Servier – Phlebolymphology

XIX. Focus on varicose vein recurrence

The novel anticoagulants for the initial and long-term treatment of VTE: state of the art
Paolo Prandoni (Italy)
Direct oral anticoagulants are now recognized as the standard of treatment for the majority of patients with venous thromboembolism. Large phase 3 randomized controlled trials showed that direct oral anticoagulants were at least as effective as and safer than vitamin K antagonists. They reduced all major bleeding, particularly intracranial bleeding, which is the most feared complication of anticoagulation.

Apixaban and rivaroxaban can be administered with a single-drug approach, using a loading dose for 1 or 3 weeks, respectively. They have the potential to increase the rate of early discharge or home treatment for selected patients with a low-risk for a pulmonary embolism. Edoxaban and rivaroxaban can be administered once daily, improving patient compliance. All direct oral anticoagulants are contraindicated in patients with severe renal insufficiency, antiphospholipid syndrome, in the presence of prosthetic valves and during pregnancy. Their benefit-risk profile in frail patients is comparable and even better than in frail patients, without the need for decreasing the dose (except for edoxaban). Recent trials have shown that direct oral anticoagulants can be also used for the initial and the long-term treatment of patients with cancer-associated thrombosis. The benefit-risk profile of edoxaban and rivaroxaban was comparable to the benefit-risk profile of low-molecular-weight heparin in trials specifically conducted for patients with cancer-associated thrombosis. However, caution should be used in patients with gastrointestinal cancer, as the potential for major bleeding complications was higher in patients treated with direct oral anticoagulants than in those treated with low-molecular-weight heparin in this subgroup of patients.

A number of recent studies have shown that the use of direct oral anticoagulants leads to an earlier vein recanalization compared with vitamin K antagonists in patients with proximal deep venous thrombosis. Accordingly, they are likely to be associated with a lower risk of postthrombotic syndrome. Finally, according to the most recent trials, we actually know that the long-term administration of low doses of apixaban and rivaroxaban confers a safe protection against the development of recurrent events either in patients with unprovoked venous thromboembolism and in patients with weak risk factors for venous thromboembolism. This evidence opens new scenarios for the long-term treatment of a wide spectrum of patients with venous thromboembolism.

Patient-oriented anticoagulation in VTE treatment: efficacy and safety of the new and old therapeutic approach are DOACs the standard of care?
Wojciech Sydor (Poland)
The introduction of direct oral anticoagulants (DOACs), which directly inhibit either thrombin (dabigatran) or factor Xa (apixaban, betrixaban, edoxaban, and rivaroxaban) has been revolutionary for the management of venous thromboembolism. Their oral administration, rapid onset/offset of action, fewer food and drug interactions, and their predictable anticoagulant effects have resolved many of the drawbacks associated with conventional therapy. DOACs are now endorsed as a first-line treatment in the majority of patients with a venous thromboembolism.

In patients with cancer, the 2016 ESC guidelines suggested low-molecular-weight heparin over vitamin K antagonists (grade 2B) and DOACs (grade 2C). However, with the publication of the results from the Hokusai-VTE Cancer and the Select-D trials, these recommendations are now out of date. The 2019 update of the ASCO guidelines instead recommends low-molecular-weight heparin, edoxaban, or rivaroxaban over vitamin K antagonists for at least 6 months in patients with cancer-associated thrombosis, stating that caution with DOACs is warranted in settings with a high risk of mucosal bleeding (ie, gastrointestinal or genitourinary malignancies). Furthermore, drug-drug interactions should be checked prior to using a DOAC.

The role of DOACs in the management of thrombophilia-associated venous thromboembolism is controversial. A recently published meta-analysis of four studies evaluating rivaroxaban, three evaluating dabigatran, and one evaluating edoxaban highlights that the rates of venous thromboembolism recurrence and bleeding events were both low and comparable in patients with various thrombophilias receiving either treatment, suggesting that DOACs are an appropriate treatment option in this population. However, Wojciech Sydor pointed out that, due to limited data, it is unclear whether these findings apply to specific subgroups, such as high-risk antiphospholipid syndrome, uncommon thrombophilias, or the use of apixaban (Elsebaie MAT, et al. J Thromb Haemost. 2019;17(4):645-656). The TRAP trial, involving only high-risk patients who were positive for lupus anticoagulant, anticardiolipin, and anti-b2-glycoprotein I antibodies of the same isotope (triple positivity), was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) due to an excess of events among patients in the rivaroxaban arm (Pengo V et al. Blood. 2018;132(13):1365-1371). Therefore, efficacy and safety of DOACs seem maintained in low-risk antiphospholipid syndrome subgroups, but their use actually is not recommended in high-risk antiphospholipid syndrome patients due to an increased risk of arterial and bleeding complications.

Conversely, DOACs should be the first choice among currently available anticoagulants in elderly patients (Giustozzi M et al. J Thromb Thrombolysis. 2019;48(3):439-453). Indeed, data from the RIETE registry showed that 22% of the 13 011 patients included were aged 80 years or older. Patients ≥80 years received long-term treatment with vitamin K antagonists less frequently (66% vs 75%; P<0.001) and with low-molecular-weight heparins more frequently vs patients aged less than 80 years (34% vs 25%; P<0.001). Major bleeding and recurrent venous thromboembolism at 3 months were reported in 3.4% and 2.1% in patients ≥80 years and in 2.1% and 2.8% in those younger than 80 years (López-Jiménez L et al; RIETE Investigators. Haematologica. 2006;91:1046- 1051). Randomized trials on venous thromboembolism patients treated with DOACs or vitamin K antagonists included 13.6% of patients aged 75 years or older. Data from a subgroup analysis of patients aged ≥75 years showed a significant reduction in recurrent venous thromboembolism (risk reduction [RR], 0.56; 95% CI, 0.38-0.82) and major bleedings (RR, 0.49; 95% CI, 0.25-0.96) in patients receiving DOACs vs those receiving vitamin K antagonists (van Es N et al. Blood. 2014;124:1968-1975).

Finally, the use of DOACs is not recommended in pregnant and breastfeeding women since they are likely to cross the placenta and the reproductive effects in humans are unknown.

Cancer-related DVT – what is new in the prevention and treatment?
Larisa Chernukha (Ukraine)
Patients with cancer are significantly more likely to develop a venous thromboembolism and experience higher rates of thromboembolism recurrence and bleeding complications during thromboembolism treatment than patients without cancer. Comprehensive management of thromboembolism in patients with cancer includes both the identification of patients who are most likely to benefit from pharmacologic prophylaxis as well as the effective treatment to reduce the risk of thromboembolism recurrence and mortality.

Larisa Chernukha summed up the latest recommendations provided by the guidelines in these settings. According to 2019 ASCO guidelines, routine pharmacological thromboprophylaxis should not be offered to all outpatients with cancer. Highrisk outpatients with cancer (Khorana score of 2 or higher prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or low-molecular-weight heparin provided there are no significant risk factors for bleeding and no drug interactions. Furthermore, hospitalized patients who have an active malignancy and acute medical illness or reduced mobility should be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications. Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should be offered pharmacologic thromboprophylaxis with either aspirin or low-molecular-weight heparin for lower-risk patients and low-molecular-weight heparin for higher-risk patients. All patients with cancer undergoing major surgical intervention should be offered preoperative pharmacologic thromboprophylaxis with either unfractionated heparin or low-molecular-weight heparin unless contraindicated because of active bleeding, high bleeding risk, or other contraindications. Extended prophylaxis with low-molecular-weight heparin for up to 4 weeks postoperatively is recommended for patients undergoing major open or laparoscopic abdominal or pelvic surgery for cancer who have high-risk features, such as restricted mobility, obesity, history of venous thromboembolism, or with additional risk factors. In lower-risk surgical settings, the decision about the appropriate duration of thromboprophylaxis should be made on a case-by-case basis.

New data on direct oral anticoagulants regarding the primary prevention of cancer-associated thrombosis in surgical patients will become available soon since these trials are still ongoing. Outcomes of trials with direct oral anticoagulants for the primary prevention in outpatients receiving chemotherapy (CASSINI with rivaroxaban and AVERT with apixaban) suggest a decrease in venous thromboembolism events but have not yet been included in the guidelines. With regard to treatment of cancer-associated thrombosis, low-molecular-weight heparin, edoxaban, or rivaroxaban for at least 6 months are preferred over vitamin K antagonists because of improved efficacy. There is an increase in the risk of major bleeding with direct oral anticoagulants, particularly observed in gastrointestinal and potentially genitourinary malignancies. Anticoagulation with low-molecular-weight heparin, direct oral anticoagulants, or vitamin K antagonists beyond the initial 6 months should be offered to select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. Anticoagulation beyond 6 months needs to be assessed on an intermittent basis to ensure a continued favorable risk-benefit profile (Key NS et al. J Clin Oncol. 2019 Aug 5. Epub ahead of print). In the near future, the results of trials with apixaban in cancer-associated thrombosis treatment will become available and this drug is likely to be mentioned by the guidelines among the options for the treatment of cancer-associated thrombosis.

Open vein concept in acute DVT treatment – still valid approach or already the past?
Niels Baekgaard (Denmark)
Catheter-directed thrombolysis or other endovenous early thrombus removal methods have to follow strict rules in terms of obtaining as much free lumen as possible. Indeed, residual thrombus is predictive of deep venous thrombosis (DVT) recurrence and of further risk for postthrombotic syndrome (PTS) in patients treated with anticoagulation alone. Niels Baekgaard pointed out that all the procedures should be implemented not only to open the veins but also to clean the veins and preserve the valves. Studies in this setting have shown a great variation in reducing the rates of PTS. The Copenhagen group demonstrated a rate of any PTS of 17% in 109 patients with iliofemoral DVT treated with catheter-directed thrombolysis after a median follow up of 71 months. The randomized CaVenT triaI showed persistent and increased clinical benefit in terms of PTS during a 5-year follow-up in favor of catheter-directed thrombolysis. However, no difference in quality of life was demonstrated.

A recent analysis from the ATTRACT trial, involving a subgroup with iliofemoral DVT alone (196 patients treated with pharmacomechanical catheter-directed thrombolysis and 195 patients in the control group), showed no difference in PTS, assessed as a Villalta score >4, between the thrombus-removal group (49%) and the control group (51%) (risk reduction [RR], 0.95; 95% CI, 0.78-1.15; P=0.59). However, a difference was found in patients with moderate-to-severe PTS (Villalta score >9 or ulcer) in favor of pharmacomechanical catheter-directed thrombolysis: 18% vs 28% (RR, 0.65; 95% CI, 0.45-0.94; P=0.021) and in patients with severe PTS (Villalta score >14 or ulcer): 8.7% vs 15% (RR, 0.57; 95% CI, 0.32-1.01; P=0.048), as in the main study. Furthermore, a positive improvement in the venous clinical severity score was found in pharmacomechanical catheter-directed thrombolysis patients at 2 years. Many factors may play a role in the success of these procedures. Among these, stenting placement seems to be an important part. Therefore, in the opinion of the author, the open vein theory is valid. However, the recently published papers have shown that the improvement in clot removal techniques might have a more and more important role on cleaning the veins in order to obtain a greater reduction in PTS.

Unmet needs in VTE clinical management
Gualtiero Palareti (Italy)
The first topic illustrated by Gualtiero Palareti was the extension of the anticoagulant treatment beyond the first 6 months of anticoagulation. Indeed, the optimal duration of anticoagulation for venous thromboembolism (VTE) remains uncertain since the benefit of anticoagulation to prevent recurrent VTE must be weighed against the risk of bleeding.

The current guidelines dichotomize VTE as unprovoked or provoked, recommending extended-duration anticoagulation with no scheduled stop date and yearly assessment of the bleeding risk, the risk of recurrence, and the patient’s preference for unprovoked events. In contrast, they recommend 3 months of anticoagulation for provoked VTE. However, recent data suggest that dichotomizing VTE into provoked and unprovoked categories to guide decisions about the duration of anticoagulation may not be the best approach. In a Danish nationwide cohort study, patients with cancer and those with unprovoked VTE had the highest risk of recurrence. However, recurrence rates in patients with provoked VTE were not negligible.

The EINSTEIN CHOICE trial randomized patients with prior provoked (59%) or unprovoked (41%) VTE to rivaroxaban (20 mg or 10 mg) or low-dose aspirin after they had received anticoagulation for 6 to 12 months. In the 20-mg rivaroxaban group, 1.4% of the patients with provoked VTE had a recurrence after the first year vs 1.8% of the patients with unprovoked VTE. In the aspirin arm, 3.6% of the patients with provoked VTE had a recurrence vs 5.6% with unprovoked VTE. The risk of recurrent VTE in patients with trauma or major surgery was 0% in both the rivaroxaban and aspirin groups. These results suggest, therefore, that a time-limited anticoagulation for patients with VTE provoked by major surgery or trauma can be correct. For all the other “provoked” events, we probably have to reconsider our approach regarding the duration of anticoagulation.

The second topic addressed by Gualtiero Palareti was related to the secondary prevention of VTE in elderly patients. In fact, the real risk of recurrence in the elderly is still uncertain. However, the risk of bleeding during anticoagulation is higher in the elderly than in young patients. The ACCP guidelines consider all patients aged ≥75 years at high risk of bleeding. In the management DULCIS study, 316 patients were aged ≥75 years at inclusion (31.3% of all patients); 162 of them (51.3%) resumed anticoagulation based on a positive D-dimer. During subsequent vitamin K antagonist treatment, 8 major bleeds occurred in patients aged ≥75 years (4.9%, 3.1% per year; 1 fatal), while only 6 events occurred in the 211 younger patients (<75 years) (2.8%, 1.7% per year). These data seem to discourage extended anticoagulant treatment using vitamin K antagonists in elderly patients after the first VTE event. Aspirin treatment for secondary VTE prevention has no favorable benefit-risk profile in elderly patients. The use of low-dose direct oral anticoagulants for extended treatment in elderly patients seems promising, but data on longer periods of therapy are necessary, especially to assess the potentially associated risk of bleeding in the long term. Indeed, the proportion of elderly patients included in these trials was very low and the duration of treatment short (1 year). Moreover, the results for both efficacy and safety were less satisfactory in the older vs younger population. Updated new evidence on the benefit-risk profile of indefinite anticoagulant therapy with direct oral anticoagulants, at different doses, is required, particularly in older patients. Observational prospective registry studies may provide us with real-life data on the advantages and side effects of generalized indefinite treatment with anticoagulants in the next few years. An Italian collaborative trial on extended treatment in elderly VTE patients using oral sulodexide, a drug without an anticoagulant effect and a low risk of bleeding, is currently underway and is planned to start at the end of the current year.

Venous problems in thoracic outlet syndrome: thrombolysis, anticoagulation, rib resection: staged or simultaneous?
Zbigniew Krasiński (Poland)
Primary upper extremity deep venous thrombosis includes idiopathic thrombosis and effort thrombosis. The latter, also called Paget-von Schroetter syndrome, typically occurs in the dominant arm after unusual physical activity. The affected patients are usually young and the male to female ratio is approximately 2 to 1. The major predisposing factor for effort thrombosis is the thoracic outlet syndrome, which is characterized by external compression of the neurovascular bundle at the thoracic outlet. The optimal treatment duration and intensity so far has not been studied in a randomized control trial. Therefore, the management of such patients remains controversial. Based on available data from prospective cohort studies, the current guidelines recommend anticoagulant treatment for at least 3 months. In addition, they suggest that thrombolytic therapy may be considered in selected patients with acute thrombosis of the arm veins and severe symptoms, but low bleeding risk. Catheter-directed thrombolysis is the preferable option due to a lower rate of bleeding complications when compared with systemic thrombolysis. It should be followed by definitive decompression of the anterior part of the thoracic outlet (costoclavicular junction), although proof of effectiveness of such decompression is lacking. Transaxillary first rib resection is the most common method of doing decompression. The major advantage of this method is that it offers excellent exposure of the anterior portion of the first rib. According to Zbigniew Krasiński, “in Paget-Schroetter syndrome, the earlier the diagnosis and treatment, the better the results.”

Optimization of anticoagulation with DOACs: role of proper selection and assessment
Jeanine Walenga (US)
The direct oral anticoagulants (DOACs) are at least as safe and effective as conventional treatment in the majority of patients with venous thromboembolism (VTE). However, many specific subgroups were excluded or underrepresented in these studies and the safety and efficacy of DOACs within these subgroups has yet to be established. The inclusion criteria for the VTE treatment trials included patients aged more than 18 years with an acute symptomatic proximal DVT and/or PE. Patients were excluded if they needed thrombolytic therapy, had a high risk of bleeding, clinically significant liver disease, creatinine clearance (CrCl) <30 mL/min, uncontrolled hypertension, or were breastfeeding or pregnant. The clinical impact of DOACs has not been fully defined for extremes in age or body weight, patients with mechanical heart valves, concomitant use of potent inhibitors or inducers of CYP3A4 or P-glycoprotein, concomitant use of antiplatelets, gastrointestinal malabsorption, thrombophilias with a high prothrombotic state (antiphospholipid syndrome, hypercoagulable state), in case of profound thrombocytopenia, nor in patients with cancer treated with chemotherapy. The main unresolved issues for the use of DOACs are managing patients with a temporary interruption of therapy and patients with DOAC-induced bleeding, defining a protocol for use with spinal anesthesia or protocol for restarting after brain bleeds, assessing their effect with laboratory test in selected circumstances. Traditional clotting assays, such as prothrombin time, partial thromboplastin time, and thrombin time, are not ideal assays to measure plasma levels of DOACs since they are either too sensitive (thrombin time) or too insensitive (prothrombin time, partial thromboplastin time). International normalized ratio is not valid for DOACs and it should not be considered. The quantitative chromogenic anti-FXa and anti-FII assays, calibrated to a specific drug, could be more useful to assess DOACs plasma levels. Recently, a product for testing DOACs in urine has been introduced by a German company; it qualitatively detects the presence or absence of these drugs in the urine.

An update on the development of antidotes for NOACs
Jawed Fareed (US)
Jawed Fareed pointed out the clinical problem of bleeding management in patients treated with anticoagulants. Older age, declining kidney function, history of bleeding, anemia, and concomitant medication use (aspirin, other antiplatelet drugs, nonsteroidal anti-inflammatory drugs, etc) are risk factors for bleeding during anticoagulant therapy. A decision pathway, considering the severity of the bleed (major vs nonmajor), acute medical and surgical management, the need for reversal, the appropriateness and time for restarting anticoagulation, and the impact of pertinent comorbidities and concomitant drug therapy should be used as a guide by all clinicians involved in the management of bleeding or in the event of emergency surgery and invasive procedures. Patient-specific factors should be considered at each step in the decision pathway algorithms. Indeed, reversal of anticoagulation is risky in patients with high thrombotic risk, such as patients with CHA₂DS₂-VASc score ≥6, stroke or transient ischemic attack in the past 3 months, VTE in the past 3 months, active cancer or other hypercoagulable state, thrombotic event when anticoagulation was interrupted previously cardiac thrombus or left-ventricular assist device. Using advanced molecular approaches, specific antidotes for dabigatran (Praxbind) and for the anti-Xa agents (andexanet alfa) have been developed. Other agents, which have been used for the control of bleeding, include prothrombin complex concentrates (activated and nonactivated) and a universal antidote, ciraparantag (Tomaselli GF et al. J Am Coll Cardiol. 2017;70(24):3042-3067).

Praxbind (idarucizumab) is an antidote developed to neutralize the effects of dabigatran. It can be used to stop the anticlotting effect of dabigatran rapidly before emergency surgery or in case of life-threatening bleeding. Praxbind is a monoclonal antibody fragment that works by attaching firmly to dabigatran and forming a complex in the blood. This rapidly stops dabigatran’s anticoagulant effects. Praxbind has been investigated in three main studies involving 141 healthy adults who previously received dabigatran. In these studies, volunteers received either Praxbind or placebo after treatment with dabigatran for 3.5 days. Praxbind was able to neutralize dabigatran’s anticoagulant effect completely within 5 minutes of administration. An interim analysis of an ongoing trial showed similar results in 123 patients who had uncontrolled bleeding or had required emergency surgery while using dabigatran. Most patients in the study were taking dabigatran to prevent stroke due to atrial fibrillation. These studies showed that Praxbind rapidly and effectively neutralizes the anticoagulant effect of dabigatran, which is sustained for an extended period of time.

Andexanet alfa, the active substance of Ondexxya, the approved commercial name in European countries, is a recombinant protein that acts as a decoy for the direct oral factor Xa inhibitors apixaban and rivaroxaban in the blood. As a result, andexanet alfa neutralizes the anticoagulant effect of these inhibitors. It is projected that andexanet alfa will also neutralize the effects of other factor Xa inhibitors, such as betrixaban and edoxaban. The effects of treatment with Ondexxya were studied in 352 patients for safety and 167 patients for efficacy. Clinical efficacy is based upon reversal of antifactor Xa activity in healthy volunteers and interim results of a study in patients with life-threatening bleeding. Ondexxya reversed the anticoagulant effects of apixaban and rivaroxaban within 2 minutes of its administration.

Ciraparantag (aripazine) is a synthetic drug that is under investigation as a universal antidote for a number of anticoagulant drugs, including factor Xa inhibitors (apixaban, betrixaban, edoxaban, and rivaroxaban), dabigatran, low-molecular-weight heparins, and unfractionated heparin. According to in vitro studies, this substance binds directly to anticoagulants by forming hydrogen bonds. Clinical studies have shown that Ciraparantag acetate, at doses of 100 mg, produced complete and sustained reversal of steady-state levels of apixaban and rivaroxaban in age-matched healthy volunteers as measured by whole blood clotting time. In previous clinical trials, Ciraparantag produced complete and sustained reversal of the DOAC edoxaban, and the low-molecular-weight heparin enoxaparin following a single intravenous bolus dose, as measured by whole blood clotting time. While the safety profile of Ciraparantag is consistent with previous trials, the most common adverse events observed were transient mild facial flushing and dysgeusia. No procoagulant signals were observed in any clinical trial to date.

Prothrombin complex concentrates, such as Kcentra, and activated prothrombin complex concentrates, such as FEIBA, have been used to neutralize DOACs. FEIBA dosages of 25 to 50 U/kg are effective in reversing the effects of DOACs. Some recent reports have shown that lower dosages can also be effective. Kcentra, a four-factor prothrombin complex concentrate can also be used at a dosage of 50 U/kg. Additionally, recombinant factor Vlla (NovoSeven) has been used to control severe bleeding. These drugs were approved long before the use of newer antidotes, such as Praxbind and Andexxa. Moreover, these plasma-based drugs have a lower cost compared with the newer antidotes.

Although the antidotes currently available for the management of bleeding with DOACs are useful for managing severe bleeding complications, these antidotes have certain adverse effects that have not been fully explored. Thrombotic complications with the use of both Praxbind and andexanet alfa have been reported. The incidence of thrombotic events within 30 days of reversal is much higher with andexanet alfa (10%) compared with Praxbind (4.8%). Some of these complications have been severe and have resulted in mortality. Andexanet alfa is a decoy protein that retains some of the biologic properties of native factor Xa; it has been shown to interfere with tissue factor pathway inhibitor, AT, and thrombomodulin. Thus, it may create an endogenous thrombotic environment. Praxbind is an antibody that forms complexes endogenously, which may have some adverse effects. Since both of these are proteins, neutralizing antibodies may also be formed. The thrombogenicity of activated prothrombin complex concentrate is also a potential complication that requires close monitoring; similarly, prothrombin complex concentrates have thrombogenic effects, which are relatively mild. Reportedly, ciraparantag may produce allergic or anaphylactoid reactions. The FDA has approved both andexanet alfa and Praxbind in order to provide clinicians with an antidote. However, this approval was based on limited clinical data and an incomplete adverse reaction profile review. The cost of the newer antidotes is rather high.

Superficial vein thrombosis – controversies in superficial venous thrombosis epidemiology and management
Willy Chi (US)
Superficial vein thrombosis (SVT) is a common condition, with an incidence greater than deep vein thrombosis (DVT). It is often associated with concomitant asymptomatic DVT. Recent studies showed that progression or recurrence of SVT is not uncommon and can present as DVT or pulmonary embolism (PE). Known risk factors for SVT include varicose veins, obesity, malignancy, age >60 years, history of thrombosis, pregnancy, infection, or smoking. Thrombophilia may have a role, but testing is not recommended because their results do not influence SVT management. Current guidelines recommend the use of low molecular- weight heparin or fondaparinux for 45 days.

The large CALISTO trial included 3002 patients with SVT who were treated with 2.5 mg fondaparinux once daily or placebo and were followed for up to 77 days. This trial excluded patients with a very high risk of SVT complications, including individuals presenting with thrombus within 3 cm of the saphenofemoral junction and those with cancer, recent SVT, or DVT/PE. Despite the exclusion of high-risk patients with SVT, the thromboembolic event rates at 45 and 77 days in the placebo arm were 5.9% and 6.3%, respectively. The prospective, randomized SURPRISE trial compared 10 mg rivaroxaban orally vs 2.5 mg fondaparinux subcutaneously over 45 days in selected high-risk patients with above-knee SVT who had additional risk factors for thromboembolic complications, such as male sex, history of DVT/PE, previous or active cancer, systemic inflammatory disease, or SVT in nonvaricose veins. Although this trial demonstrated the noninferiority of 10 mg rivaroxaban once daily compared with 2.5 mg fondaparinux once daily in the treatment of SVT, outcome event rates during treatment were numerically higher in the rivaroxaban arm, as were rates of clinically relevant nonmajor bleeding events. Surgery has been an option for the treatment of SVT. However, according to the results of a low number of studies, surgical treatment seems unable to reduce SVT extension or the occurrence of DVT or PE. Conversely, it could be useful for the reduction in pain. In the Calisto study, patients treated with fondaparinux were less frequently treated with surgery than patients treated with placebo. With regard to compression stockings, some data indicates that it can significantly stimulate a faster thrombus regression in patients with acute SVT when compared with patients receiving nondressing compression stockings. Data regarding the combination of several treatments are lacking.

Anti-DVT prophylaxis in patients undergoing thermal endovenous varicose vein treatment
Isaac K. Nyamekye (UK)
Endovenous thermal procedures may be complicated by venous thromboembolism events. In analyzing adverse events of endovenous laser therapy and radiofrequency ablation that were reported in the Manufacturer and User Facility Device Experience (MAUDE) database from January 2000 to June 2012, 30 (8%) nonfatal PEs and 123 (35%) DVTs were described. Moreover, there were 7 (2%) periprocedural deaths, all from PEs. In absence of clear recommendations by the guidelines, the goal is to identify patients at high risk of developing thrombosis, in order to offer a selective anti-DVT prophylaxis. However, the major risk factors for thrombosis in this setting are not completely understood. A preoperative risk assessment could help clinicians to better identify such patients. The most commonly used scores for this purpose are the Caprini, the Worcester, and the DOH score. A short-term pharmacological prophylaxis with low-molecular-weight heparin should be offered to intermediate-risk patients. However, a prolonged duration should be considered for patients at high risk of developing thrombosis.

New look at endovenous heat-induced thrombosis risk assessment after endovenous venous thermal procedures
Jaroslav Strejček (Czech Republic)
Endovenous thermal radiofrequency ablation is one of the most effective methods of varicose vein treatment. The term endovenous heat-induced thrombosis (EHIT) is used to describe this situation and includes, in particular, the propagation of the thrombus from the proximal section of the great saphenous vein to the femoral vein. EHIT is a relatively rare complication in technically well-performed endovenous treatment. In addition to the exact position of the endovenous instrument in relation to the saphenofemoral junction, a comprehensive assessment of anamnestic history of the patient seems useful to stratify the risk of thrombosis. A number of significant risk factors, such as male sex, higher Caprini risk scores, thrombophilic states, and obesity have been identified in studies regarding this topic. In clinical practice, different schemes, such as the Caprini score, the Thailand study system, or the Worcester scheme are used to evaluate the risk of developing EHIT, although none of them is validated. Jaroslav Strejček concluded his speech remarking that, in his center from January 2017 to June 2018, 487 endovenous treatments were performed, and due to a preoperative risk assessment, prevention, and careful posttreatment sonography controls, they observed very few EHIT complications.

How to assess the DVT recurrence risk
Paolo Prandoni (Italy)
It is well recognized that patients with acute unprovoked deep venous thrombosis or pulmonary embolism have a higher risk of recurrent venous thromboembolism (VTE) vs patients whose thrombosis is associated with acquired, transient risk factors. However, other clinical parameters can help predict the development of recurrent events. In a prospective study involving 1626 patients followed over a 10-year period after a first VTE event, among patients with secondary VTE, those with medical diseases were more likely to develop recurrent thromboembolism (31.8%) than those with recent trauma or surgery (11.4%) and those in whom the VTE was associated with hormonal therapy, pregnancy, or puerperium (20.3%) (Prandoni P et al. Haematologica. 2007;92(2):199-205). In a prospective cohort study, patients with a VTE associated with major surgery have a very low rate of recurrence (Baglin T et al. Lancet. 2003;362(9383):523-526).

More recently, a prespecified analysis of data from the EINSTEIN EXTENSION and the EINSTEIN CHOICE trials was performed in order to estimate the risk of recurrence according to the baseline risk factor profiles in patients enrolled in these trials. There were no recurrences in patients with VTE provoked by major transient risk factors. Conversely, recurrence rates in patients with VTE provoked by minor persistent or minor transient risk factors (HR, 0.81; 95% CI, 0.56-1.16) were not significantly lower than in those with unprovoked VTE (HR, 0.68; 95% CI, 0.32-1.30) (Prins MH et al. Blood Adv. 2018;2(7):788- 796).

In addition, Paolo Prandoni pointed out that there are other considerations when assessing the risk of recurrence. First, the risk of recurrent VTE is two times more frequent in men than in women. Second, the risk of recurrent pulmonary embolism after an episode of pulmonary embolism is 3 to 4 times more frequent than in patients presenting with deep venous thrombosis. In addition, extending anticoagulation for a fixed period simply delays the timing of recurrences. A number of scores, such as Vienna, DASH, DAMOVES, and HERDOO2, were developed with the aim of predicting the risk of recurrence after a first VTE episode. Among them, recently the HERDOO2 score was validated in a study showing that women with a first unprovoked VTE event and none or one of the HERDOO2 criteria have a low risk of recurrent VTE and can safely discontinue anticoagulants after completing short-term treatment (Rodger MA et al. BMJ. 2017;356:j1065). Currently, low doses of direct oral anticoagulants are also available for the extended treatment of VTEs. The ongoing Italian APIDULCIS study will assess if patients with a first unprovoked or provoked by minor risk factors VTE and persistent negative D-dimer testing after with drawal of anticoagulation will safely discontinue treatment.

Paolo Prandoni concluded his talk giving a number of personal suggestions. In the absence of contraindications to anticoagulation, indefinite anticoagulation with therapeutic doses of warfarin or low-molecular-weight heparins or direct oral anticoagulants should be considered in patients with major persistent risk factors. Patients with VTE occurring after surgery or trauma should be treated for 3 months. In patients presenting with life threatening pulmonary embolism, in those with minor persistent risk factors, and in men with unprovoked VTE, indefinite anticoagulation with low-dose direct oral anticoagulants should be considered. Risk stratification should be done in all other patients and low dose direct oral anticoagulants should be offered to patients who do not satisfy the criteria for drug discontinuation.

Options for DVT recurrence prevention in cancer and non-cancer patients – what to choose? when?
Andrew Nicolaides (Cyprus)
Recurrence of deep venous thrombosis or pulmonary embolism after completion of anticoagulation therapy is high. The most recent randomized control trials have tested various drugs aimed at reducing the risk of VTE recurrence. Aspirin reduced VTE recurrence by approximately 30% (hazard ratio [HR], 0.68; 95% CI, 0.51-0.90) without any increase in bleeding. Dabigatran was effective in reducing VTE (HR, 0.08; 95% CI, 0.02-0.25), but carried a lower risk of major or nonmajor clinically relevant bleeding than warfarin, but a higher risk than placebo (5.3% with dabigatran and 1.8% with placebo [HR, 2.92; 95% CI, 1.52-5.60]). Rivaroxaban was effective in reducing VTE (HR, 0.18; 95% CI, 0.09-0.39), but carried a higher risk of major or nonmajor clinically relevant bleeding than placebo (6.0% with rivaroxaban and 1.2% with placebo [HR, 5.19; 95% CI, 2.3-11.7]). Apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent VTE (1.7% with apixaban and 8.8% with placebo [relative risk reduction, 81%; P<0.001%]) without increasing the rate of major bleeding. Sulodexide reduced the risk of recurrence (HR, 0.49; 95% CI, 0.27-0.92), without any increase in bleeding risk. Furthermore, the risk of VTE recurrence and bleeding are not the same in every patient. Residual thrombus and elevated D-dimer are markers for increased risk of recurrence. Their presence, when combined with other risk factors, allows for the stratification of patients into high, intermediate, or low risk of VTE recurrence. Patients can also be stratified according to their risk of bleeding (high, intermediate, and low risk of bleeding). Based on the available medications and knowledge of the risk of recurrence versus the risk of bleeding, clinicians can make up a plan or algorithm for extended prophylaxis in patients with a moderate or high risk of DVT. In patients with active cancer, low-molecular weight heparin was more effective than vitamin K antagonists in preventing VTE recurrence without any increase in bleeding. Direct oral anticoagulants are more effective than low-molecular weight heparin in preventing VTE recurrence but caused more major bleeding (6.5% vs 3.7%). More studies with direct oral anticoagulants are needed.

Long term anticoagulation in VTE recurrence prevention: how to increase the safety of the anticoagulant treatment?
Wojciech Sydor (Poland)
The ACCP guidelines suggest extended anticoagulation in patients with a first unprovoked proximal deep venous thrombosis or pulmonary embolism if the risk of bleeding is low or moderate. However, only 50% of patients with unprovoked VTE are expected to have recurrences within 10 years and proposing an indefinite anticoagulation for all of them may not be correct. Currently, we have many scores that can help us estimate both the risk of recurrence and the risk of bleeding and properly select patient candidates for long-term anticoagulation. Furthermore, we have a number of agents available with reduced dose schemes, which can allow a tailored drug selection. In addition, long-term anticoagulated patients should be well educated about the risk of anticoagulation. A periodic assessment of the risk-benefit balance should be pursued, modifiable bleeding risk factors should be corrected, and drug-drug interactions should always be checked during the follow-up controls. Finally, specific antidotes for direct oral anticoagulants may be useful in the case of emergencies.

DOACS in the cancer-related DVT treatment
Larisa Chernukha (ukraine)
Risk of cancer-associated thrombosis may depend on the type and location of cancer, hospitalization, the presence of metastasis, treatments (surgery, chemotherapy), a central venous catheter, and patient-related risk factors. Until recently, the use of direct oral anticoagulants in cancer-associated thrombosis was limited due to a lack of clear evidence. Only data from a subgroup analysis of randomized controlled trials (RE-COVER, RE-COVER Il, EINSTEIN-DVT, EINSTEIN-PE, AMPLIFY, Hokusai VTE) were available. In these trials, a small number of patients with active cancer were included. Furthermore, in these trials, the comparator was vitamin K antagonists instead of low molecular- weight heparin. However, in the CLOT study, vitamin K antagonists appeared to be inferior to low-molecular-weight heparin in terms of cancer-associated thrombosis treatment, risk of recurrence, and bleeding rate. Novel oral anticoagulants have shown a nonsignificant decrease in VTE recurrence and a lower major or clinically relevant bleeding rate compared with vitamin K antagonists. However, cancer patients in these trials were healthier and had lower mortality than patients in the CLOT study. More recently, patients with active cancer were enrolled in the Hokusai VTE-Cancer, Select-D, and ADAM VTE trials.

In the Hokusai VTE-Cancer study, the recurrence rate of VTE was non significantly lower in patients who received a combination of edoxaban with low-molecular-weight heparin than on dalteparin only. The incidence of major bleeding was significantly higher in the edoxaban group. The mortality rate was not substantially different between groups, and the majority of deaths were caused by cancer. The number of deaths associated with VTE or bleeding was too small to make comparisons between groups.

In the Select-D study, rivaroxaban was associated with a lower rate of VTE recurrence compared with dalteparin at 6 months. The rate of major bleeding was numerically higher in the rivaroxaban arm, but a similar rate of fatal bleeding was found in both the groups. Overall, survival was also similar among treatment arms. In these trials, it was also noticed that patients with gastrointestinal or genitourinary cancer were at high risk of major bleeding when treated with direct oral anticoagulants.

The results of the ADAM VTE trial showed very low bleeding and VTE recurrence rates of apixaban compared with dalteparin, but these data have not yet been included in the guidelines. The 2017 ESC, 2017 ESMO, 2018 NCCN, 2018 ISTH, and 2018 Canadian Expert Consensus recommend low-molecular-weight heparin as the treatment of choice for patients with cancer-associated thrombosis for at least 6 months. Only edoxaban and rivaroxaban are mentioned and suggested for cancer patients with acute VTE, low risk of bleeding, and no drug-drug interactions with current systematic therapy. The choice of treatment should be based on the type and location of the cancer, on the risk of bleeding, concomitant chemotherapy, drug interactions, and patient preferences. The role of heparin and related glycosaminoglycans in the management of vascular diseases in the era of new oral anticoagulant drugs Jawed Fareed (US)

Undoubtedly, the introduction of direct oral anticoagulants had a major impact on the management of thrombotic and cardiovascular disorders in the context of oral anticoagulation. However, these drugs are of limited value for parenteral indications. None of these agents can be used for surgical or interventional procedures where heparin is routinely used. Therefore, in the event of a shortage of heparin, direct oral anticoagulants will be of limited value. Parenteral antithrombin agents, such as argatroban or bivalirudin, may be an option. However, there is no antidote available for the use of these antithrombin agents and the risk of hemorrhagic complications is disconcerting. Among the nonheparin glycosaminoglycan-related drugs, danaparoid, hemoclar (SP54), and sulodexide are currently available for clinical use. In comparison with sulodexide, both of these drugs are relatively weaker anticoagulants when administered parenterally. Sulodexide has a broader therapeutic index vs direct oral anticoagulants and it can be neutralized by protamine sulfate. It might be an option to substitute for heparin in such indications, such hemodialysis and interventional procedures. Indeed, pharmacodynamics data showed that sulodexide could be used as an alternative to heparin in parenteral indications. However, these indications are not currently approved for sulodexide use. The anticoagulant and antithrombotic qualities of heparins and related glycosaminoglycans are also associated with their anti-inflammatory and vasoprotective effects. Up to now, unfractionated heparin remains the anticoagulant of choice for vascular and endovascular procedures and indications. Now that the heparin supply is threatened by several factors, including the increased use of porcine mucosal heparin for the manufacturing of low molecular- weight heparin, the shortage of heparin due to outbreaks of diseases, such as African swine fever, resourcing and finding alternatives to heparin should be timely in order to avoid any serious outcomes. The development of bovine and ovine heparin and the use of alternative glycosaminoglycans, such as sulodexide may offer practical approaches to offset the heparin shortage. As a blended glycosaminoglycan, sulodexide is a good candidate for further development as a parenteral anticoagulant drug, which can be optimized for hemodialysis and interventional/surgical indications. In the opinion of Jawed Fareed, both industry and agencies need to work together in order to develop plans and a fast-track review of a number of initiatives to avoid problems that may eventually result in compromised patient care.

Anticoagulation in the arterial thrombotic complications prevention – current evidence
Pier Luigi Antignani (Italy)
The latest guidelines recommend single antiplatelet therapy in symptomatic patients with peripheral artery disease not requiring anticoagulation. More recently, The COMPASS trial showed that low-dose rivaroxaban twice a day plus aspirin once daily reduced major adverse cardiovascular and limb events when compared with aspirin but increased major bleeding. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Glycosaminoglycans, such as sulodexide, inducing vascular relaxation and increasing the production of nitric oxide, might be an option for the treatment of patients with peripheral artery disease if preliminary data can be confirmed.

First results of the German registry for superficial thrombosis – INSIGHT study
Thomas Noppeney (Germany)
Superficial vein thrombosis (SVT) and venous thromboembolism (VTE) are related entities. In the last few years, a series of observational studies conducted mainly in France may show that “isolated superficial vein thrombosis” (without concomitant deep vein thrombosis and/or pulmonary embolism) is in fact not a benign and spontaneously healing disease, but bears a potential for severe thromboembolic complications once treated inadequately. The INSIGHTS-SVT study aims to collect representative data on the current management and outcomes of superficial vein thrombosis in Germany under real-life conditions. It will document the implementation of the recently issued national superficial vein thrombosis guidelines issued by the Society for Angiology and the Society for Phlebology. It is a prospective, observational cohort study involving approximately 1200 participants followed up for 1 year. Thomas Noppeney presented the preliminary results of the study, showing that 92% of patients were treated with prophylactic doses of anticoagulants, especially fondaparinux (66%). A few patients were treated with surgery at the time of inclusion. Up to now, the incidence of the efficacy and safety end points is quite low (0.9% for death, 1.2% for pulmonary embolism, 2.5% for deep vein thrombosis, 1.6% for bleeding; 11.9% for superficial vein thrombosis persistent or extending). Overall, Thomas Noppeney emphasized that the treatment of this disease in real life seems in accordance with the recommendations of the German guidelines.