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Background: This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously., Methods: We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology., Results: The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update., Conclusion: New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations., (Copyright © 2021. Published by Elsevier Inc.)

Background: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain., Purpose: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups., Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021., Study Selection: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment., Data Extraction: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies., Data Synthesis: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs., Limitation: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs., Conclusion: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE., Primary Funding Source: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Background: In patients with acute deep vein thrombosis (DVT), pharmacomechanical catheter-directed thrombolysis (PCDT) in conjunction with anticoagulation therapy is increasingly used with the goal of preventing postthrombotic syndrome. Long-term costs and cost-effectiveness of these 2 treatment strategies from the perspective of the US healthcare system have not been compared., Methods and Results: Between 2009 and 2014, the ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis) randomized 692 patients with acute proximal DVT to PCDT plus anticoagulation (n=337) or standard treatment with anticoagulation alone (n=355). Costs (2017 US dollars) were assessed over a 24-month follow-up period using a combination of resource-based costing, hospital bills, Medicare reimbursement rates, and the Drug Topics Red Book. Health state utilities were obtained from the Short Form-36. In-trial results and US life tables were used to develop a Markov cohort model to evaluate lifetime cost-effectiveness. For the PCDT group, mean costs of the initial procedure were $13 600; per-patient costs associated with the index hospitalization were $21 509 for PCDT and $3877 for standard care (difference=$17 632; 95% CI, $16 117-$19 243). The 24-month difference in costs was $20 045 (95% CI, $16 093-$24 120). Utility scores increased significantly between baseline and 6 months for both groups, with no significant differences between groups at any follow-up time point. Projected differences in lifetime costs of $16 740 and quality-adjusted life years (QALYs) of 0.08, yield an incremental cost-effectiveness ratio for PCDT of $222 041/QALY gained. In probabilistic sensitivity analysis, the probability that PCDT would achieve a lifetime incremental cost-effectiveness ratio <$50 000/QALY or <$150 000/QALY was 1% and 25%, respectively. For iliofemoral DVT, QALY gains with PCDT were greater, yielding an incremental cost-effectiveness ratio of $137 526/QALY; for femoral-popliteal DVT, standard therapy was an economically dominant strategy., Conclusions: With an incremental cost-effectiveness ratio >$200 000/QALY gained, PCDT is not an economically attractive treatment for proximal DVT. PCDT may be of intermediate value in patients with iliofemoral DVT. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00790335.

Essentials Long-term recurrence risk after a first unprovoked VTE with negative d-dimer levels is uncertain. Anticoagulation was stopped if d-dimer was negative, and was continued if d-dimer was positive. Five years after stopping anticoagulants, recurrent VTE was 30% in men and 17% in women. Negative d-dimers do not justify stopping anticoagulants in most men but appear to in most women., Background: The long-term risk of recurrence in patients with a first unprovoked venous thromboembolism (VTE) who have negative d-dimer results is uncertain., Objectives: To determine this risk, including in subgroups based on sex., Patients and Methods: ln a prospective interventional cohort study of 410 patients with a first unprovoked VTE, anticoagulants were stopped if d-dimer was negative on therapy and 1 month after stopping therapy. Other patients remained on anticoagulant therapy. We previously reported findings after a mean of 2.2 years. The current report includes 3 years of additional follow-up in 293 of these patients., Results: During a median follow-up of 5.0 years, recurrent VTE after stopping therapy in response to negative d-dimer testing was 5.1% (95% confidence interval [CI], 3.6-6.5) per patient-year overall, 7.5% (95% CI, 5.5-10.0) in men, 3.8% (95% CI, 2.0-6.6) in women with VTE not associated with estrogens, and 0.4% (95% CI, 0.0-2.3) in women with VTE associated with estrogens (P < 0.001 for three-group comparison). Risk of recurrence at 5 years was 21.5% (95% CI, 16.4-26.5) overall, 29.7% (95% CI, 22.1-37.3) in men, 17.0% (95% CI, 8.1-25.9) in non-estrogen women, and 2.3% (95% CI, 0.0-6.8) in estrogen women., Conclusion: The long-term risk of recurrence in patients with a first unprovoked VTE who have negative d-dimer results is not low enough to justify stopping anticoagulant therapy in men, but appears to be low enough in women for many to choose stopping therapy (ClinicalTrials.gov; NCT00720915)., (© 2019 International Society on Thrombosis and Haemostasis.)

Background:  The optimal first line treatment for patients with isolated superficial venous thrombosis (SVT) of the lower extremity is unknown., Objective:  This article reports estimates of the rate of venous thromboembolic complications among patients with SVT according to treatment., Materials and Methods:  A systematic review and meta-analysis was performed using unrestricted searches of electronic databases. Reported events were transformed to event per 100 patient-years of follow-up and a random effects model was used to calculate pooled rates according to pre-specified treatment categories. The primary outcome was the occurrence of deep vein thrombosis (DVT) or pulmonary embolism (PE) during the study follow-up period., Results:  Seventeen articles, including 6,862 patients, were included in the meta-analysis. Fondaparinux had the lowest event rate with 1.4 events per 100 patient-years of follow-up (95% confidence interval [CI], 0.5-2.8, I 2  = 18%). Pooled event rates for DVT or PE ranged from 9.3 to 16.6 events per 100 patient-years across other treatment categories, and the pooled event rate for no treatment/placebo was 10.5 events per 100 patient-years (95% CI, 3.0-22.0). Major bleeding was low and similar across all treatment categories. Heterogeneity was moderate to high for most pooled estimates., Conclusion:  While pooled event rates suggest that fondaparinux achieves the lowest rate of DVT or PE, low-quality evidence for other treatments prevents firm conclusions about the optimal treatment for SVT., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) previously reported that pharmacomechanical catheter-directed thrombolysis (PCDT) did not prevent postthrombotic syndrome (PTS) in patients with acute proximal deep vein thrombosis. In the current analysis, we examine the effect of PCDT in ATTRACT patients with iliofemoral deep vein thrombosis., Methods: Within a large multicenter randomized trial, 391 patients with acute deep vein thrombosis involving the iliac or common femoral veins were randomized to PCDT with anticoagulation versus anticoagulation alone (No-PCDT) and were followed for 24 months to compare short-term and long-term outcomes., Results: Between 6 and 24 months, there was no difference in the occurrence of PTS (Villalta scale ≥5 or ulcer: 49% PCDT versus 51% No-PCDT; risk ratio, 0.95; 95% CI, 0.78-1.15; P=0.59). PCDT led to reduced PTS severity as shown by lower mean Villalta and Venous Clinical Severity Scores ( P<0.01 for comparisons at 6, 12, 18, and 24 months), and fewer patients with moderate-or-severe PTS (Villalta scale ≥10 or ulcer: 18% versus 28%; risk ratio, 0.65; 95% CI, 0.45-0.94; P=0.021) or severe PTS (Villalta scale ≥15 or ulcer: 8.7% versus 15%; risk ratio, 0.57; 95% CI, 0.32-1.01; P=0.048; and Venous Clinical Severity Score ≥8: 6.6% versus 14%; risk ratio, 0.46; 95% CI, 0.24-0.87; P=0.013). From baseline, PCDT led to greater reduction in leg pain and swelling ( P<0.01 for comparisons at 10 and 30 days) and greater improvement in venous disease-specific quality of life (Venous Insufficiency Epidemiological and Economic Study Quality of Life unit difference 5.6 through 24 months, P=0.029), but no difference in generic quality of life ( P>0.2 for comparisons of SF-36 mental and physical component summary scores through 24 months). In patients having PCDT versus No-PCDT, major bleeding within 10 days occurred in 1.5% versus 0.5% ( P=0.32), and recurrent venous thromboembolism over 24 months was observed in 13% versus 9.2% ( P=0.21)., Conclusions: In patients with acute iliofemoral deep vein thrombosis, PCDT did not influence the occurrence of PTS or recurrent venous thromboembolism. However, PCDT significantly reduced early leg symptoms and, over 24 months, reduced PTS severity scores, reduced the proportion of patients who developed moderate-or-severe PTS, and resulted in greater improvement in venous disease-specific quality of life., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00790335.

Background: The post-thrombotic syndrome frequently develops in patients with proximal deep-vein thrombosis despite treatment with anticoagulant therapy. Pharmacomechanical catheter-directed thrombolysis (hereafter "pharmacomechanical thrombolysis") rapidly removes thrombus and is hypothesized to reduce the risk of the post-thrombotic syndrome., Methods: We randomly assigned 692 patients with acute proximal deep-vein thrombosis to receive either anticoagulation alone (control group) or anticoagulation plus pharmacomechanical thrombolysis (catheter-mediated or device-mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting). The primary outcome was development of the post-thrombotic syndrome between 6 and 24 months of follow-up., Results: Between 6 and 24 months, there was no significant between-group difference in the percentage of patients with the post-thrombotic syndrome (47% in the pharmacomechanical-thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.11; P=0.56). Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P=0.049), but no significant difference in recurrent venous thromboembolism was seen over the 24-month follow-up period (12% in the pharmacomechanical-thrombolysis group and 8% in the control group, P=0.09). Moderate-to-severe post-thrombotic syndrome occurred in 18% of patients in the pharmacomechanical-thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P=0.04). Severity scores for the post-thrombotic syndrome were lower in the pharmacomechanical-thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow-up (P<0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups., Conclusions: Among patients with acute proximal deep-vein thrombosis, the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of the post-thrombotic syndrome but did result in a higher risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute and others; ATTRACT ClinicalTrials.gov number, NCT00790335 .).

Introduction: For patients with a first unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is a crucial clinical dilemma which has yet to be resolved. The decision to stop anticoagulant therapy (AT) after the initial 3-6 months or to continue AT indefinitely, is primarily governed by the long-term risk of recurrence when treatment is discontinued. This risk however, is not well established, hindering decision making., Methods and Analysis: We will conduct a systematic review and a meta-analysis of studies involving patients diagnosed with a first, symptomatic unprovoked VTE or VTE provoked by minor transient risk factors, who have completed at least 3 months of initial AT; and who were followed-up for standardised time intervals of 1, 2, 5, 10 and 20 years (±3 months) after stopping AT. We will search (from inception to January 2017) MEDLINE, Embase and the Cochrane library for randomised controlled trials and prospective observational studies. Two reviewers will conduct all screening and data collection independently. The primary outcome of the rate of recurrent VTE at the standardised time intervals will be calculated for each study from the total number of recurrent events and the corresponding number of patient-years of follow-up. We will use a random-effects model to pool study results and report a weighted estimate of the absolute rate of recurrent VTE (events per 100 patient-years) over standardised time intervals of 1, 2, 5, 10 and 20 years after discontinuing anticoagulants., Ethics and Dissemination: Ethical approval is not applicable for this study. Findings from this study will be disseminated through peer-reviewed journal publication as well as relevant national and international conference presentations., Prospero Registration Number: CRD42017056309., Competing Interests: Competing interests: MC reports receiving research support form Leo Pharma and BMS, and honoraria from Pfizer, Bayer, BMS, and Sanofi, outside the submitted work. SS reports receiving honoraria from Boehringer Ingelheim, Bayer HealthCare, Daiichi Sankyo and Sanofi, and research support from Boehringer Ingelheim, Baxter and Octapharma, outside the submitted work. FC reports having received research grant support from Pfizer, honoraria for board memberships or symposia from Bayer and AstraZeneca, and travel support from Bayer, Daiichi Sankyo, Leo Pharma, Intermune, and Actelion, outside the submitted work. PP reports receiving consultancy and lectures fees from Bayer Pharma, Sanofi, Daiichi-Sankyo and Pfizer, outside the submitted work. CB reports receiving lectures fees from Bayer HealthCare, Bristol Meyer Squibb and Boehringer Ingelheim, outside the submitted work. GA reports personal fees from Bristol-Myers-Squibb, Pfizer, Bayer Healthcare, Boehringer Ingelheim, and Daiichi Sankyo, outside the submitted work. HRB reports receiving research support and consultancy fees from Sanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics, and Boehringer Ingelheim, outside the submitted work. TAB reports receiving personal fees from Bayer, Bayer Australia, Novo Nordisk, and Glaxo Smith Klein, outside the submitted work. GP reports Advisory Board for Alfa-Wassermann, Daiichi-Sankyo, Pfizer and Roche, and speaker fees from Werfen, outside the submitted work. BH reports receiving honoraria from Cornerstone Research Group for provision of methodologic advice related to systematic reviews and meta-analysis. MAR reports receiving research support from Biomerieux, outside of the submitted work. All other authors (FK, AR, CK, SE, LP, ES and GAW) declare that they have no relevant competing interests., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective  To prospectively validate the HERDOO2 rule (Hyperpigmentation, Edema, or Redness in either leg; D-dimer level ≥250 μg/L; Obesity with body mass index ≥30; or Older age, ≥65 years), which states that women with none or one of the criteria can safely discontinue anticoagulants after short term treatment. Design  Prospective cohort management study. Setting  44 secondary or tertiary care centres in seven countries. Participants  Of 3155 consecutive eligible participants with a first unprovoked venous thromboembolism (VTE, proximal leg deep vein thrombosis or pulmonary embolism) who completed 5-12 months of short term anticoagulant treatment, 370 declined to participate, leaving 2785 enrolled participants. 2.3% were lost to follow-up. Interventions  Women with none or one of the HERDOO2 criteria were classified as at low risk of recurrent VTE and discontinued anticoagulants (intervention arm), whereas anticoagulant management for high risk women (≥2 HERDOO2 criteria) and men was left to the discretion of the clinicians and patients (observation arm). Main outcome measure  Recurrent symptomatic VTE (independently and blindly adjudicated) over one year of follow-up. Results  Of 1213 women, 631 (51.3%) were classified as low risk and 591 discontinued oral anticoagulant treatment. In the primary analysis, 17 low risk women who discontinued anticoagulants developed recurrent VTE during 564 patient years of follow-up (3.0% per patient year, 95% confidence interval 1.8% to 4.8%). In 323 high risk women and men who discontinued anticoagulants, 25 had VTE during 309 patient years of follow-up (8.1%, 5.2% to 11.9%), whereas in 1802 high risk women and men who continued anticoagulants 28 had recurrent VTE during 1758 patient years of follow-up (1.6%, 1.1% to 2.3%). Conclusions  Women with a first unprovoked VTE event and none or one of the HERDOO2 criteria have a low risk of recurrent VTE and can safely discontinue anticoagulants after completing short term treatment. Trial registration  clinicaltrials.gov NCT00967304., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The management of patients with venous thromboembolism (VTE) is a common clinical scenario that, for the most part, involves well‑established, evidence‑based treatment pathways. However, important unanswered clinical questions remain that are the focus of ongoing research. The aim of this narrative review is to provide a practical, case‑based approach to the following clinical scenarios in which therapeutic management pathways are less well established: How long to administer anticoagulation to patients with a first unprovoked VTE? How to manage complex patients with cancer‑associated VTE? When and how to treat patients with splanchnic vein thrombosis? When to use thrombolytic therapy for deep vein thrombosis?

Background: The rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS)., Objectives: To determine whether quantitative D-dimer levels using a low threshold, age- and sex-specific thresholds, or repeated measurements, would improve identification of patients at low risk of recurrent VTE., Materials and Methods: D-dimer levels were quantified in banked samples from 307 patients in DODS who had a negative qualitative D-dimer test while on, and 1month after stopping, anticoagulant therapy and the rates of recurrent VTE were determined in patients with D-dimer levels below various predefined thresholds., Results: The rate (per patient year) of recurrent VTE was: 5.9% with D-dimer levels<250μg/l at one month; 5.2% with D-dimer levels between 250 and 499μg/l at one month; 5.0% with D-dimer levels less than predefined age- and sex-specific thresholds at one month; and 6.3% when D-dimer levels were <500μg/l at both one and 7months after stopping anticoagulant therapy. These rates are similar to the overall event rate of 6.3% in patients who stopped treatment., Conclusions: Among unprovoked VTE patients who had a negative qualitative D-dimer test during and after anticoagulant therapy, low D-dimer thresholds, age and sex-adjusted thresholds or repeated measurements, did not identify subgroups with a very low rate of recurrence., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The efficacy and safety of dabigatran for treatment of venous thromboembolism (VTE) were demonstrated in two trials. It is unclear if the results pertain to patients with cancer and VTE. Data from two randomised trials comparing dabigatran and warfarin for acute VTE were pooled. Primary efficacy outcome was symptomatic recurrent VTE and related death from randomisation to the end of the treatment period. Safety outcomes were major, major and clinically relevant non-major, and any bleeding during the oral-only treatment period. Patients with active cancer (=within 5 years) at baseline or diagnosed during the study were analysed. Compared with 4,772 patients without cancer, recurrent VTE occurred more frequently in 335 patients with cancer at any time (hazard ratio [HR] 3.3; 95 % confidence interval [CI], 2.1-5.3) and more often in 114 with cancer diagnosed during the study compared to 221 with cancer at baseline (HR 2.6; 95 % CI, 1.1-6.2). There was no significant difference in efficacy between dabigatran and warfarin for cancer at baseline (HR 0.75; 95 % CI, 0.20-2.8) or diagnosed during the study (HR 0.63; 95 % CI, 0.20-2.0). Major bleeding (HR 4.1; 95 % CI, 2.2-7.5) and any bleeding (HR 1.5; 95 % CI, 1.2-2.0) were more frequent in patients with cancer than without, but with similar incidence in cancer with dabigatran or warfarin. In conclusion, in cancer patients, dabigatran provided similar clinical benefit as warfarin. VTE recurrence or bleeding were similar in patients on dabigatran or warfarin. The efficacy of dabigatran has not been assessed in comparison with low-molecular-weight heparin.

Background: Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment., Objective: To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence., Design: Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915)., Setting: 13 university-affiliated clinical centers., Patients: 410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy., Intervention: Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month., Measurements: Recurrent VTE during an average follow-up of 2.2 years., Results: In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison)., Limitations: Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study., Conclusion: The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women., Primary Funding Source: Canadian Institutes of Health Research.

Background: There is uncertainty regarding the optimal dosing regimen for the resumption of warfarin after interruption for invasive procedures., Aim: To determine the efficacy and safety of warfarin resumption with loading doses or with the most recent maintenance dose., Methods: Patients receiving warfarin treatment and planned for invasive procedures with an expected hospital stay of ≤ 1 day were randomized to resume warfarin on the day of the procedure, defined as day 1, with most recent maintenance dose or with 2 initial days of double maintenance dose. Efficacy outcomes were proportion of international normalized ratio (INR) levels ≥ 2.0 on day 5 (primary outcome) and day 10. Safety outcomes were bleeding and thromboembolic events. In addition, D-dimer levels were analyzed on days 5 and 10 in a subset of the population., Results: There were 49 patients analyzed in each group. INR of ≥ 2.0 had been achieved by day 5 for 13% in the maintenance-dose group and for 50% in the loading-dose group (relative risk [RR] 0.27, 95% confidence interval [CI] 0.10-0.60) and by day 10 for 68% and 87%, respectively (RR 0.78, 95% CI 0.65-1.00). There were no thromboembolic events, and there was one major bleed before resumption of warfarin and one minor bleed, both in the maintenance-dose group. There was no difference between the groups in the proportion of patients with excessive INRs or elevated D-dimer levels or in the median D-dimer level., Conclusion: Resumption of warfarin after minor-moderately invasive procedures with two loading doses achieves therapeutic INR faster than does only maintenance dose., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: Although venous thromboembolism (VTE) is an important cause of postoperative morbidity and mortality, there is still no consensus on the optimal strategy for VTE prevention after major surgery. The objective of this review was to determine the benefits and risks of thromboprophylaxis with both compression and anticoagulation, compared with either modality alone., Methods: A systematic review of MEDLINE, CENTRAL and Embase databases was performed to identify eligible randomized trials. The literature search and data extraction were carried out independently by two reviewers. Outcomes of interest were deep vein thrombosis (DVT), pulmonary embolism, bleeding, limb injury and mortality., Results: Twenty-five studies were eligible for inclusion. Adding compression to anticoagulation decreased the risk of DVT by 49 per cent (risk ratio (RR) 0·51, 95 per cent confidence interval 0·36 to 0·73). The corresponding funnel plot suggested publication bias and, overall, the evidence for this comparison was judged to be of low quality. Adding anticoagulation to compression decreased the risk of DVT by 44 per cent (RR 0·56, 0·45 to 0·69) while increasing the risk of bleeding (RR 1·74, 1·29 to 2·34). There was no suggestion of publication bias and the evidence for this comparison was judged to be of moderate quality., Conclusion: Combined compression and anticoagulation is more effective at preventing postoperative DVT than either modality alone. However, adding anticoagulation to compression increases the risk of bleeding, and the evidence that adding compression to anticoagulation reduces VTE risk is of low quality., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Introduction: Venous thromboembolism (VTE) is a major disease associated with short-term and long-term morbidity and mortality. Patients with a VTE provoked by surgery or immobilisation are at low risk of recurrence and do not require long-term anticoagulation; those with a VTE and metastatic cancer are at high risk of recurrence and require lifetime thromboprophylaxis. In those at intermediate risk of recurrence, it remains controversial whether prolonging anticoagulation and thus incurring treatment burden and bleeding risk is warranted., Methods and Analysis: We will conduct a systematic review and meta-analysis of randomised controlled trials enrolling patients with VTE at intermediate risk of recurrence and evaluating short-term anticoagulation (12 weeks to 9 months initial therapy) versus longer term anticoagulation (at least 6 months additional anticoagulation beyond the course of treatment in the shorter arm). Anticoagulation could consist of vitamin K antagonists or new oral anticoagulants. Outcomes of interest include recurrent non-fatal thrombosis (deep venous thrombosis and pulmonary embolism), major non-fatal bleeding and mortality. We will systematically search CINAHL, EMBASE, MEDLINE and the Cochrane Central Registry of Controlled Trials. Teams of two reviewers will, independently and in duplicate, screen titles and abstracts and complete full text reviews to determine eligibility, and subsequently abstract data and assess risk of bias in eligible trials. We will conduct meta-analyses to establish the effect of short-term versus long-term anticoagulation on the outcomes of interest and evaluate confidence in estimates (quality of evidence) using the GRADE (grading of recommendations, assessment, development and evaluation) approach., Ethics and Dissemination: Our review will facilitate evidence-based management of patients with unprovoked or recurrent VTE. For purposes of privacy and confidentiality, the systematic review will be limited to studies with deidentified data. The study will be disseminated by peer-review publication and conference presentation., Trial Registration Number: PROSPERO (CRD42014007620)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The risk of bleeding on anticoagulation varies between patients. It is uncertain whether sex influences this risk., Objectives: To determine if the risk of major bleeding differs between men and women receiving anticoagulation for atrial fibrillation or venous thromboembolism(VTE)., Methods: We searched MEDLINE, EMBASE, and Cochrane databases, and relevant conference proceedings, until February 2013. We included randomized controlled trials and prospective cohort studies of patients on therapeutic anticoagulation for atrial fibrillation or VTE. Two reviewers independently extracted data. The relative risk of bleeding in men compared to women was pooled using a random-effects model., Results: Forty-two studies including 94 293 patients were eligible; 78 044 patients (83%) had atrial fibrillation; 16 156 patients (17%) had VTE; 37 250 patients were women (40%); and there were 4147 major bleeds. The relative risk of major bleeding for men vs. women was 1.02(95% CI 0.95–1.10; P = 0.27 for heterogeniety). The relative risk was 1.02 (95% CI 0.95–1.09) in patients with atrial fibrillation and 0.80 (95% CI 0.65–0.98) in patients with VTE (P = 0.03 for subgroup effect). Type of anticoagulant,intensity of anticoagulation, and whether patients began or were already established on anticoagulants at enrollment did not influence the relative risk of major bleeding in men compared to women., Conclusions: The risk of major bleeding on anticoagulation appears to be the same in men and women, particularly if patients have atrial fibrillation. This finding is less certain for patients with VTE, in whom the risk of bleeding may be marginally lower in men compared to in women.

It takes about 3 months to complete "active treatment" of venous thromboembolism (VTE), with further treatment serving to prevent new episodes of thrombosis ("pure secondary prevention"). Consequently, VTE should generally be treated for either 3 months or indefinitely (exceptions will be described in the text). The decision to stop anticoagulants at 3 months or to treat indefinitely is dominated by the long-term risk of recurrence, and secondarily influenced by the risk of bleeding and by patient preference. VTE provoked by a reversible risk factor, or a first unprovoked isolated distal (calf) deep vein thrombosis (DVT), has a low risk of recurrence and is usually treated for 3 months. VTE associated with active cancer, or a second unprovoked VTE, has a high risk of recurrence and is usually treated indefinitely. The decision to stop anticoagulants at 3 months or to treat indefinitely is more finely balanced after a first unprovoked proximal DVT or pulmonary embolism (PE). Indefinite anticoagulation is often chosen if there is a low risk of bleeding, whereas anticoagulation is usually stopped at 3 months if there is a high risk of bleeding. The decision to continue anticoagulation indefinitely after a first unprovoked proximal DVT or PE is strengthened if the patient is male, the index event was PE rather than DVT, and/or d-dimer testing is positive 1 month after stopping anticoagulant therapy.

Background: Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism (VTE) in a previous trial. We undertook this study to extend those findings., Methods and Results: In a randomized, double-blind, double-dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days, we compared dabigatran 150 mg twice daily with warfarin. The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients (2.3%) compared with 28 of the 1289 warfarin patients (2.2%; hazard ratio, 1.08; 95% confidence interval [CI], 0.64-1.80; absolute risk difference, 0.2%; 95% CI, -1.0 to 1.3; P<0.001 for the prespecified noninferiority margin for both criteria). The safety end point, major bleeding, occurred in 15 patients receiving dabigatran (1.2%) and in 22 receiving warfarin (1.7%; hazard ratio, 0.69; 95% CI, 0.36-1.32). Any bleeding occurred in 200 dabigatran (15.6%) and 285 warfarin (22.1%; hazard ratio, 0.67; 95% CI, 0.56-0.81) patients. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 (95% CI, 0.76-1.57), for major bleeding of 0.73 (95% CI, 0.48-1.11), and for any bleeding of 0.70 (95% CI, 0.61-0.79)., Conclusion: Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE., Clinical Trial Registration Url: www.clinicaltrials.gov. Unique identifiers: NCT00680186 and NCT00291330.

Amiodarone inhibits the hepatic metabolism of warfarin, potentiating its anticoagulant effect. However, the clinical consequences of this are not well established. Our objective in this study was to characterize the risk of hospitalization for a hemorrhage associated with the initiation of amiodarone within a cohort of continuous warfarin users in Ontario. We conducted a population-based retrospective cohort study among Ontario residents aged ≥66 years receiving warfarin. Among patients with at least 6 months of continuous warfarin therapy, we identified those who were newly prescribed amiodarone and an equal number who were not, matching on age, gender, year of cohort entry, and a high-dimensional propensity score. The primary outcome was hospitalization for hemorrhage within 30 days of amiodarone initiation. Between July 1, 1994, and March 31, 2009, we identified 60,497 patients with at least 6 months of continuous warfarin therapy, of whom 11,665 (19%) commenced amiodarone. For 7,124 (61%) of these, we identified a matched control subject who did not receive amiodarone. Overall, 56 (0.8%) amiodarone recipients and 23 (0.3%) control patients were hospitalized for hemorrhage within 30 days of initiating amiodarone (adjusted hazard ratio 2.45; 95% confidence interval, 1.49-4.02). Seven of 56 (12.5%) patients hospitalized for a hemorrhage after starting amiodarone died in hospital. In conclusion, initiation of amiodarone among older patients receiving warfarin is associated with a more than twofold increase in the risk of hospitalization for hemorrhage, with a relatively high fatality rate. Physicians should closely monitor patients who initiate amiodarone while receiving warfarin., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose of Review: Deficiency of antithrombin, protein C, and protein S increases the risk of a first venous thromboembolism (VTE) by at least 10-fold and is rare (i.e., <0.5% of population), whereas factor V Leiden and the prothrombin G20210A gene increase this risk by 2-5-fold and are common (2-5% of whites). Antiphospholipid antibodies are considered acquired thrombophilic states. Testing for these abnormalities is widespread. This review will consider if the results of testing should influence how patients with VTE are treated., Recent Findings: There are no randomized trials that have compared testing for thrombophilia with no testing; consequently, current assessments of whether testing should influence treatment of VTE are based on indirect evidence. Observational studies indicate that anticoagulants are equally effective in patients with and without thrombophilia; therefore, the presence of thrombophilia should not influence the choice of anticoagulant or the intensity of therapy. A lupus anticoagulant, however, can complicate monitoring of vitamin K antagonist therapy. The risk of recurrent VTE after stopping anticoagulant therapy may be higher in patients with thrombophilia, but not enough to influence whether anticoagulants should be stopped at 3 months or continued indefinitely., Summary: Thrombophilia should rarely influence the treatment of VTE. Therefore, routine thrombophilia testing of patients with VTE is not indicated as a way to guide treatment decisions.

Four observations support that anticoagulant therapy for venous thromboembolism (VTE) has an 'active treatment' phase that is limited to about 3 months. First, <3 months of treatment is associated with a higher risk of recurrent VTE than treatment for 3 months or longer, suggesting that <3 months is inadequate therapy. Second, treatment for 3 months is associated with the same risk of recurrent VTE as treatment for 6 months or longer, suggesting that 3 months is adequate therapy. Third, the increase in recurrent VTE with too short a course of treatment is predominantly at the site of the initial thrombosis, suggesting reactivation of initial thrombosis. Fourth, the increase in recurrent VTE with too short a course of treatment occurs immediately after treatment is stopped and is short lived, again suggesting reactivation of initial thrombosis. Once the initial thrombosis has been adequately treated (i.e. the first phase of treatment), further anticoagulation serves as 'secondary prevention' of new, unrelated, episodes of thrombosis (i.e. the second phase of treatment). For most patients, therefore, anticoagulant therapy for VTE should be stopped at 3 months when the acute episode has completed treatment, or should be continued indefinitely as 'secondary prevention' if the risk of recurrence remains unacceptably high having completed 'active treatment'., (© 2012 International Society on Thrombosis and Haemostasis.)

Background: The risk of patients dying of pulmonary embolism (PE) or bleeding during the treatment of deep vein thrombosis (DVT), and whether these risks are influenced by patient age, has not been thoroughly studied., Methods: We used data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) to assess the risk of fatal PE and fatal bleeding in 16,199 patients with lower limb DVT (without symptomatic PE at the time of inclusion) during the 3 months after diagnosis, with patients categorized according to age., Results: During the 3 months of anticoagulant treatment, there were 31 fatal PEs (0.19%) and 83 fatal hemorrhages (0.51%). During the first 7 days of therapy, the frequency of fatal PEs was similar to that of fatal bleeding (12 vs 14 deaths, respectively; odds ratio [OR], 0.86; 95% confidence interval [CI], 0.39-1.87). However, from days 8 to 90, the frequency of fatal bleeding was greater than that of fatal PE (69 vs 19 deaths; OR, 3.64; 95% CI, 2.22-6.20). The higher frequency of fatal bleeding compared with fatal PE from days 8 to 90 appeared to be confined to patients who were aged ≥ 60 years. Multivariate analysis showed that patient age was independently associated with an increased risk of death from bleeding during the first 3 months: every 10 years the OR increased by 1.37 (95% CI, 1.12-1.67)., Conclusions: During the first week of treatment, the risk of fatal bleeding and fatal PE were similar. Then, particularly in patients who were aged ≥ 60 years, the risk of dying from bleeding exceeded the risk of dying from PE., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: To determine how length of anticoagulation and clinical presentation of venous thromboembolism influence the risk of recurrence after anticoagulant treatment is stopped and to identify the shortest length of anticoagulation that reduces the risk of recurrence to its lowest level., Design: Pooled analysis of individual participants' data from seven randomised trials., Setting: Outpatient anticoagulant clinics in academic centres., Population: 2925 men or women with a first venous thromboembolism who did not have cancer and received different durations of anticoagulant treatment., Main Outcome Measure: First recurrent venous thromboembolism after stopping anticoagulant treatment during up to 24 months of follow-up., Results: Recurrence was lower after isolated distal deep vein thrombosis than after proximal deep vein thrombosis (hazard ratio 0.49, 95% confidence interval 0.34 to 0.71), similar after pulmonary embolism and proximal deep vein thrombosis (1.19, 0.87 to 1.63), and lower after thrombosis provoked by a temporary risk factor than after unprovoked thrombosis (0.55, 0.41 to 0.74). Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with at 3 months or later (hazard ratio 1.52, 1.14 to 2.02) and similar if treatment was stopped at 3 months compared with at 6 months or later (1.19, 0.86 to 1.65). High rates of recurrence associated with shorter durations of anticoagulation were confined to the first 6 months after stopping treatment., Conclusion: Three months of treatment achieves a similar risk of recurrent venous thromboembolism after stopping anticoagulation to a longer course of treatment. Unprovoked proximal deep vein thrombosis and pulmonary embolism have a high risk of recurrence whenever treatment is stopped.

About half of patients with a first unprovoked proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) will have a recurrent venous thromboembolism (VTE) within 10 years if they stop treatment, and randomized trials have shown clear benefit from extended anticoagulant therapy in these patients. Although the risk of recurrence varies among patients with a first unprovoked proximal DVT or PE, and a number of factors can identify patients with a lower risk of recurrence, the safety of routinely stopping anticoagulant therapy based on the presence of these factors needs to be established in prospective studies before this is done in clinical practice. As isolated distal DVT is associated with about half the risk of recurrence of proximal DVT or PE, a first episode of unprovoked distal DVT does not justify extended anticoagulation. High risk for bleeding, and patient preference, are good reasons not to treat unprovoked proximal DVT or PE indefinitely. New anticoagulants, because they are easier to use and may be associated with less bleeding that vitamin K antagonists, have the potential to increase the proportion of patients with unprovoked VTE who are candidates for extended anticoagulant therapy.

Treatment of venous thromboembolism (VTE) should be continued until the reduction of recurrent VTE that anticoagulation is expected to achieve no longer outweighs the increase in bleeding associated with therapy, or until the patient wants to stop treatment even if treatment is expected to be of benefit. Reversibility of risk factors for VTE is the most important factor that influences risk of recurrence and duration of therapy. VTE associated with a reversible risk factor (eg, surgery) is treated for 3 months; unprovoked VTE often benefits from indefinite therapy provided patients do not have risk factors for bleeding; and cancer-associated VTE is usually treated indefinitely. A systematic approach to managing warfarin therapy improves its efficacy, safety, and acceptability., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background:  Rate of major bleeding is generally accepted as a good measure of the risks associated with anticoagulant therapy, but this may not be true if the proportion of major bleeds with the most serious consequences differs according to the indication for anticoagulant therapy., Objective: To determine whether the indication for long-term oral anticoagulant therapy influences the proportion of major bleeds that are intracranial and fatal., Patients/methods:  Two authors abstracted intracranial and fatal bleeds from randomized trials of patients who received anticoagulant therapy for a minimum of 6months for atrial fibrillation, ischemic heart disease, venous thromboembolism, prosthetic heart valves and ischemic stroke., Results: There were 877 major bleeds among 23,518 patients in 39 studies. The proportion of bleeds that were intracranial was significantly higher in patients with ischemic stroke (36%; 95% CI, 22-52%; P=0.02) compared with patients with venous thromboembolism (10%; 95% CI, 5-20%). The difference in the proportion of bleeds that were intracranial among atrial fibrillation, ischemic heart disease, venous thromboembolism and prosthetic heart valves was not statistically significant; however, the estimates varied from 10% to 27%. The proportion of bleeds that were fatal did not differ significantly according to indication, but varied from 8% to 20%. For all indications for anticoagulation, intracranial bleeds were much more likely to be fatal than extracranial major bleeds (44% vs. 4% overall)., Conclusions:  In current practise, the indication for oral anticoagulant therapy has limited influence on the proportion of major bleeds that are intracranial or fatal., (© 2010 International Society on Thrombosis and Haemostasis.)

Unanticipated elevation of the INR is common in patients receiving warfarin. We performed a prospective cohort study of 107 warfarin-treated patients with INR values of more than 10 who received a single 2.5 mg dose of oral vitamin K. During the first week, one patient experienced major bleeding, and one died. In the first 90 days after enrolment four patients had major bleeding (3.7%, 1.0% to 9.3%), eight patients (7.5%, 3.3% to 14.2%) died and two had objectively confirmed thromboembolism. Based on our low rate of observed major bleeding we conclude that 2.5 mg of oral vitamin K is a reasonable treatment for patients with INR values of more than 10 who are not actively bleeding.

Background: Fatal bleeding is a serious consequence of anticoagulant therapy, but factors associated with fatal bleeding during the first 3 months of treatment of venous thromboembolism (VTE) are uncertain., Methods: Using data from RIETE, an ongoing registry of consecutive patients with acute VTE, we assessed risk factors for fatal bleeding among all patients. We then used this information to derive a clinical model that would stratify a patient's risk of fatal bleeding during the first 3 months of treatment., Results: Of 24 395 patients, 546 (2.24%) had a major bleed and 135 (0.55%) had a fatal bleed. The gastrointestinal tract was the most common site (40% of fatal bleeds), followed by intracranial bleeding (25%). Fatal bleeding was independently associated with the following factors at the time of VTE diagnosis: age >75 years (OR, 2.16), metastatic cancer (OR, 3.80), immobility > or = 4 days (OR, 1.99), a major bleed within the past 30 days (OR, 2.64), an abnormal prothrombin time (OR, 2.09), a platelet count < 100 x 10(9) L(-1) (OR, 2.23), creatinine clearance < 30 mL min(-1) (OR, 2.27), anemia (OR, 1.54), and distal deep vein thrombosis (OR, 0.39). INR at the time of bleeding is not known. A clinical prediction rule for risk of fatal bleeding that included nine baseline factors was derived. Fatal bleeding occurred in 0.16% (95% CI, 0.11-0.23) of the low-risk, 1.06% (95% CI, 0.85-1.30) of the moderate-risk, and 4.24% (95% CI, 2.76-6.27) of the high-risk category., Conclusions: Patient characteristics and laboratory variables can identify patients at high risk for fatal bleeding during treatment of VTE.

Background: The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism., Methods: In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests., Results: A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05)., Conclusions: For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. (ClinicalTrials.gov number, NCT00291330.), (Copyright 2009 Massachusetts Medical Society.)

About half of the patients with a first idiopathic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) are expected to have a recurrent episode of venous thromboembolism (VTE) within 10 years of stopping therapy, and randomized trials have shown that this group of patients benefit from long-term anticoagulant therapy. High risks for bleeding and patient preference are compelling reasons not to treat such patients long-term. Although a number of factors are associated with a reduced risk of recurrence, they require further validation before it is appropriate to routinely stop anticoagulants after 3 months in patients with idiopathic proximal DVT or PE.

Background: Low-dose oral vitamin K decreases the international normalized ratio (INR) in overanticoagulated patients who receive warfarin therapy. Its effects on bleeding events are uncertain., Objective: To see whether low-dose oral vitamin K reduces bleeding events over 90 days in patients with warfarin-associated coagulopathy., Design: Multicenter, randomized, placebo-controlled trial. Randomization was computer-generated, and participants were allocated to trial groups by using sequentially numbered study drug containers. Patients, caregivers, and those who assessed outcomes were blinded to treatment assignment., Setting: 14 anticoagulant therapy clinics in Canada, the United States, and Italy., Patients: Nonbleeding patients with INR values of 4.5 to 10.0., Intervention: Oral vitamin K, 1.25 mg (355 patients randomly assigned; 347 analyzed), or matching placebo (369 patients randomly assigned; 365 analyzed)., Measurements: Bleeding events (primary outcome), thromboembolism, and death (secondary outcomes)., Results: 56 patients (15.8%) in the vitamin K group and 60 patients (16.3%) in the placebo group had at least 1 bleeding complication (absolute difference, -0.5 percentage point [95% CI, -6.1 to 5.1 percentage points]); major bleeding events occurred in 9 patients (2.5%) in the vitamin K group and 4 patients (1.1%) in the placebo group (absolute difference, 1.5 percentage points [CI, -0.8 to 3.7 percentage points]). Thromboembolism occurred in 4 patients (1.1%) in the vitamin K group and 3 patients (0.8%) in the placebo group (absolute difference, 0.3 percentage point [CI, -1.4 to 2.0 percentage points]). Other adverse effects were not assessed. The day after treatment, the INR had decreased by a mean of 1.4 in the placebo group and 2.8 in the vitamin K group (P < 0.001)., Limitation: Patients who were actively bleeding were not included, and warfarin dosing after enrollment was not mandated or followed., Conclusion: Low-dose oral vitamin K did not reduce bleeding in warfarin recipients with INRs of 4.5 to 10.0., Funding: Canadian Institutes of Health Research and Italian Ministry of Universities and Research.

Vitamin K antagonists are the mainstay for the treatment for venous thromboembolism. The optimum (VTE) course of oral anticoagulant therapy is determined according to the risk of recurrent VTE after stopping anticoagulant therapy and the risk of anticoagulant-related bleeding while on antivitamin K. The risk of recurrent VTE is low when the initial episode is provoked by a reversible major-risk factor (surgery), whereas this risk is high when VTE is not provoked or associated with a persistent-risk factor (cancer). Conversely, the influence of biochemical and morphological tests is uncertain. The optimum balance of the benefits and the risks of oral anticoagulant therapy is based on the frequency as well as the consequences of the risk of recurrent VTE and anticoagulant-related bleeding. After VTE provoked by a major reversible-risk factor, three months of anticoagulation is optimal, whereas after unprovoked VTE, anticoagulation should be extended. However, given the number of unresolved issues, a randomised trial comparing different durations of anticoagulation is needed.

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding. Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

Based on an individual assessment of risk factors for arterial or venous thrombosis and the risk of postoperative bleeding, this article outlines the preoperative and postoperative approach to anticoagulant management. Preceding this is a brief description of the therapies most commonly used in the perioperative period. The prevention of arterial thromboembolism is considered separately from the prevention of venous thrombosis. Perioperative management of anticoagulation can cause anxiety for patients, surgeons, anesthetists, and those who manage long-term anticoagulant therapy. Good communication between all of these parties is essential to ensure that an optimal management strategy is identified and executed.

Purpose of Review: When unfractionated heparin is used to treat acute venous thromboembolism, it is usually given by intravenous infusion with dose adjustment in response to activated partial thromboplastin time measurements. These two requirements are a barrier to treatment of venous thromboembolism with unfractionated heparin, and it is uncertain if they are necessary., Recent Findings: Two recent studies compared subcutaneous unfractionated heparin and subcutaneous low-molecular-weight heparin, each given twice-daily, for the acute treatment of venous thromboembolism. The Galilei study used an initial dose of unfractionated heparin that was partially weight-adjusted, with subsequent dosing based on activated partial thromboplastin time results. The FIDO study treated patients with a first dose of unfractionated heparin of 333 IU/kg, followed by 250 IU/kg twice-daily without dose adjustment in response to the activated partial thromboplastin time or other coagulation tests. There was no difference in either study between the unfractionated heparin and low-molecular-weight heparin groups at the end of 3 months, for recurrent venous thromboembolism (Galilei: 4.2 vs. 3.9%; relative risk (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.2. FIDO: 3.8 vs. 3.4%; RR 1.1, 95% CI 0.5 to 2.3) or major bleeding (Galilei: 1.4 vs. 1.9%; RR 0.7, 95% CI 0.2 to 2.2. FIDO: 1.7 vs. 3.4%; RR 0.5, 95% CI 0.2 to 1.3)., Summary: Recent studies suggest that twice-daily subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for the acute treatment of venous thromboembolism, and that adjustment of unfractionated heparin dose in response to activated partial thromboplastin time measurements is not necessary with a weight-adjusted dose of unfractionated heparin.

Background: Preoperative low-molecular-weight heparin (LMWH) is often used when warfarin therapy is interrupted for surgery., Objective: To determine the preoperative anticoagulant activity of LMWH following a standardized "bridging" regimen., Design: Prospective cohort study., Setting: Single university hospital., Patients: Consecutive patients who had warfarin therapy interrupted before an invasive procedure., Intervention: Enoxaparin, 1 mg/kg of body weight, twice daily. The last dose was administered the evening before surgery., Measurements: Blood anti-factor Xa heparin levels measured shortly before surgery., Results: Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels., Limitations: The small sample size limits accurate estimates of the frequency of the clinical outcomes. A single regimen of LMWH was evaluated., Conclusions: Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.

Context: When unfractionated heparin is used to treat acute venous thromboembolism, it is usually administered by intravenous infusion with coagulation monitoring, which requires hospitalization. However, subcutaneous administration of fixed-dose, weight-adjusted, unfractionated heparin may be suitable for inpatient and outpatient treatment of venous thromboembolism., Objective: To determine if fixed-dose, weight-adjusted, subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for treatment of venous thromboembolism., Design, Setting, and Patients: Randomized, open-label, adjudicator-blinded, noninferiority trial of 708 patients aged 18 years or older with acute venous thromboembolism from 6 university-affiliated clinical centers in Canada and New Zealand conducted from September 1998 through February 2004. Of the randomized patients, 11 were subsequently excluded from the analysis of efficacy and 8 from the analysis of safety., Interventions: Unfractionated heparin was administered subcutaneously as an initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours (n = 345). Low-molecular-weight heparin (dalteparin or enoxaparin) was administered subcutaneously at a dose of 100 IU/kg every 12 hours (n = 352). Both treatments could be administered out of hospital and both were overlapped with 3 months of warfarin therapy., Main Outcome Measures: Recurrent venous thromboembolism within 3 months and major bleeding within 10 days of randomization., Results: Recurrent venous thromboembolism occurred in 13 patients in the unfractionated heparin group (3.8%) compared with 12 patients in the low-molecular-weight heparin group (3.4%; absolute difference, 0.4%; 95% confidence interval, -2.6% to 3.3%). Major bleeding during the first 10 days of treatment occurred in 4 patients in the unfractionated heparin group (1.1%) compared with 5 patients in the low-molecular-weight heparin group (1.4%; absolute difference, -0.3%; 95% confidence interval, -2.3% to 1.7%). Treatment was administered entirely out of hospital in 72% of the unfractionated heparin group and 68% of the low-molecular-weight heparin group., Conclusion: Fixed-dose subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin in patients with acute venous thromboembolism and is suitable for outpatient treatment., Trial Registration: clinicaltrials.gov Identifier: NCT00182403.

Background: Individual risk of recurrent venous thromboembolism affects patient management and might differ between men and women. We did a meta-analysis to assess from available evidence whether men and women have the same risk of recurrent venous thromboembolism after stopping anticoagulant treatment., Methods: Eligible articles were identified by searches of MEDLINE (source PubMed, 1966 to February 2005), EMBase (1980 to February 2005), and the Cochrane database 2005, issue 1. Prospective cohort studies and randomised trials were eligible if they included patients with objectively diagnosed venous thromboembolism treated for a minimum of 1 month and followed up for recurrence after anticoagulant treatment was stopped. Data were extracted for study design, study quality, and the number, sex, and age of enrolled patients, risk factors for venous thromboembolism, treatment given, duration of follow-up, and the number of episodes of recurrent venous thrombosis., Findings: 15 studies (nine randomised controlled trials and six prospective observational studies) enrolling a total of 5416 individuals (2729 men), of whom 816 (523 men) had recurrent venous thromboembolism after stopping treatment, were eligible for inclusion. The pooled estimate of the relative risk (RR) of recurrent venous thromboembolism for men compared with for women was 1.6 (95% CI 1.2-2.0). Significant heterogeneity was shown among individual study findings; however, the higher risk of recurrent venous thromboembolism in men than in women was consistent across predefined subgroups. The relative risk for recurrence in men from randomised trials (RR 1.3; 95% CI 1.0-1.8) was lower than that from observational studies (2.1; 1.5-2.9). The lower risk of recurrent venous thromboembolism in women did not seem to be accounted for by a reduced rate of recurrence after venous thromboembolism associated with oestrogen treatment or pregnancy., Interpretation: Men seem to have a 50% higher risk than women of recurrent venous thromboembolism after stopping anticoagulant treatment. If confirmed by further prospective studies, this difference in risk of recurrence should be considered when duration of anticoagulant treatment is determined in individual patients.

Background and Aim of the Study: The optimal approach to anticoagulation during the early postoperative period after mechanical valve replacement, by which early thromboembolism is prevented without bleeding complications, is not yet known. The study aim was to examine the practice patterns of Canadian cardiac surgeons with regard to early postoperative anticoagulation after mechanical valve implantation., Methods: A questionnaire was sent to 100 Canadian cardiac surgeons in July 2004, and 57 responses were received. Data were collected regarding the approaches to early postoperative anticoagulation following uncomplicated isolated mechanical aortic valve replacement (AVR) and mitral valve replacement (MVR)., Results: Heparin was administered routinely after AVR and MVR by 63% and 68% of surgeons, respectively. This was most commonly initiated on postoperative day (POD) 1, and given either subcutaneously (AVR, 28%; MVR, 25%) or intravenously (AVR, 33%; MVR, 42%). Alternatively, low-molecular-weight heparin was used by 21% and 23% of surgeons after AVR and MVR, respectively. Oral warfarin was usually started on POD 1 (72% and 68%, respectively), with 40% prescribing an initial dose between 2.5 and 5.0 mg, and 51% administering between 5.1 and 7.5 mg. When heparin was not used, oral anticoagulation was more often administered earlier (AVR, p = 0.003; MVR, p = 0.006), but not at higher doses (AVR, p = 0.07; MVR, p = 0.2). Following surgery, aspirin was prescribed by 61% and 65% of surgeons after AVR and MVR, respectively., Conclusion: The study results highlighted a significant variability in the management of early postoperative anticoagulation after mechanical valve implantation. The clinical impact of these findings is unknown, and can only be assessed through a prospective trial.

Based on an individual assessment of risk factors for arterial or venous thrombosis and the risk of postoperative bleeding, this article outlines the preoperative and postoperative approach to anticoagulant management. Preceding this is a brief description of the therapies most commonly used in the perioperative period. The prevention of arterial thromboembolism is considered separately from the prevention of venous thrombosis.

The optimal approach to early postoperative anticoagulation after mechanical valve implantation remains controversial. This review article examines the pathogenesis of thrombus formation and the different strategies for early postoperative anticoagulation. The most commonly reported anticoagulation regimens had the after estimates of early postoperative thromboembolism and hemorrhage: oral anticoagulation alone (0.9%, 3.3%); oral anticoagulation with intravenous unfractionated heparin (1.1%, 7.2%); and oral anticoagulation with low molecular weight heparin (0.6%, 4.8%). Although intravenous heparin may be associated with a higher incidence of hemorrhage, a randomized trial is needed to provide the best evidence regarding early postoperative anticoagulation after mechanical valve implantation. Nearly four decades have passed since the first mechanical prosthetic valves were implanted. Frequent thromboembolic complications with the first mechanical valves led to recommendations of universal anticoagulation for these patients. Since then, several design changes and modifications have been made to improve the longevity, hemodynamics, and thrombogenicity of newer generation mechanical valves. With improved blood flow, less stasis, and less thrombogenic materials, lower rates of thromboembolism have been reported. Despite these advances however, thromboembolism and anticoagulant-related bleeding continue to account for 75% of all complications after mechanical valve replacement. Occurring most commonly within six months after implantation, these complications can adversely affect mortality and quality of life. Furthermore, the threat of their occurrence creates a psychological burden for each patient with a mechanical valve. The need for life-long anticoagulation in patients with mechanical valves is not in dispute, and the perioperative management of anticoagulation during non-cardiac surgery has been reviewed extensively. However, the approach to early postoperative anticoagulation after mechanical valve implantation is still a matter of debate. The optimal intensity and timing of anticoagulation to prevent early thromboembolism after valve replacement surgery without postoperative bleeding complications is unknown. Hence, many anticoagulation protocols have been proposed, but a lack of consensus remains. The objectives of this study were (1) to reexamine the pathogenesis of thrombus formation and the need for anticoagulation; (2) to critically review the literature on early postoperative anticoagulation strategies; and (3) provide an estimate of the incidence of bleeding and thromboembolism for each approach to early postoperative anticoagulation.

Summary. A variety of definitions of major bleeding have been used in published clinical studies, and this diversity adds to the difficulty in comparing data between trials and in performing meta-analyses. In the first step towards unified definitions of bleeding complications, the definition of major bleeding in non-surgical patients was discussed at the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis. Arising from that discussion, a definition was developed that should be applicable to studies with all agents that interfere with hemostasis, including anticoagulants, platelet function inhibitors and fibrinolytic drugs. The definition and the text that follows have been reviewed and approved by the cochairs of the subcommittee and the revised version is published here. The intention is to also seek approval of this definition from the regulatory authorities.