in patients with superficial vein thrombosis.
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9.
Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group.
Hull, RD, Raskob, GE, Brant, RF, Pineo, GF, Elliott, G, Stein, PD, Gottschalk, A, Valentine, KA, Mah, AF
Archives of internal medicine. 2000;(2):229-36
Abstract
BACKGROUND Pulmonary embolism (PE) occurs in 50% or more of patients with proximal deep-vein thrombosis. Low-molecular-weight heparin treatment is effective and safe in patients with deep vein thrombosis and may also be so in patients with PE. Recent rigorous clinical trials have established objective criteria for determining a high probability of PE by perfusion lung scanning. OBJECTIVE To compare low-molecular-weight heparin with intravenous heparin for the treatment of patients with objectively documented PE and underlying proximal deep vein thrombosis. METHODS In a multicenter, double-blind, randomized trial, we compared fixed-dose subcutaneous low-molecular-weight heparin (tinzaparin sodium) given once daily with dose-adjusted intravenous heparin given by continuous infusion using objective documentation of clinical outcomes. Pulmonary embolism at study entry was documented by the presence of high-probability lung scan findings. RESULTS Of 200 patients with high-probability lung scan findings at study entry, none of the 97 who received low-molecular-weight heparin had new episodes of venous thromboembolism compared with 7 (6.8%) of 103 patients who received intravenous heparin (95% confidence interval for the difference, 1.9%-11.7%; P = .01). Major bleeding associated with initial therapy occurred in 1 patient (1.0%) who was given low-molecular-weight heparin and in 2 patients (1.9%) given intravenous heparin (95% confidence interval for the difference, -2.4% to 4.3%). CONCLUSIONS Low-molecular-weight heparin administered once daily subcutaneously was no less effective and probably more effective than use of dose-adjusted intravenous unfractionated heparin for preventing recurrent venous thromboembolism in patients with PE and associated proximal deep vein thrombosis. Our findings extend the use of low-molecular-weight heparin without anticoagulant monitoring to patients with submassive PE.