Months Of Anticoagulant Treatment Research Articles

Effect of a 3-Month Single-Drug Approach Using Rivaroxaban for Symptomatic Proximal Deep Vein Thrombosis.

Background: Factor Xa inhibitors, such as rivaroxaban, are increasing the convenience of treatment for deep vein thrombosis (DVT). Limited evidence exists regarding clot evaluation at 3 months after treatment for DVT. Methods and Results: We retrospectively analyzed the clinical course of symptomatic proximal DVT in patients who received 3 months of anticoagulation treatment at our hospital. Patients treated with the rivaroxaban single-drug approach were classified as group A (n=42). Patients treated with unfractionated heparin (UFH) or subcutaneous fondaparinux followed by vitamin K antagonist comprised group B (n=60) as an historical cohort. The quantitative ultrasound thrombosis (QUT) score was used to quantify clot burden before and after treatment. No significant differences were observed in patient characteristics between the groups. Serum D-dimer levels in both groups significantly improved after treatment. Clot volume assessed using QUT also reduced significantly in both groups. The QUT score in groups A and B improved from 7.5 [4.8, 12.0] to 3.0 [1.8, 5.0; P=0.000] and 7.0 [4.0, 9.8] to 3.0 [2.0, 5.0; P=0.000], respectively. The change in QUT (∆QUT) was significantly greater in group A compared with group B (-4.5 [-8.25, -2.0] vs. -2.0 [-6.0, 0.0]; P=0.005). Conclusions: We were able to demonstrate the effectiveness of DVT treatment using rivaroxaban over a period of 3 months from onset, in terms of clot regression evaluated using the QUT score.

Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism: a systematic review and meta-analysis of individual participant data

We aimed to assess the relationship between residual pulmonary vascular obstruction (RPVO) on planar lung scan after completion of at least 3 months of anticoagulant therapy for acute pulmonary embolism (PE) and the risk of recurrent venous thromboembolism (VTE) or death due to PE one year after treatment discontinuation. The systematic review was registered with the International Prospective Registry of Systematic Reviews (PROSPERO: CRD42017081080). The primary outcome measure was to generate a pooled estimate of the rate of recurrent VTE at one year in patient with RPVO diagnosed on planar lung scan after discontinuation of at least 3 months of anticoagulant treatment for an acute PE. Individual data were obtained for 809 patients. RPVO (ie, obstruction >0%) was found in 407 patients (50.3%) after a median of 6.6 months of anticoagulant therapy for a first acute PE. Recurrent VTE or death due to PE occurred in 114 patients (14.1%), for an annual risk of 6.4% (95% confidence interval, 4.7%-8.6%). Out of the 114 recurrent events, 63 occurred within one year after discontinuation of anticoagulant therapy corresponding to a risk of 8.1% (6.4%-9.8%) at 1 year. The risk of recurrent VTE at one year was 5.8% (4.4-7.2) in participants with RPVO <5%, vs 11.7% (9.5-13.8) in participants with RPVO ≥5%. RPVO is a significant predictor of the risk of recurrent venous thromboembolism. However, the risk of recurrent events remains too high in patients without residual perfusion defect for it to be used as a stand-alone test to decide on anticoagulation discontinuation.

Mass-spectrometric identification of oxidative modifications in plasma-purified plasminogen: Association with hypofibrinolysis in patients with acute pulmonary embolism

ObjectivesMechanisms behind disturbed fibrinolysis in pulmonary embolism (PE) are poorly understood. We hypothesized that oxidative stress-induced changes in plasminogen contribute to impaired fibrinolysis in patients with acute PE. MethodsOxidative and other modifications were investigated using mass-spectrometry in plasminogen purified from pooled plasma of 5 acute PE patients on admission and after 3 months of anticoagulant treatment, along with plasma clot lysis time, a measure of global efficiency of fibrinolysis, and a stable oxidative stress marker, plasma 8-isoprostane. ResultsTwenty sites of oxidation, 3 sites of carbonylation and 4 sites of S-nitrosylation were identified in plasminogen. The intensity of peptides oxidized at cysteine residues with respect to unmodified peptides decreased after 3 months of anticoagulation (p = 0.018). This was not observed for oxidized methionine residues (p = 0.9). Oxidized tryptophan (n = 4) and proline (n = 2), as well as carbonylation at 3 threonine residues were selectively identified in acute PE episode, not after 3 months. This was accompanied by 12.8% decrease in clot lysis time (p = 0.043). Deamidation occurred at the arginine, previously identified to undergo the cleavage by plasminogen activator. Methylated were two lysine-binding sites important for an interaction of plasminogen with fibrin. Other identified modifications involved: glycation, acetylation, phosphorylation, homocysteinylation, carbamylation and dichlorination (88 modifications at 162 sites). ConclusionsData suggest that oxidative stress-induced changes in plasminogen molecules may contribute to less effective global fibrinolysis in patients with acute PE. The comprehensive library of posttranslational modifications in plasminogen molecules was provided, including modifications of sites reported to be involved in important biological functions.

Biomarkers of Venous Thromboembolism Recurrence after Discontinuation of Low Molecular Weight Heparin Treatment for Cancer-Associated Thrombosis (HISPALIS-Study).

Simple SummaryThe duration of anticoagulant treatment for venous thromboembolism in cancer patients is not well defined. The decision to suspend or re-introduce anticoagulation is based on an individual assessment between thrombotic and hemorrhagic risk. In this study, three biomarkers have shown the ability to help the clinician in decision making. Although these results should be evaluated in further studies, they open up a possibility of change in the management of cancer associated thrombosis patients.The most appropriate duration of anticoagulant treatment for cancer-associated venous thromboembolism (CAT) remains unclear. We have conducted a prospective multicenter study in CAT patients with more than 6 months of anticoagulant treatment to predict the risk of venous thromboembolism (VTE) recurrence after anticoagulation discontinuation. Blood samples were obtained when patients stopped the anticoagulation, at 21 days and at 90 days. In each sample we assessed different coagulation-related biomarkers: D-dimer (DD), high-sensitivity C-reactive protein (hs-CRP), P-selectin (PS), phospholipids, soluble tissue factor, factor VIII and the thrombin generation test. It was evaluated 325 CAT patients and 166 patients were included in the study, mean age 64 ± 17 years. VTE recurrence until 6 months after stopping anticoagulation treatment was 9.87% [95% confidence interval (CI): 6–15]. The biomarkers sub-distribution hazard ratios were 6.32 for ratio DD basal/DD 21 days > 2 (95% CI: 1.82–21.90), 6.36 for hs-CRP > 4.5 (95% CI: 1.73–23.40) and 5.58 for PS > 40 (95% CI: 1.46–21.30) after 21 days of stopping anticoagulation. This is the first study that has identified the DD ratio, hs-CRP and PS as potential biomarkers of VTE recurrence in cancer patients after the discontinuation of anticoagulation treatment. A risk-adapted strategy may allow the identification of the optimal time to withdraw the anticoagulation in each CAT patient.

Adherence Trajectories of Extended Direct-Acting Oral Anticoagulants and Risk of Recurrent Venous Thromboembolism and Major Bleeding: A Retrospective Cohort Study

▪Introduction: The optimal duration of extended oral anticoagulant treatment for patients with venous thromboembolism (VTE) beyond the initial 3 to 6 months of the treatment remains undetermined. Group-based trajectory modeling (GBTM) is a data-driven method that can categorize patients with similar longitudinal adherence patterns over time into distinct subgroups. This study identified distinct patient subgroups with similar adherence trajectories of extended treatment of direct-acting oral anticoagulants (DOACs), and then examined the association between adherence trajectories and the risk of recurrent VTE and major bleeding among patients with VTE.Methods: We identified patients ≥18 years with a diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE) from inpatient claims using 2013-2019 Truven Commercial and Medicare Supplemental database. Patients were included if they initiated anticoagulants within 30 days of their first VTE diagnosis, completed 6 months of therapy-defined as ≥83% proportion days covered (PDC) with oral anticoagulants during the initial 6-month treatment period, and had extended treatment with any DOACs or no extended therapy. Based on the monthly PDC as the DOAC adherence measure, we used GBTM to identify DOAC adherence trajectories during 6 months of the extended treatment. The final trajectory model was chosen by assessing the Bayesian information criteria, Nagin's criteria, and having at least 10% of patients in each trajectory group for improving clinical utility. We compared recurrent VTE and major bleeding among adherence trajectory subgroups. Patients were followed up from the initiation of the extended treatment until the occurrence of the study outcomes, discontinuation of DOACs, switching to warfarin, end of study period, or end of enrollment, whichever occurred first. Cox proportional hazard modeling with inverse probability treatment weighting (IPTW) was used to obtain hazard ratios (HR) and 95% confidence intervals (95% CI).Results: The study cohort (mean age=58.7 years and 51.1% males) consisted of 10,960 patients with extended treatment of DOACs (4,294 apixaban, 6,409 rivaroxaban, 238 dabigatran, and 19 edoxaban users) with a mean treatment duration of 7.7 months and 5,133 patients with no extended treatment following completion of an initial 6 months of anticoagulant treatment. The final GBTM models identified four distinct adherence trajectories for extended therapy including (1) patients with consistent adherence (group 1, 40.7%), (2) patients with gradually declining adherence (group 2, 14.3%), (3) patients with rapidly declining adherence (group 3, 13.1%), and (4) patients with no extended treatment (reference group, 31.9%) (Figure 1). The incidence rates of recurrent VTE were 18.6, 46.9, 84.1, and 160.7 per 10,000 person-years, and those of major bleeding were 61.0, 125.1, 168.3, and 48.7 per 10,000 person-years in group 1, group 2, group 3, and the reference group, respectively. After IPTW, demographics and clinical characteristics (e.g., HAS-BLED bleeding risk score, provoked VTE) were comparable across the four trajectory groups with <0.1 of the standardized mean difference for each pairwise comparison. Compared to the reference group, group 1 (HR=0.09, 95% CI=0.05-0.17) and group 2 (HR=0.16, 95% CI=0.04-0.58) had decreased risk of recurrent VTE without increasing risk of major bleeding (HR=1.26, 95% CI=0.76-2.10 in group 1, HR=2.28, 95% CI=0.96-5.36 in group 2). There was no difference in the risk of recurrent VTE (HR=0.32, 95% CI=0.09-1.16) in group 3 but they had an increased risk of major bleeding (HR=2.69, 95% CI=1.00-7.23). The findings were consistent across different types of DOACs, suggesting a class effect of DOACs as extended therapy.Conclusions: We identified 4 distinct trajectories of DOAC adherence during the 6 months of extended therapy among patients who completed 6 months of initial treatment. Compared to no extended treatment, persistent use of DOACs during extended treatment was associated with a lower risk of recurrent VTE without increasing major bleeding risk, whereas a rapid decline in adherence was associated with an increased risk of major bleeding with no difference in the risk of recurrence. Our findings provide evidence on the benefits of continuing and being adherent to extended anticoagulant treatment in patients with VTE without increasing the risk of major bleeding. [Display omitted] DisclosuresKang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Jones: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Lo-Ciganic: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding; MERCK: Research Funding. DeRemer: BMS advisory board attendee: Honoraria; Portola Pharmaceuticals: Current equity holder in publicly-traded company; BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Dietrich: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Huang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Murphy: North American Thrombosis Foundation: Honoraria. Park: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding.

Comparative Effectiveness and Safety of Extended Anticoagulant Therapy Among Medicare Beneficiaries with Venous Thromboembolism

▪Introduction: Approximately 30% of patients with venous thromboembolism (VTE) experience a recurrence within 10 years of the initial event with their recurrence risk peaking during the first 6-12 months. Two large randomized clinical trials AMPLIFY-EXT and PADIS-PE reported that extended treatment with apixaban and warfarin beyond 6 months of initial treatment reduced recurrent VTE without increasing the rate of major bleeding compared to placebo, respectively. Little is known about real-world effectiveness and safety of extended oral anticoagulation beyond 6 months of initial treatment for Medicare beneficiaries with VTE, despite the fact that VTE disproportionately affects the elderly. We assessed the effectiveness and safety of extended use of apixaban and warfarin beyond 6 months of initial treatment for prevention of recurrent VTE and adverse major bleeding events among Medicare beneficiaries with newly diagnosed VTE.Methods: A retrospective cohort study using 2014-2018 Medicare data (5% samples in 2014-2016 and 15% samples of Medicare beneficiaries in 2017-2018) was conducted for patients aged ≥18 years with a diagnosis of deep vein thrombosis or pulmonary embolism ascertained from inpatient claims. Patients were included if they initiated anticoagulants within 30 days of their first VTE diagnosis, completed 6 months of therapy defined as ≥83% proportion days covered with oral anticoagulants during the initial 6-month period, and received extended treatment with either apixaban or warfarin or no extended therapy. We compared the risks of recurrent VTE and major bleeding between apixaban, warfarin, and no treatment groups. To adjust for differences in baseline characteristics and clinical factors (e.g., HAS-BLED score, active cancer, and provoked VTE) between groups, we used the stabilized inverse probability treatment weighting (IPTW) method. Follow-up continued until the occurrence of the first event, switch to the comparator, disenrollment, death, or end of the study period. Multivariable Cox proportional hazards modeling with IPTW was used to obtain adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI).Results: The study cohort (mean age=74 ±12 years, 40% male, 76% White) consisted of 2,315 users of extended apixaban treatment (83% with 5 mg twice a day and 17% with 2.5 mg twice a day; mean duration=6.2 months), 2,757 users of extended warfarin treatment (mean duration=8.2 months), and 2,328 patients with no extended treatment following completion of an initial 6 months of anticoagulant treatment. The incidence rates of recurrent VTE were 0.42, 1.73, and 1.72 per 100 person-years, and those of major bleeding were 2.28, 3.62, and 1.43 per 100 person-years in the apixaban, warfarin, and no treatment groups, respectively (Table 1). Compared to no extended treatment, the use of apixaban was associated with an 80% decreased risk of recurrent VTE (aHR=0.19, 95%CI=0.06-0.55) without increasing the risk of major bleeding (aHR=1.19, 95%CI=0.65-2.19); the use of warfarin did not lower the risk of recurrent VTE (aHR=0.75, 95%CI=0.42-1.37) but increased the risk of major bleeding (aHR=1.92, 95%CI=1.13-3.25). Compared to the use of warfarin, the use of apixaban was associated with a decreased risk of recurrent VTE (aHR=0.26, 95% CI=0.09-0.76) and no difference in major bleeding risk (aHR=0.61, 95%CI=0.36-1.06). These findings remained consistent in subgroup (e.g., patients with provoked vs. unprovoked VTE, patients with active cancer vs. those without, and patients with chronic kidney diseases vs. those without) and sensitivity analyses (e.g., ≥92% proportion days covered with oral anticoagulants during the initial 6-month period).Conclusions: Compared to no extended therapy, extended anticoagulation with apixaban was associated with a reduced risk of recurrent VTE without increasing the risk of major bleeding, whereas warfarin did not lower risk of recurrent VTE but increased the risk of major bleeding among Medicare beneficiaries with VTE. In the head-to-head comparison, the use of apixaban was more effective than warfarin in preventing recurrent VTE, without increasing the risk of major bleeding events. Our findings suggest that apixaban is an effective and safer option for extended treatment of VTE when compared to warfarin or no treatment among Medicare beneficiaries with VTE. [Display omitted] DisclosuresPark: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Kang: BMS/Pfizer Alliance American Thrombosis InvestigatorInitiated Research Program: Research Funding. Huang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Lo-Ciganic: MERCK: Research Funding; BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Dietrich: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Murphy: North American Thrombosis Foundation: Honoraria. DeRemer: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding; Portola Pharmaceuticals: Current equity holder in publicly-traded company; BMS advisory board attendee: Honoraria.

The Impact of Dabigatran and Rivaroxaban on Variation of Platelet Activation Biomarkers and DRT Following Percutaneous Left Atrial Appendage Closure.

Background: The current post-procedure antithrombotic recommendation for left atrial appendage closure (LAAC) remains empiric. This study was designed to compare variations in platelet activation biomarkers and device-related thrombosis (DRT) under different antithrombotic regimens following LAAC.Methods: This study enrolled 105 consecutive patients with atrial fibrillation who underwent LAAC successfully and received post-procedure anticoagulation with either dabigatran (N = 33) or rivaroxaban (N = 72). After 3 months of anticoagulation treatment, thromboelastogram was used to evaluate thrombin receptor–activating peptide (TRAP)–induced platelet aggregation (PA). Measurements of platelet activation biomarkers, including thrombin–antithrombin complex (TAT), P-selectin, von Willebrand disease (vWF), and CD40L, were performed immediately before the LAAC procedure and after 3 months of post-procedure anticoagulation. Repeated transesophageal echocardiography was performed to evaluate DRT during follow-ups.Results: Three (4.2%) patients in the rivaroxaban and 4 (12.1%) patients in the dabigatran group experienced DRT events (odds ratio (OR) = 0.315, 95% confidence interval (95%CI): 0.066–1.489, p = 0.129) during follow-ups. The TRAP-induced PA was statistically significantly higher in the dabigatran group (62.9% vs 59.7%, p = 0.028*). Statistically significant increases in plasma concentration of TAT, P-selectin, and vWF were observed after 3 months of exposure to dabigatran when compared with rivaroxaban. An increased expression of platelet activation biomarkers was observed in DRT subjects compared with non–DRT subjects in terms of P-selectin and vWF (65.28 ± 13.93 ng/L vs 32.14 ± 12.11 ng/L, p = 0.037; 501.92 ± 106.48 U/L vs 280.98 ± 54.10 U/L, p = 0.045; respectively). Multivariate regression analysis indicated that the use of dabigatran might be an independent predictor of DRT (p = 0.022; OR = 4.366, 95%CI: 0.434–10.839). Furthermore, the CHA2DS2-VASc score (OR = 2.076, p = 0.016) and CD40L levels (OR = 1.015, p = 0.021) were independent predictors of increased D-dimer levels.Conclusions: Post-LAAC anticoagulation with dabigatran may increase the risk of DRT by enhancing platelet reactivity. In light of this potential increased risk in DRT, the authors recommend against using dabigatran for post-procedural anticoagulation in patients who have undergone LAAC.

Management of Patients With Venous Thromboembolism After the Initial Treatment Period.

Venous thromboembolism (VTE) is a common medical problem seen in primary care settings. The most common long-term adverse sequelae are recurrent thromboembolism and incomplete resolution of the embolic material, which may result in pulmonary hypertension after pulmonary embolism and post-thrombotic changes in the leg after deep vein thrombosis. Although there are detailed guidelines for diagnosing and treating acute VTE, there are few focused articles that provide recommendations for primary care physicians (PCPs) about how to manage VTE patients after completion of the initial period of anticoagulation treatment. In this article, we highlight several important clinical decisions that must be addressed after the first 3 months of anticoagulation treatment is complete, with a focus on particular management issues for PCPs. The 2 most important decisions the PCP must make are to determine, first, if symptoms of acute VTE have indeed resolved, and second, if they have resolved, to assess the long-term risk of recurrent VTE versus the risk of potential bleeding and decide if anticoagulation should be stopped, or if indefinite anticoagulation treatment is indicated. Among higher-risk patients who may benefit from indefinite anticoagulation, the PCP should discuss both the risks and benefits of anticoagulation treatment, empowering the patient to actively participate in this important shared decision-making process.

Factor V Leiden Testing and Its Effects on Decision-Making: An Institutional Survey

Introduction: The incidence of factor V Leiden is documented to be around 5% in Caucasian population and is a known risk factor for venous thromboembolism (VTE). However, the incidence of recurrent VTE for heterozygous factor V Leiden mutation (FVL) is not significantly different from non-carriers. As per established guidelines, 3 months of anticoagulant treatment is enough in cases of provoked VTE, and does not require a hypercoagulability panel. Guidelines also dictate that in case of heterozygous factor V Leiden, there should be no change in duration of treatment for provoked VTE. Methods: We studied answers acquired through a survey questionnaire administered to healthcare providers at Reading Hospital, Tower Health System. An anonymous online survey was used for acquiring this data, which included specialty, practice setting, degree (physician's vs non-physician practitioners) and years of experience (0-3, 4-10, 11-20, &gt;20). As part of a larger survey, practitioners were asked anticoagulation duration for two patients with provoked VTE, one of which was noted to be heterozygous for FVL mutation, and answers were compared. he data was then filtered for incomplete responses and de-identified. SPSS software was then used for further descriptive analysis. One-way ANOVA and t-tests were used to analyze differences between various groups. Results: A total of 404 responders provided answers to all the questions. For provoked DVT with no mention of FVL testing , 372 (92%) providers used anticoagulants for duration of 3 months, and 32 (8%) continued anticoagulants for excessive duration (28 for 12 months, 4 chose indefinite therapy). For question 2, which included heterozygous factor V mutation; 257 (63.6%) used anticoagulants for 3 months, whereas 147 (36.4%) continued anticoagulants for excessive duration (29 for 12 months, 118 chose indefinite therapy). Independent sample t-test was performed to analyze difference between the duration of anti-coagulant prescribed by physicians versus non-physician practitioners (NPP). Physicians (mean 79.70) did significantly better compared to NPP (mean 58.40), with P-value&lt;0.001. In case of practice setting, there was no significant difference between in-patient versus out-patient providers, with P-value of 0.26. One-way ANOVA results used to analyze difference between 4 groups for years of experience was non-significant (p=0.18). Conclusion: It was observed in our study that FVL testing may incorrectly influence decision-making in anticoagulation duration. This could be attributed to several factors, such as lack of knowledge of current guidelines, incorrect estimation of the risk of recurrent VTE, and poor understanding of the indications for indefinite treatment. It is also important acknowledge the variation in the use of anti-coagulation between physicians and NPP. A wide multi-institutional survey analysis in the future can help acknowledge these factors to prevent excessive use of anticoagulants and reduce risk of bleeding. Furthermore, given the potential harm associated with excessive anticoagulation, testing for FVL should be judiciously monitored and limited to more skilled practitioners. Disclosures No relevant conflicts of interest to declare.

Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis

ObjectivesTo determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, and the cumulative incidence...

Long-Term Management of Venous Thromboembolism: Lessons from EINSTEIN CHOICE and Other Extension Trials.

Many patients with venous thromboembolism (VTE) are at risk of recurrence if anticoagulant therapy is stopped. Whereas 3 months of anticoagulation treatment is sufficient for patients with VTE provoked by major surgery or trauma, in many cases a longer course is needed. Extended therapy with vitamin K antagonists (VKAs) requires frequent coagulation monitoring and dose adjustments to ensure that the international normalized ratio (INR) remains within the therapeutic range; furthermore, there is a risk of major bleeding even if a therapeutic INR is maintained. Therefore, more convenient and safer anticoagulants are needed.The non-VKA oral anticoagulants (NOACs)-apixaban, dabigatran, edoxaban and rivaroxaban-simplify extended therapy because they can be given in fixed doses without routine coagulation monitoring. Randomized clinical trials have demonstrated the efficacy and safety of NOACs for extended VTE treatment, but bleeding remains a concern. Patients and physicians may, therefore, be reluctant to continue anticoagulation beyond 3 to 6 months except in patients at high risk of recurrence. Acetylsalicylic acid (ASA) is often prescribed instead of an anticoagulant because of its perceived lower risk of bleeding; however, the recent EINSTEIN CHOICE trial demonstrated that once-daily rivaroxaban at a dose of either 20 or 10 mg reduced the risk of recurrent VTE by 70% compared with ASA without significantly increasing the risk of bleeding. In this review, we discuss the EINSTEIN CHOICE trial in the context of previous trials for extended VTE treatment and examine some of the lessons that can be applied to clinical practice.

A Prothrombotic State in Patients With a History of Left Ventricular Thrombus

Left ventricular thrombus (LVT) is associated with a hypercoagulable state and occurs most frequently after myocardial infarction (MI). Blood prothrombotic alterations might predispose to LVT formation, its recurrence, and subsequent cerebrovascular events. We investigated 58 patients with a history of LVT unrelated to recent MI or LV ejection fraction <25% and 58 well-matched control subjects. We determined plasma clot permeability, fibrinolytic efficiency, thrombin generation, and endothelial markers after 3 to 6 months of anticoagulant treatment. During follow-up we recorded LVT and thromboembolic events. Patients with LVT more often had LV akinesia, congestive heart failure, and prothrombotic state as evidenced by increased endogenous thrombin potential, lower antithrombin, lower clot permeability, and longer clot lysis time associated with lower antiplasmin, higher plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, and von Willebrand factor. During follow-up (57.5 ± 8.1 months for LVT patients and 59.6 ± 5.3 months for controls) strokes, transient ischemic attacks, or LVT occurred in 18 (31%) LVT patients and in 6 (10.3%) control subjects (4.1 vs 1.4% per year, p = 0.006). LVT recurred in 10 (2.3%/year) patients, who had higher risk of stroke/transient ischemic attacks (relative risk = 4.73, 95% confidence interval 1.8 to 40.4). The most compact clot formation at baseline, defined as the lowest quartile of clot permeability (≤5.4 × 10-9 cm2) was a predictor of recurrent LVT (relative risk = 4.67, 95% confidence interval 1.32 to 18.37). This study shows that a persistent prothrombotic state involving enhanced thrombin generation, hypofibrinolysis, and formation of more compact fibrin clots characterizes patients who develop LVT not related to MI and those prone to its recurrence.

Przewlekłe leczenie przeciwkrzepliwe

AbstractUnprovoked venous thromboembolism (VTE) - proximal venous thrombosis or pulmonary embolism - should be treated either 3 months or indefinitely if the risk of bleeding is low. This article summarizes the efficacy and safety of extended therapy of VTE with direct oral anticoagulants (DOAC) in comparison with warfarin, as well as the role of of acetylsalicylic acid (ASA) for the long-term prevention of recurrent VTE. As the Survet study showed, for some patients who have already completed at least 6 months of anticoagulant treatment for their index VTE event, an oral glycosaminoglycan - sulodexide associated with compression therapy is a good choice, because it decreases the incidence of recurrences of VTE without detectable risks for the patients’ safety.

“HERDOO2” clinical decision rule to guide duration of anticoagulation in women with unprovoked venous thromboembolism. Can I use any d-Dimer?

BackgroundThe “HERDOO2 rule” is a prospectively validated clinical decision rule used to identify low-risk women who can safely discontinue anticoagulants after completing 5–12 months of anticoagulant treatment for unprovoked venous thromboembolism. The VIDAS®d-Dimer (DD) assay, a component of the rule, was used in the derivation and validation of the rule at half the usual diagnostic cut-point for exclusion of venous thrombosis. It is unknown if other commercial DD assays used at a corresponding cut-point will categorize patients at high concordance with the VIDAS® DD. ObjectiveTo determine if other available automated quantitative DD assays have high enough concordance with the VIDAS® DD assay to allow their use within the “HERDOO2” clinical decision rule. MethodsFrozen plasma samples from a sub-set (n = 248) of female participants in the “HERDOO2” validation study were tested using five DD assays: VIDAS®, Innovance®, HemosIL®, Tina-quant® and Liatest®, with duplicate testing for 50 samples. First, using the mean DD for 50 samples with duplicate results, we determined the optimal cut-point values for each test that corresponded with a VIDAS® DD result of 250 μg/L using linear regression analysis. Next, kappa analysis was conducted on the DD results of the remaining 198 samples to determine concordance between each tested DD at the respective optimal cut-point and the VIDAS® DD at 250 μg/L. In a separate analysis we determined the concordance at half the usual venous thrombosis exclusion cut-point. ResultsRegression analysis of the DD results in 50 samples identified the optimal cut-point for each DD assay to match a VIDAS® DD cut-point of 250 μg/L: Innovance® 177 μg/L, Liatest® 233 μg/L, Tina-quant® 48 μg/L and HemosIL® 56 μg/L. Next, in 198 different samples, the concordance of VIDAS® DD (≥250 μg/L or <250 μg/L) was explored at the optimal cut-point of the other DD assays. The concordance was poor for all DD assays: Innovance® (kappa 0.38 (95% CI, 0.26–0.51)), Liatest® (kappa 0.38 (95% CI, 0.25–0.50)), HemosIL® (kappa 0.36 (95% CI, 0.23–0.49)) and Tina-quant® (kappa 0.30 (95% CI, 0.16–0.43)). Similar poor concordance was identified using half of the diagnostic DD cut-point for each tested assay: Innovance® (kappa 0.44 (95% CI, 0.32–0.56)), Liatest® (kappa 0.38 (95% CI, 0.25–0.51)), HemosIL® (kappa 0.04 (95% CI, −0.01—0.08)) and Tina-quant® (kappa 0.04 (95% CI, −0.004–0.07)). ConclusionThe “HERDOO2 rule” is the only prospectively validated clinical decision rule that can be used to identify low-risk women with unprovoked venous thrombosis who can safely discontinue anticoagulants. An important implementation issue is whether any commercial DD assay can be used in the HERDOO2 rule, and at what cut-point. Our analysis shows that the HemosIL®, Innovance®, Liatest® and Tina-quant® DD assays should not be used in the “HERDOO2” rule due to poor concordance with the VIDAS® DD assay and unacceptable misclassification of women at high and low risk of recurrent venous thrombosis.

Risk Stratification for Bleeding Complications in Patients With Venous Thromboembolism: Application of the HAS-BLED Bleeding Score During the First 6Months of Anticoagulant Treatment.

BackgroundThe Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile International Normalized Ratio (INR), Elderly, Drugs or alcohol use (HAS‐BLED) score has strong predictive validity for major bleeding complications, but limited validation has been conducted in venous thromboembolism (VTE). This study evaluates the HAS‐BLED score in a large cohort of VTE patients.Methods and ResultsA retrospective cohort of adults ≥18 years with primary diagnosis of VTE between January 1, 2010 and November 31, 2013 were identified in an insurance claims database. Patients were tracked until death, any bleed event, or end of study period. HAS‐BLED score and components were evaluated via proportional hazard models. Cumulative incidence functions were reported at 30, 60, 90, and 180 days. N=132 280 patients with a VTE were identified, with 73.8% having HAS‐BLED scores of 0 to 2, 3.6% score ≥4, and 4789 bleeding events (3.6% all patients). A 1‐point HAS‐BLED score increase was associated with 20% to 30% bleeding rate increase overall, but in a cancer cohort only the increase from 3‐ to 4‐points was significant for all bleeds (csHR=1.41, 95% CI: 1.17–1.69; sdHR=1.40, 95% CI: 1.17–1.69) and major bleeds (csHR=1.66, 95% CI: 1.26–2.20; sdHR=1.66, 95% CI: 1.25–2.19). Adding cancer to the model as an independent covariate provided the strongest association among all covariates, with csHR=2.25 (95% CI: 1.98–2.56) and sdHR=2.11 (95% CI: 1.85–2.41) in the model for major bleeds.ConclusionsThe HAS‐BLED score has good predictive validity for bleeding risks in patients with VTE. The addition of cancer as an independent bleeding risk factor merits consideration, possibly as part of the “B” criterion (“bleeding tendency or predisposition”).

Altered plasma clot properties increase the risk of recurrent deep vein thrombosis: a cohort study

AbstractIt has been demonstrated that fibrin clots generated from plasma samples obtained from patients with prior thromboembolic events are denser and less susceptible to lysis. Such a prothrombotic fibrin clot phenotype has been suggested as a new risk factor for venous thromboembolism, but its prognostic value is unclear. To assess whether abnormal clot properties can predict recurrent deep vein thrombosis (DVT), we studied 320 consecutive patients aged 18 to 70 years following the first-ever DVT. Plasma clot properties were evaluated after 3 months of anticoagulant treatment since the index event. A mean duration of anticoagulation was 10 months (range, 4-20). Recurrent DVT was observed in 77 patients (25%; 6.6%/year) during a median follow-up of 44 months. Recurrences of DVT were associated with faster formation (−9% lag phase) of denser fibrin networks (−12% fibrin clot permeability [Ks]) and 4% higher maximum absorbance of plasma clots that displayed impaired fibrinolytic degradation (+25% prolonged clot lysis time [CLT]) and a 5% slower rate of increase in D-dimer levels during clot degradation (D-Drate; all P < .05). Proximal DVT alone, higher C-reactive protein, D-dimer, peak thrombin, lower Ks, shorter lag phase, decreased D-Drate, and prolonged CLT were independent predictors of recurrences (all P < .05). Individuals characterized by low Ks (≤7.3 × 10−9 cm2) and prolonged CLT (>96 min) were at the highest risk of recurrent DVT (odds ratio, 15.8; 95% confidence interval, 7.5-33.5). Kaplan-Meier curves showed that reduced Ks and prolonged CLT predicted recurrent DVT. We demonstrate that unfavorably altered clot properties may predict recurrent DVT after anticoagulation withdrawal.

Controversias en el abordaje de la trombosis en cáncer: tromboprofilaxis secundaria extendida y retrombosis

We present the case of a 45-year-old man with locally advanced lung adenocarcinoma diagnosed with deep vein thrombosis and synchronous pulmonary embolism. After 6 months of anticoagulant treatment with low molecular weight heparin, the dose was reduced to prophylactic levels and a new episode of bilateral deep vein thrombosis occurred. After reintroducing heparin to the previous dose, the patient suffered a massive pulmonary embolism. The authors conducted a review of the evidence about anticoagulant treatment beyond 6 months and the approach of rethrombosis in anticoagulated patients.

Six Weeks Versus 3 Months of Anticoagulant Treatment for Pediatric Central Venous Catheter-related Venous Thromboembolism.

Central venous catheters (CVCs) are the single most important predisposing factor for the development of pediatric venous thromboembolism (VTE). Treatment recommendations suggest anticoagulation for the duration of 6 weeks to 3 months. This project investigated clinical outcomes associated with 6 weeks compared with 3 months of enoxaparin therapy following diagnosis of a CVC-related VTE. This retrospective cohort study enrolled patients aged 18 years and below treated with enoxaparin with/without unfractionated heparin for a radiologically confirmed CVC-related VTE. Patients were identified using the pharmacy database, radiologic imaging, and medical records. Patients were divided into 2 groups based on the duration of anticoagulation (6+1 or 12±2 wk) and data were analyzed using descriptive statistics. Seventy-four patients were included. Higher rates of complete thrombosis resolution were observed in children treated for 6 weeks at treatment cessation (39.4%) and long-term follow-up (61.5%), compared with 3 months (11.8% and 9.0%, respectively). Six weeks of treatment for CVC-related VTE may provide noninferior clinical outcomes compared with 3 months of anticoagulation. An international randomized-controlled trial (Kids-DOTT) is underway to explore the optimal duration of anticoagulation for acute-provoked VTE in children. This manuscript highlights that data from such studies is urgently needed.

Acute Pulmonary Embolism after Discharge: Duration of Therapy and Follow-up Testing.

Pulmonary embolism (PE) is a frequent cause of death and serious disability with a risk extending far beyond the acute phase of the disease. Anticoagulant treatment reduces the risk for death and recurrent VTE after a first PE. The optimal duration of anticoagulation after a first episode of PE remains controversial and should be made on an individual basis, balancing the estimated risk for recurrence without anticoagulant treatment against bleeding risk under anticoagulation. Current recommendations on duration of anticoagulation are based on a 3% per year risk of major bleeding expected during long-term warfarin treatment. Anticoagulant therapy should be discontinued after the initial 3 to 6 months in those patients who had the first episode in association with temporary risk factors. After 3 to 6 months of anticoagulant treatment, patients with a first unprovoked event and an estimated low risk for bleeding complications should be evaluated for indefinite treatment on an individualized basis. None of the clinical prediction models for recurrent VTE are able to actually drive duration of anticoagulation. If the favorable safety profile of direct oral anticoagulants from clinical trials would be confirmed in real-life, extension of anticoagulation could be reconsidered in large proportions of patients after an unprovoked PE. The most feared late sequela of PE is chronic thromboembolic pulmonary hypertension. Although there has been progress in both the diagnosis and management of this disease in recent years, further data are needed to provide recommendations regarding long-term follow-up after PE.

Low discriminating power of the modified Ottawa VTE risk score in a cohort of patients with cancer from the RIETE registry.

Treatment of patients with cancer-associated venous thromboembolism (VTE) remains a major challenge. The modified Ottawa score is a clinical prediction rule evaluating the risk of VTE recurrences during the first six months of anticoagulant treatment in patients with cancer-related VTE. We aimed to validate the Ottawa score using data from the RIETE registry. A total of 11,123 cancer patients with VTE were included in the analysis. According to modified Ottawa score, 2,343 (21 %) were categorised at low risk for VTE recurrences, 4,525 (41 %) at intermediate risk, and 4,255 (38 %) at high risk. Overall, 477 episodes of VTE recurrences were recorded during the course of anticoagulant therapy, with an incidence rate for low, intermediate, and high risk groups of 6.88 % (95 % CI 5.31-8.77), 11.8 % (95 % CI 10.1-13.6), and 21.3 % (95 % CI 18.8-24.1) patient-years, respectively. Overall mortality had an incidence rate of 21.1 % (95 % CI 18.2-24.3), 79.4 % (95 % CI: 74.9-84.1), and 134.7 % (95 % CI: 128.3-141.4) patient-years, respectively. The accuracy and discriminating power of the modified Ottawa score for VTE recurrence was modest, with low sensitivity, specificity and positive predictive value, and a C-statistics of 0.58 (95 % CI: 0.56-0.61). In our analysis, the modified Ottawa score did not accurately predict VTE recurrence among patients with cancer-associated thrombosis, thus hindering its use in clinical practice. It is time to define a new score including other clinical predictors.