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1.
Genetic polymorphisms in the FVII gene is associated with lower extremity deep venous thrombosis: A case-control study.
Liu, JW, Chen, DQ
Journal of cellular biochemistry. 2018;(8):6715-6722
Abstract
This study aims to explore the associations between FVII gene polymorphisms (R353Q, 5'F7, and -402G/A) and lower extremity deep venous thrombosis (LEDVT) in a Chinese Han population. LEDVT patients (153) and healthy people (174) were, respectively, as case and control groups and evaluated related biochemical indicators. Gene polymorphisms of R353Q, 5'F7, and -402G/A of FVII, serum FVII level, antithrombin activity, plasma fibrinogen content, and plasma D-dimer (D-D) level were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), ELISA, chromogenic substrate assay, coagulating assay, and Immunoturbidimetry assay, respectively. Compared with the control group, the case group had a higher level of body mass index (BMI), glucose, and fibrinogen, and lower level of total cholesterol (TC). Notable differences were found in GG genotype, G and A alleles, as well as distribution of recessive model of -402G/A. The serum FVII level of GG genotype was higher than that of GA and AA genotypes. FIB and D-D had a higher level had a lower level in GG genotype when compared with GA and AA genotypes. Smoking, drinking, serum FVII level, and -402G/A-GG were the independent risk factors for LEDVT. This study demonstrates that -402G/A of FVII may be a risk factor for LEDVT patients in a Chinese Han population.
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Apixaban-induced subdural bleeding: case presentation and literature review.
Alayad, E, Khairy, S, Aloraidi, A
BMJ case reports. 2018
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Abstract
Apixaban is a factor Xa inhibitor which is a non-vitamin K dependent oral anticoagulant known tocause the lowest rate of intracranial bleeding among the same kind of inibitors. In this paper, we report a rare case in a 60-year-old man with a history of hypertension and oligodendroglioma on apixaban for deep venous thrombosis who presented to our hospital with decreased level of consciousness and slurred speech with rapid deterioration. We highlight the risk of subdural bleeding requiring immediate neurosurgical intervention due to apixaban, with literature review.
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Rationale, design, and protocol of a randomized controlled trial of the safety and efficacy of dabigatran etexilate versus dose-adjusted warfarin in patients with cerebral venous thrombosis.
Ferro, JM, Dentali, F, Coutinho, JM, Kobayashi, A, Caria, J, Desch, M, Fraessdorf, M, Huisman, H, Diener, HC
International journal of stroke : official journal of the International Stroke Society. 2018;(7):766-770
Abstract
Rationale To prevent recurrent venous thrombotic events after acute cerebral venous or dural sinus thrombosis, guidelines recommend long-term oral anticoagulation with vitamin K antagonists. Non-vitamin K oral anticoagulant experience in cerebral venous or dural sinus thrombosis is limited to case reports and series. Aim To compare dabigatran with dose-adjusted warfarin in patients with cerebral venous or dural sinus thrombosis for the prevention of recurrent venous thrombotic event. Sample size One hundred and twenty patients. Methods and design This study is a phase III, prospective, randomized, parallel-group, open-label, multicenter, exploratory trial with blinded endpoint adjudication. Patients with acute cerebral venous or dural sinus thrombosis after 5-15 days of treatment with parenteral heparin are randomized to either dabigatran etexilate 150 mg twice daily or dose-adjusted (international normalized ratio 2-3) warfarin (≤24 weeks). Study outcome The primary endpoint is a composite of patients with new venous thrombotic event (recurring cerebral venous or dural sinus thrombosis, deep venous thrombosis of any limb, pulmonary embolism, and major bleeding (International Society on Thrombosis and Hemostasis definition)) during the treatment period. Statistics will be descriptive (number and frequencies). Study timelines Inclusion started in December 2016. Final results are expected by the end of 2018. Discussion This exploratory trial is the first to compare vitamin K with non-vitamin K antagonists in cerebral venous or dural sinus thrombosis. It will provide evidence to guide physicians and patients in choosing oral anticoagulants to prevent venous thrombotic event after acute cerebral venous or dural sinus thrombosis. ClinicalTrials.gov number: NCT02913326.
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The relationship between gene polymorphism of MTRR A66G and lower extremity deep venous thrombosis.
Xu, J, Zhou, W
Hematology (Amsterdam, Netherlands). 2018;(10):828-832
Abstract
OBJECTIVE To investigate the relationship between gene polymorphism of MTRR A66G and lower extremity deep venous thrombosis (DVT). METHODS Two hundred and two patients with DVT as experimental group and 240 normal adults (control group) were enrolled in this study and white blood cells were collected, respectively. Polymorphism of the 66 loci in MTRR gene was detected by polymerase chain reaction-sequence-specific primers (PCR-SSP) in two groups. The frequency of genotype and allele distribution of each group was compared. RESULTS The frequency of AA, AG and GG genotypes in 66 sites of MTRR gene were 26.76%, 4 3.66% and 29.58% in DVT group and 43.57%, 44.28% and 12.14% in control group, respectively. There was no significant difference in the distribution frequency between two groups (χ = 3.2, P > .5). CONCLUSIONS The gene polymorphism of MTRR A66G may not be an independent genetic risk factor in DVT in China.
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Heparin promotes recanalization of venous thrombotic occlusions.
Poredos, P, Poredos, P, Jezovnik, MK
International angiology : a journal of the International Union of Angiology. 2018;(4):261-268
Abstract
Thrombosis is a consequence of disbalance between the procoagulant and fibrinolytic activity of blood and is frequently associated with chronic sequelae, which are the consequence of chronic occlusion of affected veins. Treatment of venous thrombosis should not be oriented in the prevention of thrombus progression and associated thromboembolic events, but also in stimulation of thrombolysis and recanalization of occluded veins, which are one of the most important preventive mechanisms of late sequelae, including post-thrombotic syndrome. The treatment of acute venous thrombosis (superficial and deep) is based on drugs with anticoagulant activity, like antagonists of vitamin K, heparins, and new oral anticoagulants. One of the most frequently used anticoagulant drugs is heparin, particularly the low molecular weight heparin (LMWH). It was shown that besides strong anticoagulant activity heparin has pro-fibrinolytic effects, which promote thrombolysis and recanalization of occluded veins. LMWH markedly increases tissue factor pathway inhibitor levels and a release of tissue plasminogen activator from vascular endothelium. Heparins are also capable of increasing the nitrogen oxide level, which is responsible for circulatory homeostasis.
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Phase II Study of Sorafenib Combined with Concurrent Hepatic Arterial Infusion of Oxaliplatin, 5-Fluorouracil and Leucovorin for Unresectable Hepatocellular Carcinoma with Major Portal Vein Thrombosis.
He, MK, Zou, RH, Li, QJ, Zhou, ZG, Shen, JX, Zhang, YF, Yu, ZS, Xu, L, Shi, M
Cardiovascular and interventional radiology. 2018;(5):734-743
Abstract
BACKGROUND Sorafenib is recommended for the first-line treatment of advanced hepatocellular carcinoma (HCC). However, the median progression-free survival (PFS) of patients with HCC and major portal vein tumor thrombosis treated with sorafenib monotherapy is no more than 3 months. A prospective single-arm phase II study was conducted to determine whether adding hepatic arterial infusion chemotherapy of oxaliplatin, 5-fluorouracil and leucovorin to sorafenib could improve on these results. METHODS Thirty five patients were treated with sorafenib 400 mg orally twice a day, oxaliplatin 85 mg/m2 HAI on day 1, leucovorin 400 mg/m2 HAI on days 1, and 5-fluorouracil 2800 mg/m2 on days 1 and 2, repeated every 21 days. The primary end point was the 3-month PFS rate. RESULTS The 3-, 6-, and 12-month PFS rates were 82.9, 51.4, and 22.9%, respectively. The median PFS and overall survival was 6.7 and 13.2 months, respectively. The objective response rate was 40%, and the disease control rate was 77.1% by RECIST criteria. Five (14.3%) patients achieved conversion to complete resection after the study treatment, and one of them experienced a pathological complete response. Treatment-related deaths did not occur. Grade 3-4 toxicities consisted of increases in aspartate aminotransferase (31.4%), hand-foot syndrome (17.1%), thrombocytopenia (14.3%), and neutropenia (8.6%). CONCLUSIONS The combination treatment met the pre-specified end point of a 3-month progression free survival rate exceeding 65% and was clinical tolerable. The merits of this approach need to be established with a phase III trial. Clinical trial number http://ClinicalTrials.gov (No. NCT02981498).
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Clinical observation of the efficacy of low-molecular-weight heparin calcium in prophylaxis of the deep venous thrombosis following the gynecological tumor surgery.
Wei, N, Qi, Y, Yang, H, Guo, L
Pakistan journal of pharmaceutical sciences. 2018;(6(Special)):2835-2839
Abstract
Present study is conducted to investigate the efficacy and safety of application of low-molecular-weight heparin calcium in the prophylaxis of deep venous thrombosis (DVT) following the laparoscopic surgery for gynecological tumors, so as to provide reference for the selection of anti-coagulant procedure in clinical practice. A total of 180 patients who underwent the laparoscopic surgery for the gynecological tumors in this hospital between January 2015 and December 2017 were enrolled in this study, and according to the anti-coagulant procedure, they were divided into two groups, i.e. the control group and the observation group, with 90 patients in each group. In the control group, 90 patients were free from the anti-coagulant agent or drugs affecting the coagulant functions, while those in the observation group received the subcutaneous injection of low-molecular-weight heparin calcium for consecutive 5 days. Then we compared the serological indicators, prothrombin time (PT), cross-section diameter of the lower limb, hemodynamic indicator and the incidence rate of complications. Following postoperative 5 days, the levels of fibrinogen and D-dimer in the observation group were (2.66±0.72) g/L and (0.61±0.17) μg/mL, significantly lower than those in the control group, and the differences had statistical significance (t=4.667, P=0.019; t=3.967, P= 0.029). At 3 d and 5 d after operation, PTs in the observation group were (13.74±3.92) s and (13.84±3.13) s, also superior to the control group (t=3.031, P=0.042; t=3.553, P =0.034). In the observation group, the cross-section diameter of lower limb and blood flow rate were (20.22±3.51) cm and (0.93±0.17) m/s, respectively, which were better than the control group, and the difference had statistical significance (t=4.412, P=0.021; t =4.724, P=0.019). In the observation group, the incidence rate of complications was only 3.33%, significantly lower than 10.00% in the control group (c2 =6.158, P=0.004). The application of the low-molecular-weight heparin calcium for anti-coagulation in the prophylaxis of the DVT following the laparoscopic surgery of gynecological tumor can better ameliorate the hemodynamics of patients, and prevent the formation of DVT.
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Developments of Anticoagulants and New Agents with Anti-Coagulant Effects in Deep Vein Thrombosis.
Dang, YP, Chen, YF, Li, YQ, Zhao, L
Mini reviews in medicinal chemistry. 2017;(4):338-350
Abstract
Deep Vein Thrombosis (DVT) has been known as a common medical problem all over the world. Thrombus traveling in blood vessels may lead to pulmonary embolism (PE), associated with high rates of mortality. Anticoagulant therapy is the mainstay treatment of DVT. Common anticoagulants, Vitamin K antagonists (VKAs), unfractionated heparin (UFH) and Low-molecular-weight heparin (LMWH) have been used in clinical application over decades, but can increase the risk of hemorrhage. Thereby, several new oral anticoagulants (NOACs) have been developed, which includes direct thrombin inhibitors (DTI) and direct factor Xa inhibitors. To be contrast with VKAs and UFH, NOACs have many advantages such as rapid offset action, few drug/food interactions and no need for routine coagulation monitoring, etc. Many NOACs are still being evaluated in Phase III clinical trials such as Betrixaban and Darexaban (YM150). However, NOACs still have problems to be solved such as lack of antidotes and laboratory monitoring, high drug costs, etc. Besides, several agents have already shown the potential to be new anticoagulants. Factor Xa play an important role in thrombin generation and coagulation pathway. Thus, the new compounds directly targeting on factor Xa for prevention DVT are highly anticipated. DPC423, a new series of 6-substituted coumarin derivatives and Phenyltriazolinones as potent factor Xa inhibitors have been recently reported. Recent studies revealed that agents extracted from botanicals not only have anti-coagulant effects but also possess other pharmacological activities such as anti-inflammation to alleviate the post-thrombotic syndromes. All the evidence above suggests that many new compounds might have great potential to be more effective and safe oral anticoagulants.
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Platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis.
Colli, A, Gana, JC, Yap, J, Adams-Webber, T, Rashkovan, N, Ling, SC, Casazza, G
The Cochrane database of systematic reviews. 2017;(4):CD008759
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Abstract
BACKGROUND Current guidelines recommend screening of people with oesophageal varices via oesophago-gastro-duodenoscopy at the time of diagnosis of hepatic cirrhosis. This requires that people repeatedly undergo unpleasant invasive procedures with their attendant risks, although half of these people have no identifiable oesophageal varices 10 years after the initial diagnosis of cirrhosis. Platelet count, spleen length, and platelet count-to-spleen length ratio are non-invasive tests proposed as triage tests for the diagnosis of oesophageal varices. OBJECTIVES Primary objectives To determine the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices of any size in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology. To investigate the accuracy of these non-invasive tests as triage or replacement of oesophago-gastro-duodenoscopy. Secondary objectives To compare the diagnostic accuracy of these same tests for the diagnosis of high-risk oesophageal varices in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology.We aimed to perform pair-wise comparisons between the three index tests, while considering predefined cut-off values.We investigated sources of heterogeneity. SEARCH METHODS The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE (OvidSP), Embase (OvidSP), and Science Citation Index - Expanded (Web of Science) (14 June 2016). We applied no language or document-type restrictions. SELECTION CRITERIA Studies evaluating the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices via oesophago-gastro-duodenoscopy as the reference standard in children or adults of any age with chronic liver disease or portal vein thrombosis, who did not have variceal bleeding. DATA COLLECTION AND ANALYSIS Standard Cochrane methods as outlined in the Cochrane Handbook for Diagnostic Test of Accuracy Reviews. MAIN RESULTS We included 71 studies, 67 of which enrolled only adults and four only children. All included studies were cross-sectional and were undertaken at a tertiary care centre. Eight studies reported study results in abstracts or letters. We considered all but one of the included studies to be at high risk of bias. We had major concerns about defining the cut-off value for the three index tests; most included studies derived the best cut-off values a posteriori, thus overestimating accuracy; 16 studies were designed to validate the 909 (n/mm3)/mm cut-off value for platelet count-to-spleen length ratio. Enrolment of participants was not consecutive in six studies and was unclear in 31 studies. Thirty-four studies assessed enrolment consecutively. Eleven studies excluded some included participants from the analyses, and in only one study, the time interval between index tests and the reference standard was longer than three months. Diagnosis of varices of any size. Platelet count showed sensitivity of 0.71 (95% confidence interval (CI) 0.63 to 0.77) and specificity of 0.80 (95% CI 0.69 to 0.88) (cut-off value of around 150,000/mm3 from 140,000 to 150,000/mm3; 10 studies, 2054 participants). When examining potential sources of heterogeneity, we found that of all predefined factors, only aetiology had a role: studies including participants with chronic hepatitis C reported different results when compared with studies including participants with mixed aetiologies (P = 0.036). Spleen length showed sensitivity of 0.85 (95% CI 0.75 to 0.91) and specificity of 0.54 (95% CI 0.46 to 0.62) (cut-off values of around 110 mm, from 110 to 112.5 mm; 13 studies, 1489 participants). Summary estimates for detection of varices of any size showed sensitivity of 0.93 (95% CI 0.83 to 0.97) and specificity of 0.84 (95% CI 0.75 to 0.91) in 17 studies, and 2637 participants had a cut-off value for platelet count-to-spleen length ratio of 909 (n/mm3)/mm. We found no effect of predefined sources of heterogeneity. An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P < 0.001) and spleen length (P < 0.001). Diagnosis of varices at high risk of bleeding. Platelet count showed sensitivity of 0.80 (95% CI 0.73 to 0.85) and specificity of 0.68 (95% CI 0.57 to 0.77) (cut-off value of around 150,000/mm3 from 140,000 to 160,000/mm3; seven studies, 1671 participants). For spleen length, we obtained only a summary ROC curve as we found no common cut-off between studies (six studies, 883 participants). Platelet count-to-spleen length ratio showed sensitivity of 0.85 (95% CI 0.72 to 0.93) and specificity of 0.66 (95% CI 0.52 to 0.77) (cut-off value of around 909 (n/mm3)/mm; from 897 to 921 (n/mm3)/mm; seven studies, 642 participants). An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P = 0.003) and spleen length (P < 0.001). DIagnosis of varices of any size in children. We found four studies including 277 children with different liver diseases and or portal vein thrombosis. Platelet count showed sensitivity of 0.71 (95% CI 0.60 to 0.80) and specificity of 0.83 (95% CI 0.70 to 0.91) (cut-off value of around 115,000/mm3; four studies, 277 participants). Platelet count-to-spleen length z-score ratio showed sensitivity of 0.74 (95% CI 0.65 to 0.81) and specificity of 0.64 (95% CI 0.36 to 0.84) (cut-off value of 25; two studies, 197 participants). AUTHORS' CONCLUSIONS Platelet count-to-spleen length ratio could be used to stratify the risk of oesophageal varices. This test can be used as a triage test before endoscopy, thus ruling out adults without varices. In the case of a ratio > 909 (n/mm3)/mm, the presence of oesophageal varices of any size can be excluded and only 7% of adults with varices of any size would be missed, allowing investigators to spare the number of oesophago-gastro-duodenoscopy examinations. This test is not accurate enough for identification of oesophageal varices at high risk of bleeding that require primary prophylaxis. Future studies should assess the diagnostic accuracy of this test in specific subgroups of patients, as well as its ability to predict variceal bleeding. New non-invasive tests should be examined.
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Pentasaccharides for the treatment of deep vein thrombosis.
Brandao, GM, Junqueira, DR, Rollo, HA, Sobreira, ML
The Cochrane database of systematic reviews. 2017;(12):CD011782
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Abstract
BACKGROUND Standard treatment of deep vein thrombosis (DVT) is based on antithrombotic therapy, initially with parenteral administration of unfractionated heparin or low molecular weight heparins (LMWH) for five to seven days, then subsequent long-term therapy with oral vitamin K antagonists (e.g. warfarin). Pentasaccharides are novel anticoagulants that may be favourable over standard therapy due to their predictable effect, no need for frequent monitoring or re-dosing, and few known drug interactions. Heparin-induced thrombocytopenia, a harmful effect of heparins, appears to be rare during treatment with pentasaccharides. OBJECTIVES To assess the efficacy and harms of pentasaccharides for the treatment of deep vein thrombosis. SEARCH METHODS The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (22 March 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2) (searched 22 March 2017). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles for additional citations. SELECTION CRITERIA We included randomised controlled trials in which people 18 years of age or older with a DVT confirmed by standard imaging techniques were allocated to receive a pentasaccharide (fondaparinux, idraparinux, or idrabiotaparinux) for the treatment of DVT in comparison with standard therapy or other treatments. DATA COLLECTION AND ANALYSIS We extracted data characterising the included trials according to the methods, participants, interventions, and outcomes. We assessed risk of bias using Cochrane's 'Risk of bias' tool and employed the GRADE methodology to evaluate the quality of the evidence.The main primary outcome for efficacy was recurrent venous thromboembolism (VTE), and the main primary outcome for harm was major and clinically relevant bleeding. Since our outcomes were dichotomous, we calculated the risk ratio (RR) with a 95% confidence interval (CI). We combined the effects of different comparisons through a meta-analysis using a fixed-effect model. MAIN RESULTS We included five randomised controlled trials of 6981 participants comparing pentasaccharides with standard therapy or other pentasaccharides. The quality of the evidence varied depending on the outcome and was judged as of moderate to very low quality. We downgraded the quality of the evidence due to risk of bias or imprecision, or both.Two studies evaluated fondaparinux, at doses of 5.0 mg, 7.5 mg, and 10.0 mg, plus vitamin K antagonist in comparison with standard therapy. A meta-analysis of these two studies showed no clear difference in the risk of recurrent VTE (RR 0.80, 95% CI 0.43 to 1.47; 2658 participants); moderate-quality evidence. The frequencies of major bleeding were similar between interventions in the initial period of treatment (approximately five days) (RR 1.15, 95% CI 0.39 to 3.44; 2645 participants) and at three months' follow-up (RR 1.05, 95% CI 0.64 to 1.71; 2645 participants). We judged the quality of the evidence as moderate.One study (757 participants) compared idrabiotaparinux (3.0 mg) with idraparinux (2.5 mg) and demonstrated no clear difference in the risk of recurrent VTE at six months' follow-up (RR 0.72, 95% CI 0.31 to 1.69); low-quality evidence. Major bleeding during the initial treatment period was not reported. Major bleeding at six-month follow-up was less frequent in participants receiving idrabiotaparinux versus participants treated with idraparinux (RR 0.21, 95% CI 0.06 to 0.71); low-quality evidence.The effect of an initial treatment with LMWH followed by three months of idraparinux (10 mg) showed no clear difference from standard therapy for risk of recurrent VTE (RR 1.51, 95% CI 0.26 to 8.90; 263 participants); very low-quality evidence; one study. Major bleeding during the initial treatment period was not reported. The frequency of major and other clinically relevant bleeding at three months' follow-up ranged from 2% to 15% in participants receiving LMWH and increasing doses of idraparinux of 2.5 mg, 5 mg, 7.5 mg, or 10 mg. When dosage groups were combined, there was no clear difference in major plus other clinically relevant bleeding or in major bleeding alone between the idraparinux treatment group and the standard therapy group (RR 1.30, 95% CI 0.70 to 2.40; 659 participants; RR 3.76, 95% CI 0.50 to 28.19; 659 participants, respectively); very low-quality evidence.One study (2904 participants) compared idraparinux (2.5 mg) to standard therapy. There was no clear difference in the risk of recurrent VTE at three months' follow-up (RR 0.98, 95% CI 0.64 to 1.48); low-quality evidence. Major bleeding during the initial treatment period was not reported. Major bleeding at three months of follow-up appeared to be similar in the idraparinux group and the standard therapy group (RR 0.71, 95% CI 0.34 to 1.47); very low-quality evidence. AUTHORS' CONCLUSIONS We found moderate-quality evidence that the effects of fondaparinux at doses of 5.0 mg, 7.5 mg, and 10.0 mg plus vitamin K antagonist are similar in terms of recurrent VTE and risk of major bleeding compared with standard treatment for DVT.Low-quality evidence suggests equal efficacy of idraparinux at 2.5 mg and the equimolar dose of 3.0 mg of idrabiotaparinux with regard to recurrent VTE, but a higher frequency of major bleeding was observed in participants treated with idraparinux.We judged evidence on the effectiveness of idraparinux compared with standard therapy, with or without initial treatment with LMWH, and on associated bleeding risk to be low to very low quality, therefore we have very limited confidence in the estimated effects.The observed similar effectiveness in terms of recurrent DVT and harmful effects in terms of bleeding risk with fondaparinux plus vitamin K antagonist compared to standard treatment for DVT suggest that it may be an alternative to conventional anticoagulants for the treatment of DVT in certain circumstances.