Initial Treatment Of Venous Thromboembolism Research Articles

Balancing risks of recurrent venous thromboembolism and bleeding with extended anticoagulation: a decision analysis

BackgroundA decision to stop or continue anticoagulation after 3 months of anticoagulation for venous thromboembolism (VTE) should be made by weighing individual risks of recurrence and bleeding. ObjectivesTo determine the optimal ratio of recurrence risk reduction to increase the risk of bleeding in terms of maximizing quality-adjusted life years (QALYs) gained. MethodsUsing a microsimulation model, outcomes within 5 years were simulated after assigning extended treatment if absolute recurrence risk reduction outweighed absolute increase in clinically relevant bleeding risk (International Society on Thrombosis and Haemostasis definition), weighted by a certain ratio. Data were simulated based on the Bleeding Risk Study, a prospective cohort including patients after ≥3 months of anticoagulation for unprovoked VTE or provoked VTE with history of VTE. The VTE-PREDICT risk score was used to estimate 5-year risks of recurrent VTE and clinically relevant bleeding. ResultsAmong 10,000 individuals (mean age, 60.2 years, 36% female), the ratio of 0.90 (95% CI, 0.51-3.40; ie, bleeding is considered 0.90 the severity of recurrent VTE), with 99% of patients assigned extended anticoagulation, was considered optimal and resulted in 93 (95% CI, −23 to 203) additional QALYs compared with the least favorable ratio (5.10, 0% extended anticoagulation). At the optimal ratio, treatment based on VTE-PREDICT yielded 44 (95% CI, −69 to 157) additional QALYs versus standard of care. ConclusionWith the current evidence, the optimal ratio between relevant bleeding risk and absolute recurrence risk reduction remains uncertain. Our results confirm that clinical equipoise exists regarding the decision to stop or continue anticoagulation after initial VTE treatment, emphasizing the importance of shared decision-making.

Clinical Outcomes of Direct Oral Anticoagulants vs Warfarin for Extended Treatment of Venous Thromboembolism

Extending the duration of oral anticoagulation for venous thromboembolism (VTE) beyond the initial 3 to 6 months of treatment is often recommended, but it is not clear whether clinical outcomes differ when using direct oral anticoagulants (DOACs) or warfarin. To compare rates of recurrent VTE, hospitalizations for hemorrhage, and all-cause death among adults prescribed DOACs or warfarin whose anticoagulant treatment was extended beyond 6 months after acute VTE. This cohort study was conducted in 2 integrated health care delivery systems in California with adults aged 18 years or older who received a diagnosis of incident VTE between 2010 and 2018 and completed at least 6 months of oral anticoagulant treatment with DOACs or warfarin. Patients were followed from the end of the initial 6-month treatment period until discontinuation of anticoagulation, occurrence of an outcome event, health plan disenrollment, or end of the study follow-up period (December 31, 2019). Data were obtained from the Kaiser Permanente Virtual Data Warehouse and electronic health records. Data analysis was conducted from March 2022 to January 2023. Dispensed prescriptions of DOACs or warfarin after a 6-month initial treatment for VTE. The primary outcomes were rates per 100 person-years of recurrent VTE, hospitalizations for hemorrhage, and all-cause death. Comparison of DOAC and warfarin outcomes were performed using multivariable Cox proportional hazards regression. A total of 18 495 patients (5477 [29.6%] aged ≥75 years; 8973 women [48.5%]) with VTE who were treated with at least 6 months of anticoagulation were identified, of whom 2134 (11.5%) were receiving DOAC therapy and 16 361 (88.5%) were receiving warfarin therapy. Unadjusted event rates were lower for patients receiving DOAC therapy than warfarin therapy for recurrent VTE (event rate per 100 person-years, 2.92 [95% CI, 2.29-3.54] vs 4.14 [95% CI, 3.90-4.38]), hospitalizations for hemorrhage (event rate per 100 person-years, 1.02 [95% CI, 0.66-1.39] vs 1.81 [95% CI, 1.66-1.97]), and all-cause death (event rate per 100 person-years, 3.79 [95% CI, 3.09-4.49] vs 5.40 [95% CI, 5.13-5.66]). After multivariable adjustment, DOAC treatment was associated with a lower risk of recurrent VTE (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.52-0.82). For patients prescribed DOAC treatment, the risks of hospitalization for hemorrhage (aHR, 0.79; 95% CI, 0.54-1.17) and all-cause death (aHR, 0.96; 95% CI, 0.78-1.19) were not significantly different than those for patients prescribed warfarin treatment. In this cohort study of patients with VTE who continued warfarin or DOAC anticoagulation beyond 6 months, DOAC treatment was associated with a lower risk of recurrent VTE, supporting the use of DOACs for the extended treatment of VTE in terms of clinical outcomes.

How do different anticoagulants compare for initial treatment of venous thromboembolism in adults with cancer?

How do different anticoagulants compare for initial treatment of venous thromboembolism in adults with cancer?

Blood thinners for the initial treatment of blood clots in people with cancer

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Lara A Kahale, Charbel F Matar, Maram B Hakoum, Ibrahim G Tsolakian, Victor ED Yosuico, Irene Terrenato, Francesca Sperati, Maddalena Barba, Holger Schnemann, Elie A Akl. Anticoagulation for the initial treatment of venous thromboembolism in people with cancer. Cochrane Database of Systematic Reviews 2021, Issue 12. Art. No.: CD006649. DOI:10.1002/14651858.CD006649.pub8

Anticoagulation for the initial treatment of venous thromboembolism in people with cancer.

Compared with people without cancer, people with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE. To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in people with cancer. We performed a comprehensive search in the following major databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid) and Embase (via Ovid). We also handsearched conference proceedings, checked references of included studies, and searched for ongoing studies. This update of the systematic review is based on the findings of a literature search conducted on 14 August 2021. Randomised controlled trials (RCTs) assessing the benefits and harms of LMWH, UFH, and fondaparinux in people with cancer and objectively confirmed VTE. Using a standardised form, we extracted data - in duplicate - on study design, participants, interventions, outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, symptomatic VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach. Of 11,484 identified citations, 3073 were unique citations and 15 RCTs fulfilled the eligibility criteria, none of which were identified in the latest search. These trials enrolled 1615 participants with cancer and VTE: 13 compared LMWH with UFH; one compared fondaparinux with UFH and LMWH; and one compared dalteparin with tinzaparin, two different types of low molecular weight heparin. The meta-analyses showed that LMWH may reduce mortality at three months compared to UFH (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.40 to 1.10; risk difference (RD) 57 fewer per 1000, 95% CI 101 fewer to 17 more; low certainty evidence) and may reduce VTE recurrence slightly (RR 0.69, 95% CI 0.27 to 1.76; RD 30 fewer per 1000, 95% CI 70 fewer to 73 more; low certainty evidence). There were no data available for bleeding outcomes, postphlebitic syndrome, quality of life, or thrombocytopenia. The study comparing fondaparinux with heparin (UFH or LMWH) found that fondaparinux may increase mortality at three months (RR 1.25, 95% CI 0.86 to 1.81; RD 43 more per 1000, 95% CI 24 fewer to 139 more; low certainty evidence), may result in little to no difference in recurrent VTE (RR 0.93, 95% CI 0.56 to 1.54; RD 8 fewer per 1000, 95% CI 52 fewer to 63 more; low certainty evidence), may result in little to no difference in major bleeding (RR 0.82, 95% CI 0.40 to 1.66; RD 12 fewer per 1000, 95% CI 40 fewer to 44 more; low certainty evidence), and probably increases minor bleeding (RR 1.53, 95% CI 0.88 to 2.66; RD 42 more per 1000, 95% CI 10 fewer to 132 more; moderate certainty evidence). There were no data available for postphlebitic syndrome, quality of life, or thrombocytopenia. The study comparing dalteparin with tinzaparin found that dalteparin may reduce mortality slightly (RR 0.86, 95% CI 0.43 to 1.73; RD 33 fewer per 1000, 95% CI 135 fewer to 173 more; low certainty evidence), may reduce recurrent VTE (RR 0.44, 95% CI 0.09 to 2.16; RD 47 fewer per 1000, 95% CI 77 fewer to 98 more; low certainty evidence), may increase major bleeding slightly (RR 2.19, 95% CI 0.20 to 23.42; RD 20 more per 1000, 95% CI 14 fewer to 380 more; low certainty evidence), and may reduce minor bleeding slightly (RR 0.82, 95% CI 0.30 to 2.21; RD 24 fewer per 1000, 95% CI 95 fewer to 164 more; low certainty evidence). There were no data available for postphlebitic syndrome, quality of life, or thrombocytopenia. Low molecular weight heparin (LMWH) is probably superior to UFH in the initial treatment of VTE in people with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review. The decision for a person with cancer to start LMWH therapy should balance the benefits and harms and consider the person's values and preferences.

Discordance between Treatment Guideline Recommendations and Real-World Practice in a Group of Large Integrated Delivery Networks for Venous Thromboembolism (VTE) Patients: A Closer Look at VTE Patients with Cancer

Background: For patients with VTE, current American Society of Hematology (ASH) guideline panel suggests using direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs) where VKAs are required to be bridged with a parenteral anticoagulant (PAC). For patients with VTE and cancer, current guidelines recommend DOACs over low molecular weight heparin (LMWH) and LMWH over unfractionated heparin (heparin) for the initial treatment of VTE. Limited evidence is available about the patterns of anticoagulant treatment for VTE in routine clinical practice of large healthcare delivery networks in the United States (US) and whether the VTE treatments are aligned with current guidelines. This study aimed to assess real-world anticoagulant treatment patterns among VTE patients using harmonized electronic health record (EHR) data from four Integrated Delivery Networks (IDNs) in the US.Methods: This was a retrospective, longitudinal, multicenter, cohort study using harmonized EHR data from both inpatient and outpatient settings. The study population included adult patients prescribed DOACs, warfarin, and/or PAC therapy as inpatient or outpatient treatment within ≤30 days of VTE diagnosis, between June 2015 through May 2018. Data from the four IDNs was pooled to describe demographic characteristics and treatment patterns among VTE patients overall and by subgroups.Results: A total of 10,527 patients who were treated with OACs after VTE diagnosis were included for analysis. The mean (SD) age was 61.9 (5.98) years, with 46.1% aged 65 or older. More than half (53.2%) were female, and White patients comprised the majority (74.4%), followed by African American patients (22.8%). Obese and morbidly obese patients comprised 39.1% and 16.1% of patients, respectively. Among all VTE patients, warfarin-only (n=3545; 33.7%) was the most commonly used OAC treatment, followed by warfarin + PAC (n=3128; 29.7%), rivaroxaban-only (n=1357; 12.9%), rivaroxaban + PAC (n=853; 8.1%), apixaban + PAC (n=839; 8.0%), apixaban-only (n=762; 7.2%), and Other OAC (n=357; 3.4%) (Table 1). When stratifying VTE patients by age, gender, race and BMI, some variations in OAC treatment were observed. Among both older (≥65 years) and younger (<65 years) patients, warfarin-only was most commonly used, then warfarin + PAC. Warfarin-only was more commonly used among obese (36.3%) and morbidly obese (40.4%) patients than non-obese (29.8%) patients. OAC treatment patterns were generally comparable among men and women. Among White patients, approximately equal proportions of patients received warfarin + PAC (31.9%) and warfarin-only (31.0%). However, among African-American patients, a higher proportion of patients used warfarin-only (40.9%) vs. warfarin + PAC (24.5%).Patterns of anticoagulant treatments including OACs and/or parental anticoagulants among VTE patients with cancer were further analyzed (Figure 1). Among VTE patients with cancer (n=3657), heparin had the highest use (26.7%), then enoxaparin (22.7%); approximately the same proportion of cancer patients received warfarin-only (16.0%) and warfarin + PAC (16.9%). Of DOACs, rivaroxaban-only was the most commonly used treatment (4.9%), then apixaban + PAC (3.5%), and lastly, rivaroxaban + PAC (3.4%) among cancer patients.Conclusion: Current VTE treatment guidelines recommend warfarin to be bridged with PAC, however, warfarin-only therapy remained the most used treatment option followed by warfarin + PAC. While rivaroxaban and apixaban are not required to be bridged with PAC, such practices were observed for a large proportion of apixaban- and rivaroxaban-treated VTE patients. VTE treatment among patients with cancer was not completely aligned with current guidelines, as heparin was more commonly used than LMWH (enoxaparin). Our findings suggest greater efforts are needed to improve anticoagulant treatment practices among VTE patients. [Display omitted] DisclosuresDhamane: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rosenblatt: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Jiang: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Guo: Bristol Myers Squibb: Ended employment in the past 24 months. Dorsch: Agency for Health Research and Quality: Research Funding; National Institutes of Health/National Institute of Aging: Research Funding; American Health Association Health IT Research Network: Research Funding; Janssen Pharmaceuticals: Honoraria; Bristol Myers Squibb/Pfizer: Research Funding; Amgen: Research Funding. Luo: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company.

Long-Term Survival After Venous Thromboembolism: A Prospective Cohort Study.

Background: Little is known about long-term survival after the initial treatment of venous thromboembolism (VTE). In a prospective cohort study, we aimed to assess the long-term mortality and key predictor variables relating to disease severity, treatment intensity, and comorbidities.Materials and Methods: Between 1988 and 2018, 6,243 consecutive patients with VTE from a University outpatient unit were prospectively included and followed until December 2019; clinical characteristics, measures of disease severity, and treatment details were recorded. Dates of death were retrieved from the Swiss Central Compensation Office.Results: Overall, 254 deaths occurred over an observation period of 57,212 patient-years. Compared to the Swiss population, the standardized mortality ratio was 1.30 (95% CI: 1.14, 1.47; overall mortality rate: 4.44 per 1,000 patient-years). The following predictors were associated with increased mortality: Unprovoked VTE (hazard ratio [HR]: 5.06; 95% CI: 3.29, 7.77), transient triggering risk factors (HR: 3.46; 95% CI: 2.18, 5.48), previous VTE (HR: 2.05; 95% CI: 1.60, 2.62), pulmonary embolism (HR: 1.45, 95% CI: 1.10, 1.89), permanent anticoagulant treatment (HR: 3.14; 95% CI: 2.40, 4.12), prolonged anticoagulant treatment (7–24 months; HR: 1.70; 95% CI: 1.16, 2.48), and cardiovascular comorbidities. Unprovoked VTE, previous VTE, permanent and prolonged anticoagulation remain independent risk factors after adjustment for age, sex, and comorbidities.Conclusion: Survival after VTE was significantly reduced compared to the Swiss general population, especially in patients with more severe disease, cardiovascular comorbidities, and longer anticoagulant treatment.

Prediction models for recurrence and bleeding in patients with venous thromboembolism: A systematic review and critical appraisal

IntroductionPrediction models for recurrence and bleeding are infrequently used when deciding on anticoagulant treatment duration after venous thromboembolism (VTE) due to concerns about performance and validity. Our aim was to critically appraise these models by systematically summarizing data from derivation and validation studies. Materials and methodsMEDLINE and CENTRAL were searched until November 15th, 2019. Studies on prediction models for recurrence or bleeding after at least 3 months of anticoagulation in adult patients with VTE were included. The PROBAST, ROBINS-I and RoB2 tools were used to assess risk of bias and applicability. ResultsSelection yielded 18 studies evaluating 8 models for recurrence (7 on development; 9 on validation; 1 update). Generally, models for recurrent VTE appeared to perform poorly to moderately in external validation studies (C-statistics 0.39–0.66, one 0.83). However, impact studies show that HERDOO2 and Vienna prediction model may identify patients with unprovoked VTE at low recurrence risk. Sixteen studies evaluating 14 models for anticoagulation-related bleeding were identified (7 on development; 9 on validation). Although some models seemed promising in development studies, their predictive performance was poor to moderate in external validation (C-statistics 0.52–0.71). All but 3 studies were considered at high risk of bias, mainly due to limitations in the statistical analysis. ConclusionsPrognostic models for recurrence and anticoagulation-related bleeding risk often have important methodological limitations and insufficient predictive accuracy. These findings do not support their use in clinical practice to weigh risks of recurrence and bleeding when deciding on continuing anticoagulation after initial treatment of VTE.

Treatment Patterns and Clinical Outcomes in Korean Cancer Patients With Venous Thromboembolism: A Retrospective Cohort Study.

This study assessed epidemiologic data and clinical outcomes, including venous thromboembolism (VTE) recurrence and bleeding events, in patients with cancer-associated VTE, and assessed factors associated with clinical outcomes. Data were extracted from retrospective medical-chart review of adult patients diagnosed with cancer-associated deep vein thrombosis or pulmonary embolism who received anticoagulation treatment for ≥3 months. Patients were classified by: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and other anticoagulants. First VTE recurrence and bleeding events, and factors associated with their occurrence, were assessed during the initial 6 months of treatment. Overall, 623 patients (age: 63.7 ± 11.3 years, 49.3% male) were included (119, 132, and 372 patients in LMWH, DOACs and other anticoagulants groups, respectively). The cumulative 6-month incidence of VTE recurrence was 16.6% (total), 8.3% (LMWH), 16.7% (DOACs), and 20.7% (other); respective bleeding events were 22.5%, 11.0%, 12.3%, and 30.7%). VTE recurrence and bleeding rates differed only between LMWH and other anticoagulants (HR 2.4, 95% CI: 1.2-5.0 and 3.6, 1.9-6.8, respectively). These results highlight the importance of initial VTE treatment choice for preventing VTE recurrence and bleeding events. LMWH or DOACs for ≥3 months can be considered for effective VTE management in cancer patients.

The correlations between anti-factor Xa activity values and PT/APTT at peak and trough times in patients with venous thromboembolism using high dose of apixaban

Abstract Background The high dose (20mg/day) of apixaban is used for the initial treatment of venous thromboembolism for the first week. Although patients taking direct oral anticoagulants do not require routine coagulation monitoring, the correlations between anti-factor Xa activity (AXA) and routine coagulation markers such as prothrombin time (PT) and activated partial thromboplastin time (APTT) at peak and trough times especially when using high dose of apixaban have not been reported so far. Purpose The purpose is to assess the correlations between AXA values and PT/APTT at peak and trough times in patients with venous thromboembolism using high dose of Apixaban. Methods Twenty-six patients (10 male; 71±15 years) with proximal venous thromboembolism or pulmonary embolism using high dose (20mg/day) of apixaban were enrolled. We measured AXA, using chromogenic assay with the HemosIL Liquid Heparin kit, PT and APTT at peak and trough times. The peak time was defined as 3 hours after the intake of apixaban, and the trough time was defined as that immediately before the intake of apixaban. Results A significant and strong positive correlation was observed between AXA and PT at both peak and trough times (R=0.795, p&amp;lt;0.01 and R=0.766, p&amp;lt;0.01, respectively). A significant and moderate positive correlation was observed between AXA and APTT at trough time (R=0.527, p&amp;lt;0.01), but no correlation was observed between AXA and APTT at peak time (R=0.366, p=0.07). Conclusion Our findings reveal the relationship between AXA and PT at peak and trough times has a significant strong correlation. These results suggest measuring of PT may be alternative and effective way of monitoring of AXA values when using high dose of apixaban. Figure 1 Funding Acknowledgement Type of funding source: None

Once-daily vs. twice-daily dosing of enoxaparin for the management of venous thromboembolism: A systematic review and meta-analysis.

The present study aimed to determine whether there is any difference in the efficacy and safety of once-daily vs. twice-daily enoxaparin when used for the initial treatment of venous thromboembolism (VTE). The PubMed, Embase, Cochrane Central Register of Controlled Trials, Science Direct and Google Scholar databases were searched for studies comparing once-daily and twice-daily enoxaparin for the initial treatment of VTE added from inception up to 1st October 2019. Studies utilizing any other low-molecular-weight heparin and using enoxaparin for VTE prophylaxis were excluded. A total of 6 studies were included in the systematic review and 5 in the meta-analysis. Only one study was a randomized controlled trial (RCT). Pooled analysis of 460 patients receiving once-daily enoxaparin and 464 patients receiving twice-daily enoxaparin indicated no significant difference between the two dosing regimens regarding VTE recurrence [odds ratio (OR)=1.48, 95%CI: 0.75-2.89, P=0.26; I2=0%]. No significant difference in major hemorrhagic complications was noted (OR=1.21, 95%CI: 0.52-2.81, P=0.66; I2=0%). Sub-group analysis based on study type and use of enoxaparin for bridging therapy did not change the overall results. In cancer patients, no statistically significant difference in the recurrence of VTE was obtained between once-daily and twice-daily enoxaparin, but the confidence intervals were wide with a tendency to favor twice-daily dosing (OR=2.28, 95%CI: 0.91-5.75, P=0.08; I2=0%). The overall quality of the studies was determined to be average. To conclude, while the present results suggested no significant difference in efficacy and safety of once-daily vs. twice-daily enoxaparin when used for the initial treatment of VTE, the quality of the evidence may not have been sufficiently high to support the conclusions with confidence. Further high-quality and adequately powered RCTs are required to corroborate the present results.

Cost-effectiveness of rivaroxaban versus apixaban for the initial treatment of venous thromboembolism and extended prevention of recurrences in the UK

Aim: To evaluate the relative cost-effectiveness of using rivaroxaban vs apixaban for the initial treatment plus extended prevention of venous thromboembolism (VTE) in the UK. Extended prevention was assessed using a 10-mg rivaroxaban dose, as the 20-mg dose has already been evaluated.Methods: A Markov model compared the health outcomes and costs of treating VTE patient cohorts with either rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily for 6 months, then extended prevention with 10 mg once daily) or apixaban (10 mg twice daily for 1 week, followed by 5 mg twice daily for 6 months, then extended prevention with 2.5 mg twice daily) over a lifetime horizon. The model included an initial acute treatment and prevention phase (0–6 months) and an extended prevention phase (6–18 months). Efficacy and safety data were derived from two network meta-analyses. Reference treatment comparators were derived from the EINSTEIN-Pooled study and EINSTEIN-CHOICE trial. Healthcare costs and utility data were derived from published literature.Results: The rivaroxaban regimen was associated with increased quality-adjusted life years (QALYs) and slightly lower total costs compared with apixaban over a lifetime horizon. Deterministic and probabilistic sensitivity analyses demonstrated that rivaroxaban remained a cost-effective alternative to apixaban over a wide range of parameters. Incremental cost-effectiveness ratio estimates were below the £20,000 per QALY threshold in 74.1% of 2,000 model simulations. Scenario analyses further supported that rivaroxaban is a cost-effective alternative to apixaban.Limitations: Clinical and safety inputs were derived from network meta-analysis, which are subject to inherent limitations whereby small differences between study designs may severely impact efficacy and safety outcomes. Furthermore, these inputs were based on data from clinical trials, which may not reflect real-world data.Conclusions: Rivaroxaban was associated with a slightly lower total cost and increased QALYs compared with apixaban for VTE management in the UK over a lifetime horizon.

Updates on Prophylaxis for Deep Venous Thrombosis and Venous Thromboembolism

Purpose To concisely present recommendations and guidelines for venous thromboembolism (VTE) treatment and prevention for common subgroups of surgical patients as a comprehensive reference for clinical surgical practice.Methods Thorough literature review, including the consensus guidelines and recommendations of various professional surgical societies, was evaluated and conglomerated to provide a comprehensive reference for practicing surgeons. Common surgical patient subgroups were investigated for differing recommendations. Recommendations, guidelines, and resources were tabulated into user-friendly formats for easy reference purposes.Results Substantial updates have been made to the recommendations for VTE prevention and treatment. The American College of Chest Physicians (ACCP) have updated their VTE recommendations. The Eastern Association for the Surgery of Trauma has also released updated recommendations regarding VTE management. The Society of American Gastrointestinal and Endoscopic Surgeons has recalled their own specific recommendations for VTE treatment and prophylaxis in support of tenth edition of the ACCP guidelines on the subject.Conclusions VTE affects up to 25% of hospitalized patients, with up to 30% of those experiencing complications. Risk stratification is important in choosing therapy for prevention and management of VTE. Management of VTE depends on precipitating factors and future risk of VTE progression versus bleeding. Low-molecular-weight heparin is the preferred anticoagulant for initial treatment of VTE. The tenth edition of ACCP VTE guidelines provides comprehensive management recommendations.

Anticoagulant Preferences and Concerns among Venous Thromboembolism Patients.

Background Warfarin and direct oral anticoagulants (DOACs) are used for the initial treatment and secondary prevention of venous thromboembolism (VTE), and have similar efficacy. Patient concerns and preferences are important considerations when selecting an anticoagulant, yet these are not well studied. Methods VTE patients ( n = 519) were surveyed from online sources (clotconnect.org, stoptheclot.org and National Blood Clot Alliance Facebook followers [ n = 495]) and a haematology clinic in Vermont ( n = 24). Results Patients were 83% females and on average (±standard deviation [SD]) 45.7 ± 13.1 years; 65% self-reported warfarin as their initial VTE treatment and 35% a DOAC. Proportions reporting being extremely concerned about the following outcomes were as follows: recurrent VTE 33%, major bleeding 21%, moderate bleeding 16% and all-cause death 29%. When asked about oral anticoagulant characteristics, patients strongly preferred anticoagulants that are reversible (53%), and for which blood drug levels can be monitored (30%). Lower proportions agreed with statements that regular blood testing is inconvenient (18%), that they are comfortable using the newest drug versus an established drug (15%) and that it is difficult to change their diet to accommodate their anticoagulant (17%). In multivariable-adjusted models, patients tended to have had as their initial treatment, and to currently be taking, the oral anticoagulant option they personally preferred. Discussion Patients held the greatest concern for recurrent VTE and mortality, regardless of which treatment they were prescribed. Potential weaknesses of warfarin (e.g., dietary restrictions, regular monitoring) were generally not considered onerous, while warfarin's advantages (e.g., ability to monitor) were viewed favourably.

Anticoagulation for the initial treatment of venous thromboembolism in people with cancer.

Compared with people without cancer, people with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE. To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in people with cancer. A comprehensive search included a major electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2018, Issue 1), MEDLINE (via Ovid) and Embase (via Ovid); handsearching of conference proceedings; checking of references of included studies; use of the 'related citation' feature in PubMed; and a search for ongoing studies. This update of the systematic review was based on the findings of a literature search conducted on 14 January 2018. Randomized controlled trials (RCTs) assessing the benefits and harms of LMWH, UFH, and fondaparinux in people with cancer and objectively confirmed VTE. Using a standardized form, we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interested included all-cause mortality, symptomatic VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach. Of 15440 identified citations, 7387 unique citations, 15 RCTs fulfilled the eligibility criteria. These trials enrolled 1615 participants with cancer and VTE: 13 compared LMWH with UFH enrolling 1025 participants, one compared fondaparinux with UFH and LMWH enrolling 477 participants, and one compared dalteparin with tinzaparin enrolling 113 participants. The meta-analysis of mortality at three months included 418 participants from five studies and that of recurrent VTE included 422 participants from 3 studies. The findings showed that LMWH likely decreases mortality at three months compared to UFH (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.40 to 1.10; risk difference (RD) 57 fewer per 1000, 95% CI 101 fewer to 17 more; moderate certainty evidence), but did not rule out a clinically significant increase or decrease in VTE recurrence (RR 0.69, 95% CI 0.27 to 1.76; RD 30 fewer per 1000, 95% CI 70 fewer to 73 more; moderate certainty evidence).The study comparing fondaparinux with heparin (UFH or LMWH) did not exclude a beneficial or detrimental effect of fondaparinux on mortality at three months (RR 1.25, 95% CI 0.86 to 1.81; RD 43 more per 1000, 95% CI 24 fewer to 139 more; moderate certainty evidence), recurrent VTE (RR 0.93, 95% CI 0.56 to 1.54; RD 8 fewer per 1000, 95% CI 52 fewer to 63 more; moderate certainty evidence), major bleeding (RR 0.82, 95% CI 0.40 to 1.66; RD 12 fewer per 1000, 95% CI 40 fewer to 44 more; moderate certainty evidence), or minor bleeding (RR 1.53, 95% CI 0.88 to 2.66; RD 42 more per 1000, 95% CI 10 fewer to 132 more; moderate certainty evidence)The study comparing dalteparin with tinzaparin did not exclude a beneficial or detrimental effect of dalteparin on mortality (RR 0.86, 95% CI 0.43 to 1.73; RD 33 fewer per 1000, 95% CI 135 fewer to 173 more; low certainty evidence), recurrent VTE (RR 0.44, 95% CI 0.09 to 2.16; RD 47 fewer per 1000, 95% CI 77 fewer to 98 more; low certainty evidence), major bleeding (RR 2.19, 95% CI 0.20 to 23.42; RD 20 more per 1000, 95% CI 14 fewer to 380 more; low certainty evidence), or minor bleeding (RR 0.82, 95% CI 0.30 to 2.21; RD 24 fewer per 1000, 95% CI 95 fewer to 164 more; low certainty evidence). LMWH is possibly superior to UFH in the initial treatment of VTE in people with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review. The decision for a person with cancer to start LMWH therapy should balance the benefits and harms and consider the person's values and preferences.

ORAL ANTICOAGULANTS IN THE TREATMENT OF VENOUS THROMBOEMBOLIC COMPLICATIONS: FOCUS ON APIXABAN

Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is a common condition associated with a significant clinical and economic burden. Anticoagulant therapy is the mainstay of treatment for VTE. Current guidelines recommend the use of either low molecular weight heparins or fondaparinux overlapping with and followed by a vitamin K antagonist for the initial treatment of VTE, with the vitamin K antagonist continued when long-term anticoagulation is required. These traditional anticoagulants have practical limitations that have led to the development of direct oral anticoagulants that directly target either Factor Xa or thrombin and are administered at a fixed dose without the need for routine coagulation monitoring. The paper reviews results of the trials of apixaban application for treatment and/or long-term secondary prevention of VTE. The paper analyses effectiveness and safety of apixaban in different groups of patients, as well as features of apixaban application in every day practice.

Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism.

Venous thromboembolism (VTE) is a prevalent and serious condition. Its medical treatment requires anticoagulation, usually with either unfractionated or low molecular weight heparin (LMWH). Administration of unfractionated heparin (UFH) is usually intravenous (IV) but can be subcutaneous as well. This is an update of a review first published in 2009. To assess the effects of subcutaneous UFH versus intravenous UFH, subcutaneous LMWH or any other anticoagulant drug for the initial treatment of venous thromboembolism. For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched 30 November 2016) and CENTRAL (2016, Issue 10). The Cochrane Vascular Information Specialist also searched trials registries for details of ongoing or unpublished studies. Randomised controlled trials comparing subcutaneous UFH to control, such as subcutaneous LMWH, continuous intravenous UFH or other anticoagulant drugs in participants with acute venous thromboembolism. Two review authors (JS and LR) independently extracted data and assessed the risk of bias in the trials. We used meta-analyses when we considered heterogeneity low. The primary outcomes were symptomatic recurrent venous thromboembolism (deep vein thrombosis and/or pulmonary embolism), VTE-related mortality, adverse effects of treatment including major bleeding, and all-cause mortality. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI). We included one additional study in this update, bringing the total number of studies in the review to 16 randomised controlled trials, with a total of 3593 participants (1745 participants in the intervention group and 1848 participants in the control group). Eight trials used intravenous UFH as the control treatment, seven trials used LMWH, and one trial had three arms with both drugs as the controls. We did not identify trials comparing subcutaneous UFH with other anticoagulant drugs. We downgraded the quality of the evidence to low due to lack of blinding in studies, which led to a risk of performance bias, and also for imprecision, as reflected by the wide confidence intervals.When comparing subcutaneous versus IV UFH, there was no difference in the incidence of symptomatic recurrent VTE at three months (odds ratio (OR) 1.66, 95% confidence interval (CI) 0.89 to 3.10; 8 studies; N = 965; low-quality evidence), symptomatic recurrent deep vein thrombosis (DVT) at three months (OR 3.29, 95% CI 0.64 to 17.06; 1 study; N = 115; low-quality evidence), pulmonary embolism (PE) at three months (OR 1.44, 95% CI 0.73 to 2.84; 9 studies; N = 1161; low-quality evidence), VTE-related mortality at three months (OR 0.98, 95% CI 0.20 to 4.88; 9 studies; N = 1168; low-quality evidence), major bleeding (OR 0.91, 95% CI 0.42 to 1.97; 4 studies; N = 583; low-quality evidence) or all-cause mortality (OR 1.74, 95% CI 0.67 to 4.51; 8 studies; N = 972; low-quality evidence). There were no episodes of asymptomatic VTE occurring within three months of the commencement of treatment.When comparing subcutaneous UFH versus LMWH, there was no difference in the incidence of recurrent VTE at three months (OR 1.01, 95% CI 0.63 to 1.63; 5 studies; N = 2156; low-quality evidence), recurrent DVT at three months (OR 1.38, 95% CI 0.73 to 2.63; 3 studies; N = 1566; low-quality evidence), PE (OR 0.84, 95% CI 0.36 to 1.96; 5 studies, N = 1819; low-quality evidence), VTE-related mortality (OR 0.53, 95% CI 0.17 to 1.67; 8 studies; N = 2469; low-quality evidence), major bleeding (OR 0.72, 95% CI 0.43 to 1.20; 5 studies; N = 2300; low-quality evidence) or all-cause mortality (OR 0.73, 95% CI 0.50 to 1.07; 7 studies; N = 2272; low-quality evidence). There were no episodes of asymptomatic VTE occurring within three months of the commencement of treatment. There is no evidence of a difference between subcutaneous versus intravenous UFH for preventing VTE recurrence, VTE-related or all-cause mortality, and major bleeding. According to GRADE criteria, the quality of the evidence was low. There is also no evidence of a difference between subcutaneous UFH and LMWH for preventing VTE recurrence, VTE-related or all-cause mortality or major bleeding.

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for the initial treatment of venous thromboembolism.

Low molecular weight heparins (LMWHs) have been shown to be effective and safe in preventing venous thromboembolism (VTE). They may also be effective for the initial treatment of VTE. This is the third update of the Cochrane Review first published in 1999. To evaluate the efficacy and safety of fixed dose subcutaneous low molecular weight heparin compared to adjusted dose unfractionated heparin (intravenous or subcutaneous) for the initial treatment of people with venous thromboembolism (acute deep venous thrombosis or pulmonary embolism). For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (15 September 2016). In addition the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 15 September 2016) and trials' registries. Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous unfractionated heparin (UFH) in people with VTE. Two review authors independently selected trials for inclusion, assessed for quality and extracted data. Six studies were added to this update resulting in a total of 29 included studies (n = 10,390). The quality of the studies was downgraded as there was a risk of bias in some individual studies relating to risk of attrition and reporting bias; in addition several studies did not adequately report on the randomisation methods used nor on how the treatment allocation was concealed.During the initial treatment period, the incidence of recurrent venous thromboembolic events was lower in participants treated with LMWH than in participants treated with UFH (Peto odds ratio (OR) 0.69, 95% confidence intervals (CI) 0.49 to 0.98; 6238 participants; 18 studies; P = 0.04; moderate-quality evidence). After a follow-up of three months, the period in most of the studies for which oral anticoagulant therapy was given, the incidence of recurrent VTE was lower in participants treated with LMWH than in participants with UFH (Peto OR 0.71, 95% CI 0.56 to 0.90; 6661 participants; 16 studies; P = 0.005; moderate-quality evidence). Furthermore, at the end of follow-up, LMWH was associated with a lower rate of recurrent VTE than UFH (Peto OR 0.72, 95% CI 0.59 to 0.88; 9489 participants; 22 studies; P = 0.001; moderate-quality evidence). LMWH was also associated with a reduction in thrombus size compared to UFH (Peto OR 0.71, 95% CI 0.61 to 0.82; 2909 participants; 16 studies; P < 0.00001; low-quality evidence), but there was moderate heterogeneity (I² = 56%). Major haemorrhages occurred less frequently in participants treated with LMWH than in those treated with UFH (Peto OR 0.69, 95% CI 0.50 to 0.95; 8780 participants; 25 studies; P = 0.02; moderate-quality evidence). There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (Peto OR 0.84, 95% CI 0.70 to 1.01; 9663 participants; 24 studies; P = 0.07; moderate-quality evidence). This review presents moderate-quality evidence that fixed dose LMWH reduced the incidence of recurrent thrombotic complications and occurrence of major haemorrhage during initial treatment; and low-quality evidence that fixed dose LMWH reduced thrombus size when compared to UFH for the initial treatment of VTE. There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (moderate-quality evidence). The quality of the evidence was assessed using GRADE criteria and downgraded due to concerns over risk of bias in individual trials together with a lack of reporting on the randomisation and concealment of treatment allocation methods used. The quality of the evidence for reduction of thrombus size was further downgraded because of heterogeneity between studies.

New developments in anticoagulants: Past, present and future.

Thrombosis is a leading cause of death and disability worldwide, and anticoagulants are the mainstay of its prevention and treatment. Starting with unfractionated heparin (UFH) and vitamin K antagonists (VKAs) such as warfarin, the choices of anticoagulants have exploded in the past 20 years. With over 90 % subcutaneous bioavailability, no need for coagulation monitoring and dose adjustment, and a lower risk of heparin-induced thrombocytopenia, low-molecular-weight heparin and fondaparinux have replaced UFH for prevention and initial treatment of venous thromboembolism and for secondary prevention in cancer patients. In patients undergoing percutaneous interventions, bivalirudin is often used instead of UFH. Oral anticoagulation therapy has advanced with the introduction of the non-vitamin K antagonist oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban and edoxaban. With efficacy at least equal to that of VKAs but with greater safety and convenience, the NOACs are now replacing VKAs for many indications. This paper a) highlights these advances, b) outlines how specific reversal agents for the NOACs will enhance their safety, c) reviews some of the ongoing trials with the NOACs, and d) describes the inhibitors of factor XII and XI that are under investigation as anticoagulants.

Cost-effectiveness of Apixaban Versus Other Oral Anticoagulants for the Initial Treatment of Venous Thromboembolism and Prevention of Recurrence

PurposeTo assess the cost-effectiveness of apixaban versus rivaroxaban, low-molecular-weight heparin (LMWH)/dabigatran, and LMWH/vitamin K antagonist (VKA) for the initial treatment and prevention of recurrent thromboembolic events in patients with venous thromboembolism (VTE). MethodsA Markov model was developed to evaluate the pharmacoeconomic effect of 6 months of treatment with apixaban versus other anticoagulants over a lifetime horizon. Network meta-analyses were conducted using the results of the Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy (AMPLIFY), EINSTEIN-pooled, and RE-COVER I and II trials for the following end points: recurrent VTE, major bleeds, clinically relevant non-major bleeds, and treatment discontinuations. The analysis was conducted from the perspective of the United Kingdom National Health Service. The outcomes evaluated were the number of events avoided in a 1000-patient cohort, total costs, life years, quality-adjusted life years (QALYs), and cost per QALY gained over a patient’s lifetime. FindingsTreatment for 6 months with apixaban was projected to result in fewer recurrent VTE and bleeding events in comparison to rivaroxaban, LMWH/dabigatran, and LMWH/VKA. Apixaban was cost-effective compared with LMWH/VKA at an incremental cost-effectiveness ratio of £2520 per QALY gained and was a dominant (ie, lower costs and higher QALYs) alternative to either rivaroxaban or LMWH/dabigatran. Sensitivity analysis indicated that results were robust over a wide range of inputs. ImplicationsThe assessment of the effects and costs of apixaban in this study predicted that apixaban is a dominant alternative to rivaroxaban and LMWH/dabigatran and a cost-effective alternative to LMWH/VKA for 6 months of treatment of VTE and the prevention of recurrence.