Inferior Vena Cava Filters: A Clinical Review and Future Perspectives.

Anticoagulation represents the first line treatment for venous thromboembolism (VTE). However, inferior vena cava (IVC) filter insertion can be considered as a possible therapeutic strategy when anticoagulant therapy is contraindicated, to avoid embolization from the lower limbs to pulmonary circulation. Other possible indications are debated among experts. Both permanent and retrievable caval filters are available in clinical practice. Retrievable filters can be removed when no longer necessary, as their use may be indicated only for a limited amount of time. Moreover, caval filter insertion is not devoid of possible complications, particularly in cases of permanent or long-dwelling filters. A multidisciplinary approach is recommended to review the appropriateness of caval filter use and to define the best timing for retrieval.

Six-week low-molecular-weight heparin versus 12-week warfarin for calf deep vein thrombosis: A randomized, prospective, open-label study.

Current guidelines suggest a 3-month anticoagulant treatment course for isolated distal deep vein thrombosis (IDDVT), but shorter durations of treatment are frequently prescribed in clinical practice. We investigated whether a 6-week treatment with low-molecular-weight heparin (LMWH) at intermediate dosage can be an effective and safe alternative to vitamin K antagonists (VKA) in patients with IDDVT (non-inferiority trial). In a multicenter, open-label, randomized trial, 260 outpatients with symptomatic IDDVT were randomly assigned to receive either LMWH followed by VKA for 12 weeks or LMWH 1 mg/kg subcutaneously twice a day for 2 weeks followed by 1 mg/kg subcutaneously once a day for 4 weeks. The follow-up was 6 months and the primary endpoint was the composite measure of recurrent venous thromboembolism (VTE) defined as: recurrence or extension of IDDVT, proximal DVT, and pulmonary embolism (PE). The study was stopped prematurely due to slow recruiting rates. The primary efficacy outcome occurred in 14 patients receiving LMWH (10.8%) and in five patients receiving VKA (3.8%); risk difference was 0.069 (95% CI: 0.006-0.132), hazard ratio 2.8 (95% CI: 1.04-7.55). There was one PE in the VKA group and one proximal DVT in the LMWH group. IDDVT recurrence was 10.0% in the LMWH group versus 3.1% in the VKA group (p = .024). Two patients had clinically relevant bleedings (1.6%) in the LMWH group versus one (0.8%) in VKA group (p = .56). In conclusion, VKA for 12 weeks seems superior to LMWH for 6 weeks in reducing the risk of VTE recurrences in our cohort of outpatients with IDDVT.

Management and Outcomes of Isolated Distal Deep Vein Thromboses: A Questionable Trend toward Long-Lasting Anticoagulation Treatment. Results from the START-Register.

Background Isolated distal deep vein thromboses (IDDVT) are frequently diagnosed; however, their natural history and real risk of complications are still uncertain. Though treatment is still not well standardized, international guidelines recommend no more than 3 months of anticoagulation therapy. We investigated how Italian clinicians treat IDDVT patients in their real life in our country. Methods Baseline characteristics and clinical history of the patients enrolled in the prospective, observational, multicenter START-Register for a first IDDVT or proximal DVT (PDVT) were analyzed. Results Overall, 412 IDDVT patients were significantly younger, with better renal function, and more frequent major transient risk factors, when compared with 1,173 PDVT patients. The anticoagulation duration was >180 days in 52.7% of IDDVT patients (70.7% in PDVT). During treatment, bleeding occurred in 5.6 and 2.8% patient-years in IDDVT and PDVT, respectively ( p = 0082). Bleeding was more frequent in IDDVT than PDVT patients treated with warfarin (6.8 vs. 3.2 patient-years, p = 0.0228, respectively). Thrombotic complications occurred in 1.1 and 2.4% patient-years in IDDVT and PDVT patients, respectively. Analyzing together the two groups, 66.1% of bleeds and 86.1% thrombotic complications occurred after 90 days anticoagulation treatment. Conclusion The large majority of IDDVT patients received anticoagulation for more than 3 months. Most bleeding and thrombotic complications occurred after the first 90 days of anticoagulation therapy. These results indicate that an extended anticoagulation beyond 90 days in IDDVT patients is associated with increased risk of complications. Whether an extended treatment may lower recurrences after anticoagulation withdrawal should be assessed by specifically designed studies.

Direct oral anticoagulants for extended treatment of venous thromboembolism: insights from the EINSTEIN CHOICE study.

The risk of recurrence of venous thromboembolism (VTE) persists after interruption of the initial anticoagulation therapy. New evidence shows that direct oral anticoagulants are effective for extended treatment of VTE and may reduce the risk of all-cause mortality. The optimal duration of anticoagulation after VTE is, however, controversial and complicated by the need for individualised assessment and balance between thrombosis and bleeding risks. Three direct oral anticoagulants (rivaroxaban, apixaban and dabigatran) have been studied for extended treatment of VTE. Dabigatran was shown to be safer than vitamin K antagonists and similarly effective for the prevention of recurrent VTE. Dabigatran, apixaban and rivaroxaban resulted in significant decreases in the rate of recurrent symptomatic VTE when compared to placebo, without a statistically significant difference in the risk of major bleeding. The latest guidelines of the American College of Chest Physicians suggest the use of low-dose aspirin to prevent VTE recurrence in patients who want to stop anticoagulation. In the randomised, double-blind, phase 3 EINSTEIN CHOICE trial, once-daily rivaroxaban at doses of 20 mg or 10 mg and 100 mg of aspirin were compared in VTE patients for whom there was clinical equipoise for extended anticoagulation. Either a treatment dose (20 mg) or a prophylactic dose (10 mg) of rivaroxaban significantly reduced the risk of VTE recurrence without a significant increase in bleeding risk compared with aspirin. The EINSTEIN CHOICE trial included patients with provoked or unprovoked VTE. Patients with VTE provoked by minor persistent or minor transient risk factors enrolled in this trial had not-negligible VTE recurrence rates. These new findings on extended therapy suggest the possibility of anticoagulation regimens at intensities tailored to the patients' risk profiles and VTE characteristics, with a shift of the risk-benefit balance in favour of extended treatment.

The risk of post-thrombotic syndrome in patients with proximal deep vein thrombosis treated with the direct oral anticoagulants.

The novel direct oral anticoagulants (DOAC) have been shown to be at least as effective as and safer than conventional anticoagulants for the initial and long-term treatment of venous thromboembolic disorders. However, the rate of post-thrombotic syndrome (PTS) in patients with deep-vein thrombosis (DVT) treated with the DOACs is unknown. With the adoption of the Villalta scale, we assessed the rate of PTS at the end of the follow-up period in a consecutive series of 309 outpatients with acute proximal DVT who had received at least 3 months of treatment with a DOAC and had been followed-up for up to 3 years. The rate of PTS development was compared with that recorded in a historical cohort of 1036 consecutive patients who had been treated with vitamin K antagonists (VKA) and had received a similar follow-up examination. Logistic regression analysis, including propensity scoring to adjust for differing probabilities of undergoing VKA/DOAC, was used to identify predictors of PTS. PTS developed in 87 patients (28.2%) treated with the DOACs (severe in 12), and in 443 patients (42.8%) treated with VKAs (severe in 61). After adjusting for estimated propensity score, age, gender, concomitant symptoms of pulmonary embolism, duration of anticoagulation and development of residual vein thrombosis, the risk of PTS in the DOAC-treated patients was reduced by 54% in comparison to patients treated with conventional anticoagulation (odds ratio 0.46; 95% CI 0.33 to 0.63). We conclude that in comparison to VKAs, the use of the direct oral anticoagulants has the potential to offer a more favorable prognosis in terms of PTS development.

Patients with isolated pulmonary embolism in comparison to those with deep venous thrombosis. Differences in characteristics and clinical evolution.

BACKGROUND: Patients with acute pulmonary embolism (PE) often have leg deep vein thrombosis (DVT); sometimes, however, a DVT is not detected (isolated PE, I-PE). We aimed at assessing the proportion of patients with I-PE, and their characteristics and clinical evolution compared to those with DVT with/without PE (DVT/PE). METHODS: Among 3573 patients included in the START2-Register for a venous thromboembolic event, 2880 (80.6%) had DVT/PE, the remaining I-PE (19.4%). RESULTS: Patients with I-PE were older [(≥75 years, OR 1.4 (95%CI 1.13-1.69)], and more frequently females [OR 1.4 (1.19-1.67)]. Young females (aged ≤ 50 years) with an index event occurring during hormonal contraception (HC), were more prevalent in I-PE [OR 1.96 (1.26-3.03)]. At multivariate analysis, age > 75 years, female sex, heart failure, cancer and use of HC were risk factors significantly associated with I-PE, whereas thrombophilic alterations were associated with DVT/PE. During a follow-up of 4504 years (during anticoagulation), the rate of bleeding events was 1.1% patient/years and 1.0% patient/years in I-PE and DVT/PE, respectively. Venous thromboembolic events were equally prevalent in DVT/PE or I-PE (1.94% vs 0.86%, ns), whereas arterial complications were more prevalent in the latter group (1.01% vs 0.28%, p = 0.008). CONCLUSION: I-PE and DVT/PE have important differences. Older age, female sex, heart failure and cancer, were risk factors for I-PE; thrombophilic alterations were associated with DVT/PE. HC use was more frequent in the I-PE group. The prevalence of arterial complications was higher in patients with I-PE. Further studies, specifically designed on this issue, are warranted.

Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in high-risk patient groups: cancer and critically ill.

BACKGROUND: Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups. OBJECTIVE: To present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill. METHODOLOGY: To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts. RESULTS: The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment. CONCLUSIONS: Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug-drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins.

Treatment of venous thromboembolism with tinzaparin in oncological patients.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in patients with cancer. For over a decade, the gold standard of treatment and secondary prevention of cancer-associated thrombosis (CAT) has been represented by low-molecular-weight heparins (LMWHs), which are currently recommended as the first-line treatment for CAT. Among the LMWHs that were more extensively tested in patients with CAT, tinzaparin is a LMWH produced by the enzymatic degradation of porcine-derived unfractionated heparin. The efficacy of tinzaparin in this setting is supported by well-grounded evidence. However, there is a need to discuss the positioning of tinzaparin in the continuously evolving treatment scenario of VTE therapy in cancer patients. In this paper, which was developed by a group of clinicians with wide experience in the treatment of VTE in cancer patients, we discuss the current therapeutic options and the role of tinzaparin for the treatment of CAT.

Overall mortality in combined pulmonary fibrosis and emphysema related to systemic sclerosis.

Objectives: This multicentre study aimed to investigate the overall mortality of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) and to compare CPFE-SSc characteristics with those of other SSc subtypes (with interstitial lung disease-ILD, emphysema or neither). Methods: Chest CTs, anamnestic data, immunological profile and pulmonary function tests of patients with SSc were retrospectively collected. Each chest CT underwent a semiquantitative assessment blindly performed by three radiologists. Patients were clustered in four groups: SSc-CPFE, SSc-ILD, SSc-emphysema and other-SSc (without ILD nor emphysema). The overall mortality of these groups was calculated by Kaplan-Meier method and compared with the stratified log-rank test; Kruskal-Wallis test, t-Student test and χ² test assessed the differences between groups. P<0.05 was considered statistically significant. Results: We enrolled 470 patients (1959 patient-year); 15.5 % (73/470) died during the follow-up. Compared with the SSc-ILD and other-SSc, in SSc-CPFE there was a higher prevalence of males, lower anticentromere antibodies prevalence and a more reduced pulmonary function (p<0.05). The Kaplan-Meier survival analysis demonstrates a significantly worse survival in patients with SSc-CPFE (HR vs SSc-ILD, vs SSc-emphysema and vs other-SSc, respectively 1.6 (CI 0.5 to 5.2), 1.6 (CI 0.7 to 3.8) and 2.8 (CI 1.2 to 6.6). Conclusions: CPFE increases the mortality risk in SSc along with a highly impaired lung function. These findings strengthen the importance to take into account emphysema in patients with SSc with ILD.

Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in at-risk patient groups: pregnancy, elderly and obese patients.

BACKGROUND: Venous thromboembolism (VTE) accounts for an estimated 900,000 cases per year in the US alone and constitutes a considerable burden on healthcare systems across the globe. OBJECTIVE: To understand why the burden is so high, qualitative and quantitative research was carried out to gain insights from experts, guidelines and published studies on the unmet clinical needs and therapeutic strategies in VTE prevention and treatment in three populations identified as being at increased risk of VTE and in whom VTE prevention and treatment were regarded as suboptimal: pregnant women, the elderly and obese patients. METHODOLOGY: A gap analysis methodology was created to highlight unmet needs in VTE management and to discover the patient populations considered most at risk. A questionnaire was devised to guide qualitative interviews with 44 thrombosis and haemostasis experts, and a review of the literature on VTE in the specific patient groups from 2015 to 2017 was completed. This was followed by a Think Tank meeting where the results from the research were discussed. RESULTS: This review highlights the insights gained and examines in detail the unmet needs with regard to VTE risk-assessment tools, biomarkers, patient stratification methods, and anticoagulant and dosing regimens in pregnant women, the elderly and obese patients. CONCLUSIONS: Specifically, in pregnant women at high risk of VTE, low-molecular-weight heparin (LMWH) is the therapy of choice, but it remains unclear how to use anticoagulants when VTE risk is intermediate. In elderly patients, evaluation of the benefit of VTE prophylaxis against the bleeding risk is particularly important, and a head-to-head comparison of efficacy and safety of LMWH versus direct oral anticoagulants is needed. Finally, in obese patients, lack of guidance on anticoagulant dose adjustment to body weight has emerged as a major obstacle in effective prophylaxis and treatment of VTE.

Antithrombotic therapy for venous thromboembolism in patients with cancer: expert guidance.

INTRODUCTION: Most of the current clinical guidelines recommend the use of Low-Molecular-Weight Heparins (LMWHs) for cancer-associated thrombosis (CAT). The Hokusai VTE-cancer trial reported the first results of a direct comparison between a direct oral anticoagulant (DOAC), edoxaban, and LMWH in this setting. AREAS COVERED: This review aims to critically appraise the currently available evidence on the efficacy and safety of anticoagulant agents for the long-term treatment of CAT and to provide an expert opinion and guidance in this field. EXPERT OPINION: Based on the available evidence, DOACs represent a valid alternative to LMWH for the treatment of CAT for the majority of patients with active cancer. Currently, most solid evidence comes from the Hokusai VTE-cancer study, which showed that edoxaban is non-inferior to the LMWH dalteparin, with a trend toward fewer recurrent venous thromboembolic events, but with more major bleeding events. Similar findings were reported with rivaroxaban, although the study was not sufficiently powered to allow definitive conclusions. The majority of bleeding events occurred in the upper gastrointestinal tract and in patients with gastrointestinal cancer. Thus, LMWH remains the preferred option for patients with gastrointestinal cancer. Additional studies aimed to confirm these findings with other DOACs are now warranted.

Multidisciplinary approach to the management of patients with pulmonary embolism and deep vein thrombosis: a consensus on diagnosis, traditional therapy and therapy with rivaroxaban.

Despite the availability of updated guidelines for the diagnosis and treatment of venous thromboembolism (VTE), the management of this disorder in clinical practice is often not standardized, given the different degree of compliance with official recommendations by the various involved specialists. The aim of this consensus paper, as a result of a board of experts in thromboembolism, is to define strategies to improve the quality of patients' care and the efficiency of healthcare resources utilization, by means of: (a) analysis of the guidelines for diagnosis and treatment of VTE; (b) analysis of diagnostic and therapeutic algorithms currently used in clinical practice by different specialists; (c) agreement on a common algorithm for diagnosis and treatment of VTE in different clinical settings; (d) definition of the possible role of the new oral anticoagulant agents (NOAC), such as rivaroxaban, based on their potential benefits for both acute and chronic therapy. The so-called "single drug approach" (as opposed to the traditional heparin/VKA combination), which can be adopted with these drugs, makes anticoagulation more convenient for both patients and healthcare providers, without the need for a close monitoring of the hemocoagulative status, and with a concomitant reduction of length of hospitalization and treatment costs. Among NOACs, in this paper we focused on rivaroxaban only because it was the unique available NOAC in Italy for the treatment of VTE at the time the manuscript was written. Concerning rivaroxaban, the results of two phase III, randomized and controlled trials confirm the non-inferiority of this drug compared to standard therapy (enoxaparin/warfarin) for the treatment of patients with pulmonary embolism (EINSTEIN PE Study) or deep vein thrombosis (EINSTEIN DVT Study) in terms of both efficacy and safety, supporting its use as an effective therapeutic option for these disorders.

Real-Life Management of Venous Thromboembolism With Rivaroxaban: Results From EXperience VTE, an Italian Epidemiological Survey.

Two large randomized controlled trials examined the efficacy and safety of rivaroxaban for the treatment of venous thromboembolism (VTE). The aim of this epidemiological study was to analyze a cohort of Italian patients affected by VTE who were treated with rivaroxaban in clinical practice. The data were collected by physicians using an online electronic questionnaire. The study was performed during a 6-month period from January to June 2014. We analyzed the clinical characteristics, risk factors for VTE, comorbidities, diagnostic techniques, and treatments in the whole population and in the subgroups with deep vein thrombosis (DVT) only, pulmonary embolism (PE) only, and DVT+PE. Overall, 75.9% of patients were affected by DVT; 20% of patients had DVT and PE; and 4.8% of patients had only PE. Approximately 90% of patients were symptomatic upon diagnosis, and 46.3% of patients required hospitalization. More than half of the patients switched to rivaroxaban after receiving another anticoagulant therapy. The main reasons for changing treatment included difficulties in managing vitamin K antagonists, patient choice, and prothrombin time-international normalized ratio (PT-INR) instability. The switch to rivaroxaban occurred after a mean of 1.8 PT-INR measurements. Clinical characteristic were overall similar to those of patients enrolled in prior clinical trials evaluating the safety and efficacy of rivaroxaban.

An association between residual vein thrombosis and subclinical atherosclerosis: Cross-sectional study.

BACKGROUND: The association between venous and arterial thrombotic disorders is still unclear. We assessed the association between residual vein thrombosis (RVT) and subclinical atherosclerosis in a cohort of patients with unprovoked (or associated with weak risk factors) proximal deep-vein thrombosis (DVT). METHODS: In a multicenter cross-sectional study, consecutive patients over 40years free from atherosclerotic disorders received the ultrasound assessment of the leg vein system and that of carotid arteries approximately three months after an episode of proximal DVT. In each center the evaluation was done by two independent assessors. The presence of RVT was defined as the incompressibility of at least 4mm in either the popliteal or the common femoral vein, and that of subclinical atherosclerosis as the presence of increased (>0.9mm) intima-media tickness (IMT) and/or carotid plaques. RESULTS: Out of 252 patients (mean age, 67; males, 53%; unprovoked, 77%), the presence of RVT was found in 139 (55.2%). An increased IMT was shown in 76 (54.7%) patients with and in 35 (31.0%) without RVT (p<0.001). At least one carotid plaque was found in 80 (57.6%) patients with and in 36 (31.9%) without RVT (p<0.001). After adjusting for the baseline characteristics, the odds ratio of subclinical atherosclerosis (increased IMT and/or carotid plaques) was 2.8 (95% CI, 1.6 to 4.7). CONCLUSION: The ultrasound detection of RVT after an episode of proximal DVT that is either unprovoked or triggered by weak risk factors is associated with a higher prevalence of subclinical atherosclerosis. These findings may have implications for patient prognosis.

Is it reasonable to use a lower DOACs dose in some patients with VTE? Yes.

In the Hokusai-VTE trial, 733 patients were treated with the reduced dose edoxaban regimen, which maintained efficacy and safety compared with the 60 mg dose, and was safer than warfarin. The prophylactic doses of apixaban and rivaroxaban reduced the risk of recurrent venous thromboembolism (VTE) in the extended treatment trials. Dabigatran 110 mg was approved by the European Medicine Agency for VTE treatment. Further data from registries and real-world studies will help to clarify whether patients, with other specific characteristics, can benefit from the reduced dose of direct oral anticoagulants.

The introduction of biosimilars of low molecular weight heparins in Europe: a critical review and reappraisal endorsed by the Italian Society for Haemostasis and Thrombosis (SISET) and the Italian Society for Angiology and Vascular Medicine (SIAPAV).

Recently, the European Medicines Agency (EMA) authorized the introduction and marketing of Thorinane® and Inhixa®, biosimilars of the Low Molecular Weight Heparin (LMWH) enoxaparin. The authorization path is considerably different from the guidelines published by the EMA in 2009, as well as from the recommendations from the International Society on Thrombosis and Haemostasis published in 2013. Indeed, both of them recommended that LMWHs biosimilars therapeutic equivalence should be demonstrated in at least one adequately designed clinical trial. Shortly after enoxaparin biosimilars approval, EMA published a revised version of its guideline, no longer requiring the execution of a clinical study in patients at risk of venous thromboembolism. Also the assessment of safety shows some relevant flaws, as it relies only on a 20 healthy volunteers study, clearly underpowered to draw any conclusions about the safety profile of the drug. In our opinion, the approach taken by EMA for approval of enoxaparin biosimilars raises serious concerns about their actual, clinical "similarity". On these grounds, with the endorsement of the Italian Society for Haemostasis and Thrombosis (SISET) and the Italian Society for Angiology and Vascular Medicine (SIAPAV), we elaborated the present document aimed at reviewing and reappraising some critical points regarding the introduction of biosimilars of LMWH in Europe. Moreover, we would strongly advise the Italian National Health Authorities not to entrust safety assessment to the post-marketing surveillance only, but to promote well designed and powered studies aimed at establish the actual efficacy and safety of LMWH biosimilars.

Recanalization rate in patients with proximal vein thrombosis treated with the direct oral anticoagulants.

BACKGROUND: The recanalization rate in patients with deep venous thrombosis (DVT) of the legs treated with the direct oral anticoagulants (DOAC) is unknown. METHODS: In an Italian cohort, we investigated the rate of residual vein thrombosis (RVT) after three and/or six months in 352 patients with proximal DVT who had been treated with the DOACs as a stand-alone therapy or lead-in parenteral anticoagulants, and compared it to that recorded in a historical cohort of 1094 patients in which vitamin K antagonists (VKAs) had been employed. In both cohorts, RVT was defined as the ultrasound persistence of thrombotic material resulting in a diameter of at least 4mm of incompressibility of the proximal veins. RESULTS: RVT was detected in 143 patients treated with DOACs (41.2%) after three months and in 58 patients (21.1%) after six months; the corresponding figure in patients treated with conventional anticoagulation was 52.3% and 54.5%, respectively. After adjusting for the baseline characteristics, the odds ratio of RVT in patients treated with the DOACs as compared with those treated with conventional anticoagulation was 0.63 (95% CI, 0.48-0.81) after three months, and 0.17 (95% CI; 0.11-0.26) after six months. CONCLUSIONS: In patients with proximal DVT treated with the DOACs, the persistence of ultrasound detectable RVT is likely to occur less frequently than in patients treated with conventional anticoagulation. These results may have implications for the prognosis of patients with DVT.