II. Venous diseases
2.1. Venous thromboembolic diseases
F. A. Allaert (France)
From 2005 to 2009, 693 997 deep venous thrombosis (DVT) or pulmonary embolisms (PE) were found during hospitalization in France. Prevalence was around 8.6% in a population of 43.5% males and 56.5% females.
DVT alone was responsible for 57.7% of cases, while PE, with or without DVT, accounted to 48.3% of cases.
The main reason for hospitalization was cardiovascular diseases (13.5%), tumors (10.6%), respiratory diseases (8.6%), and digestives diseases (6.4%).
Around 140 000 cases of DVT or PE are treated each year in French Hospitals. The mortality rate is close to 10 % for DVT and PE occurring during hospitalization.
In this session the authors reported data from RIETE (Registro Informatizado de la Enfermedad TromboEmbolica), an ongoing, multicenter, observational registry of consecutive patients with symptomatic, objectively proven, acute venous thromboembolism (VTE).
A. Visonà (Italy) stated that in elderly patients with dementia it is difficult to determine the correct incidence of venous thromboembolism (VTE). Impaired mobility causes increased VTE risk, while concomitant therapy results in increased bleeding risk. Moreover, the balance between the efficacy and safety of anticoagulants is uncertain. In a total of 30 895 patients, 1087 had dementia. During the 3-month study period 4.6% of these patients had fatal pulmonary embolism (PE), while, the incidence of PE in patients without dementia was 1.5%. Fatal bleeding occurred in 1.7% of patients with dementia, and in 0.6% of patients without dementia. Patients with dementia initially presenting with PE died from PE or bleeding in 9% and 2.2% of cases, respectively, and those initially presenting with deep venous thrombosis (DVT) alone died from PE and bleeding in 0.9% and 1.2% of cases, respectively. Patients with dementia had a 3-fold higher incidence of fatal PE and fatal bleeding than patients without dementia. With initial presentation of PE the risk of fatal PE in patients with dementia is 4-fold higher than that of fatal bleeding. With initial presentation of DVT alone, the risk of fatal PE is lower than the risk of fatal bleeding.
I. Tzoran (Israel) presented data about silent PE in patients with DVT. Major outcomes such as symptomatic PE or major bleeding occur within 90 days of DVT diagnosis. Out of 2375 patients with DVT, 842 had silent PE and among these, cancer was diagnosed in 33% of cases and prior VTE in 17%. The cumulative incidence of major bleeding events was higher in patients with no silent PE at baseline. DVT patients with silent PE at baseline had an increased incidence of symptomatic PE events. In DVT patients with no silent PE, the risk of major bleeding was higher than the risk of symptomatic PE. Screening for silent PE in DVT patients at increased risk for bleeding may be useful in some subgroups of patients.
P. Di Micco (Italy) reported some findings in patients with thrombocytopenia (platelet count < 80000) at onset of VTE. Thrombocytopenia is uncommon and usually associated with malignancy. Low molecular weight heparins are usually used at reduced doses while the use of fondaparinux is considered for long-term treatment. The outcome of patients with thrombocytopenia is poor and is associated with increased complications like fatal bleeding and fatal PE. M. Monreal (Spain) examined the clinical presentation and outcome of patients with bleeding and VTE. A total of 6855 patients were enrolled in their study, 1635 of whom had comorbidities. In these patients, there were higher percentages of fatal bleeding (1.4% vs 0.3%) and fatal PE (4% vs 1.1%) compared with patients with no comorbidities within the 3 months of follow-up. In another study of 170 VTE patients with a recent major bleeding episode, with a follow-up of less than 3 months, fatal bleeding was found in 4% of patients, while fatal recurrent PE was found in 2.4%. In VTE patients with recent major bleeding, the incidence of cumulative survival decreased and cumulative new bleeding increased especially for gastrointestinal bleeding.
The risk of major bleeding (3.8%) and fatal PE (4.7%) was high in patients with hemorrhagic stroke who subsequently developed VTE.
L. Bertoletti (France) talked about chronic obstructive pulmonary disease (COPD) and VTE. COPD is a moderate VTE risk factor. Pulmonary embolism was the main clinical presentation of VTE in patients with COPD. COPD was associated with an increased risk of dying from fatal PE after an initial VTE event. Patients with COPD experienced higher rates of overall mortality and bleeding under thrombotic therapy during a 3-month follow-up. The therapeutic management of VTE remains a challenge with a higher risk of fatal PE and a higher risk of bleeding.
D. Jimenez (Spain) suggested that risk stratification models are useful. In particular, the simplified Pulmonary Embolism Severity Index (sPESI) is accurate and easy to use; within 3 months of follow up it may identify patients at low risk of death after a diagnosis of PE as well as patients with cancer and PE.
2.1.2. Risk factors
F. A. Allaert (France)
Tumors produce procoagulant factors (TF, mucins, APCR). Extrinsic factors like surgery and chemotherapy may play a role.
The incidence of deep venous thrombosis +pulmonary embolism during cancer ranges from 15% to 20%, and its prevalence is 4 to7 times higher.
According to guidelines, hospitalized patients with cancer should receive prophylaxis. It is important to adapt this prophylaxis to each phase of cancer progression (initial phase, during chemotherapy, remission).
F. A. Allaert (France)
Venous thrombosis (VT) is a common disease that frequently recurs. Thrombotic risk assessment is important to balance the risks and benefits of anticoagulation treatment. Only patients at high risk of recurrence will benefit from long-term anticoagulation treatment, whereas it will expose low-risk patients to a risk of bleeding.
The risk of recurrence is high in patients in whom the initial VT was unprovoked (ie, the event occurred in the absence of a temporary risk such as surgery, trauma, pregnancy, or use of female hormones). The risk of recurrence was 25% in a cohort of patients from Austria with unprovoked VT or pulmonary embolism 5 years after the event and it increased with time. In contrast, patients who had VT after surgery or used female hormones were at a lower risk of recurrence.
In their study, Hull and colleagues reported that all the patients with recurrence of VT had had initial proximal deep thrombosis and that there was no recurrence in patients who had had distal deep vein thrombosis.
The low rate of recurrence in patients with isolated calf vein thrombosis has been confirmed by several other studies. Data from one study group showed that the risk of recurrence of VT is more than 2-fold higher in patients with symptomatic pulmonary embolism than in patients with isolated deep vein thrombosis.
The risk of recurrent VT is strongly predicted by the sex of the patients. Men with a first unprovoked VT have a nearly 4-fold increased risk of recurrence compared with women.
First conclusion: men who suffered from a first unprovoked VT, proximal VT/pulmonary embolism have a high risk of recurrence. In these patients, extended secondary prevention should be considered.
Residual vein thrombosis is a possible predictor of the recurrence of VT but it is modestly associated with an increased risk of recurrence and it is not a predictor of recurrent VT in patients with unprovoked DVT. Moreover, the association with the risk of recurrence depends on the definition of residual vein thrombosis. It is premature to make a clinical decision on the basis of residual vein thrombosis measurement results.
Laboratory screening for thrombophilia to identify increased risk of VT has often been advocated and is now done on a routine basis around the world. However, there is no proof that thrombophilia screening helps prevent VT recurrence. VT has many causes and many patients have more than one abnormality and the effect of combined defects is not known. Routine testing of patients can lead to overtreatment or cause unnecessary concern. Furthermore, routine laboratory thrombophilia screening is no longer warranted.
D-dimer concentration is related to the occurrence of VT. In a meta-analysis of 7 randomized controlled trials including 1880 patients with first unprovoked VT, the annual recurrence rates were 8.9% in patients with high D-dimer levels, and 3.5% in patients negative for D-dimers. Results from two other trials showed that patients with a low D-dimer concentration have a low risk of recurrence.
In a prospective cohort study, 929 patients with a first unprovoked venous thrombosis or pulmonary embolism were followed up after discontinuation of anticoagulation treatment. The clinical variables were age, sex, location, and body mass index. The laboratory variables were: factor V Leiden (FV Leiden), prothrombin mutation, and D-dimer. Only the patient’s sex, thrombosis location, and the concentration of D-dimer were related to an increased risk of VT recurrence.
In the future, D-dimer levels together with clinical risk factors could help establish rules to predict the risk of VT recurrence.
F. A. Allaert (France)
Deep vein thrombosis (DVT) and pulmonary embolism (PE) are two manifestations of the same disorder: venous thromboembolism (VTE). Low-molecular-weight heparin is the treatment of choice for both DVT and PE. Secondary thromboprophylaxis with vitamin K antagonists should be started as soon as the diagnosis is confirmed. The dose of vitamin K antagonist should be adjusted to a target international normalized ratio (INR) of 2.5. For most patients with PE, thrombolysis is not recommended. Vena cava filters should be restricted to patients with active bleeding or risk of serious bleeding, and to those in whom PE has recurred despite adequate anticoagulation.
Duration of anticoagulation should be at least 3 months because shorter courses double the recurrence rates. More prolonged anticoagulation therapy should be considered in the presence of specific clinical risk factors. Global markers of coagulation, particularly D-dimers, may discriminate between low- and high-risk patients for the recurrence of VTE.
The new oral anticoagulants have the potential to simplify the long-term treatment of patients with VTE by obviating the need for periodic laboratory monitoring while being associated with a favorable benefit-to-risk ratio. They include compounds that inhibit factor Xa, such as rivaroxaban, and compounds that inhibit thrombin, such as dabigatran etexilate.
The results of the RECOVER and EINSTEIN randomized clinical trials, which studied initial and long-term treatment of VTE patients with dabigatran etexilate and rivaroxaban, respectively, have been reported. In RECOVER, the administration of dabigatran etexilate at the dose of 150 mg twice daily for 6 months in patients with acute VTE was found to be as effective as warfarin in patients who had been treated with heparins or fondaparinux for the initial 7 to 10 days and was associated with a statistically significant reduction in the incidence of major or clinically relevant bleeding complications. In EINSTEIN, the administration of rivaroxaban in patients with acute deep vein thrombosis from the beginning at the dose of 15 mg twice daily for 3weeks followed by 20 mg once daily for 3 to 12 months was found at least as effective and as safe as conventional enoxaparin-warfarin treatment. Of interest, rivaroxaban was found to be significantly more effective than comparators regarding the combined end point of recurrent VTE plus major bleeding. In addition, prolonging rivaroxaban at the dose of 20 mg once daily for an additional 6 to 12 months in patients who had received rivaroxaban or warfarin for at least 3 months achieved an 82% reduction in the risk of recurrent events over placebo and was associated with less than 1% major bleeding complications.
In the RE-MEDY trial, dabigatran demonstrated noninferiority to warfarin, with fewer bleeds, but there were more acute coronary syndrome events in the dabigatran group than in those taking warfarin.
The challenging aspects of treating VTE with the newer anticoagulants are: determining the optimal duration of anticoagulation, using a single-drug approach, patients at the extremes of age and bodyweight (advanced age, over/underweight), compliance and adherence, and monitoring.
R. Hull (Canada)
Clinical trials differ from real life. The patients in trials are selected and have better care, the treatment is usually of short duration, and the studies have insufficient power to detect adverse effects. Clinical studies provide good evidence of the efficacy of a drug and support its labeling for a specific indication. The question is whether it is possible to generalize the results of a study. Postmarketing studies can then bring important signals and may sometimes lead to changes in prescribing information. Looking at the history of the development of the older anticoagulants approved for venous thromboembolism prophylaxis, one such case was enoxaparin. It caused bleeding in patients with renal insufficiency and intraspinal hematoma following epidural anesthesia with subsequent long-term or devastating paralysis. This led to labeling changes and black box warning from the FDA later on.
Another such case was fondaparinux. Shortly after its approval, there were several spontaneous reports of serious bleeding in patients with renal insufficiency or low body weight. Bleeding is the main safety issue with anticoagulants but in clinical studies, the patients with high bleeding risk are primarily excluded. However, later on, they may potentially be exposed to the drug without appropriate clinical experience. Because of this, the availability of an antidote seems to be a necessity for new anticoagulants. Contrary to the older anticoagulants, there are no specific antidotes for the new anticoagulants as yet, though some are currently under development. According to official reports, since its approval dabigatran has already been linked to 542 deaths, 3781 serious adverse events, and 2367 bleeding events. Moreover, a subanalysis of the RE-LY study revealed that for elderly patients, warfarin is safer. The other problem with all the new oral anticoagulants is the risk of overdose in patients with renal impairment or the potential drug interactions. In conclusion, it is still too early to say whether the new anticoagulants cause more or less bleeding than the older ones. Real-life practice teaches us that the results of clinical trials may not be sufficient and clinicians should consider additional factors before implementing these new drugs into their daily practice.
Part 1. Should we switch patients who are well-controlled on vitamin K-antagonists to new antithrombotic drugs?
M. Penka (Czech Republic)
The author demonstrated his opinion using one example of the therapeutic indications of anticoagulants: the prevention of strokes in patients with atrial fibrillation. Warfarin is effective in preventing strokes but only if the therapy is well managed and patients spend more than 75% of time in the therapeutic range of the international normalized ratio (INR). There are multiple factors contributing to changes in warfarin dosage. Limitations of warfarin include its multitarget mode of action, narrow therapeutic window, intra- and interpatient variability, the reluctance of physicians to prescribe it, and a dislike on the part of patients. On the other hand, the new oral anticoagulants are single-target drugs; their dosing is simple, they have only few interactions and have demonstrated very good efficacy and safety in phase 3 clinical trials in atrial fibrillation patients. In conclusion, the author found the current experience with the new drugs to be very convincing and according to him they will replace warfarin.
E. Minar (Austria)
The opposing speaker chose another example of an indication for anticoagulation treatment—venous thromboembolism—and mentioned the results of phase 3 clinical studies with the new oral anticoagulants in venous thromboembolism treatment. Therefore, the two speakers only partially dealt with the same topic. However, some of their arguments targeted the same controversial issues, especially the bleeding risk inevitably associated with every anticoagulant. The effect of warfarin can be controlled quite reliably and it is also possible to use lower INR targets in at-risk populations. However, patients with risk factors for bleeding have been excluded from clinical trials with new anticoagulants. Their short halflife and lack of need for regular monitoring may, in fact, be a problem in patients with poor compliance. Another source of problems is the potential fluctuation of renal function, especially in older fragile populations. There is also a lack of validated laboratory tests to measure the anticoagulation effect of new anticoagulants. Furthermore, their long-term effect is unknown, as is their costeffectiveness and the risk of combining them with other antithrombotics. The author concluded with a slogan: “Never change a winning team.”
Part 2. Percutaneous treatment of ileofemoral thrombosis
M. Rocek (Czech Republic)
The speaker briefly explained the techniques used for the interventional treatment of ileofemoral venous occlusion—catheter-directed local thrombolysis, mechanical thrombectomy, the combination of both techniques, and adjunctive techniques such as balloon angioplasty and stenting—and he mentioned some indications for inferior vena cava filter implantation. Several interesting cases of complicated but finally successful procedures were demonstrated. The author found endovascular treatment better than surgery due to its efficacy and safety and also the potential to shorten hospital stays.
E. Minar (Austria)
The second speaker did not mention case reports but looked at the problem from a more general point of view. He mentioned the aims of the treatment of acute deep vein thrombosis (DVT)—the prevention of thrombus extension, pulmonary embolism, and postthrombotic syndrome (PTS). Unfortunately, there is only little data concerning PTS prevention. PTS may develop following proximal as well as distal DVT. The previous guidelines for antithrombotic therapy of the American College of Chest Physicians (ACCP) published in Chest in 2008 recommended to consider catheter-directed thrombolysis (CDT) for ileofemoral thrombosis. However, in the last ACCP guidelines (published this year) the authors suggest anticoagulation therapy alone over CDT. The speaker then demonstrated the results of some clinical studies of interventional therapy for ileofemoral thrombosis. He stated that most data were of low-quality and also stressed the small additional risk of bleeding associated with those interventional procedures.
In his view, CDT is an alternative only for a minority of patients. In the discussion, the participants expressed their opinion that interventional therapy should be an alternative especially in younger patients.
Part 3. Is routine testing for thrombophilia useful?
J. J. Michiels (The Netherlands)
The author cited the literature concerning the prevalence of thrombophilic defects in venous thromboembolism—not only deep vein thrombosis of the leg and pulmonary embolism, but also superficial thrombophlebitis, abdominal vein thrombosis, and even some cases of arterial thrombosis. The author named the tests that should be used in those patients. According to him, testing for thrombophilia is useful in some situations associated with increased thrombotic risk.
S. Eichinger-Hasenauer (Austria)
The opposing speaker first explained the general rationale for carrying out tests. The condition tested should be frequent, the pathophysiology of the defect should be well understood, and a reliable test should be available. The main question, however, is whether the test result influences the treatment or management of the patient to his/her benefit.
For S. Eichinger, thrombophilia has a low prevalence and knowledge of the presence of a specific defect does not influence therapy. Thrombophilia testing is not useful even in the rare cases of thrombosis in unusual sites because their pathophysiology is not clearly understood. There is not enough data about the risk of venous thromboembolism recurrence in patients with thrombophilia. S. Eichinger does not consider thrombophilia testing useful in asymptomatic carriers either, because thrombotic risk may be adequately and simply derived from family history. Moreover, there are insufficient data on the efficacy and safety of lowmolecular- weight heparin in asymptomatic carriers of thrombophilic defects during pregnancy.
A. Nicolaides (UK) summarized the rationale and methodology of the 2012 5th revision of the International Consensus Statement. The key questions are:
• What is the evidence? The evidence determines the grade of recommendation.
• In the absence of evidence, what new studies are needed?
The aims are to provide a clear and concise account of the evidence on the efficacy (or harm) of the various methods available for the prevention and management of venous thromboembolism (VTE). An additional aim is to provide recommendations based on such evidence.
Literature searches were performed by an independent agency (Pharmaceutical Strategic Initiatives). Only fully published, peer-reviewed papers of randomized comparisons were used to determine the level of evidence.
Randomized controlled trials (RCTs) with consistent results and systematics review provide high-level evidence. Single rigorously performed RCTs that are methodologically reliable and sufficiently large to give clear results and are applicable to most patients in most circumstances also provide high-level evidence. RCTs with less consistent results and with limited power or other methodological problems provide moderate-level evidence. Moderate-level evidence is also provided by RCTs results that are extrapolated to the target population from a different group of patients. Well-conducted observational studies with consistent results that are directly applicable to the target population provide low-level evidence. In the absence of evidence or in case of low-level evidence, the key questions that should be addressed by future studies need to be postulated.
Because the international consensus statement on venous thromboembolism is an international document not focused on the clinical practice of a single country or continent, and because of the variability in costs in different parts of the world, the authors have refrained from incorporating considerations of costs in their recommendations. They believe that decisions about costs and resource allocations for health care interventions are more appropriately made by individual health care systems as they may vary considerably between countries. Therefore, considerations of cost or cost-effectiveness are not considered in individual recommendations. However, recognizing that health care systems do not have unlimited resources, a section that summarizes the available evidence regarding the cost-effectiveness of primary prevention and treatment of VTE has been included. This section is for use by appropriate decision-makers.
Evidence is presented for outcomes such as the incidence of asymptomatic deep venous thrombosis at screening as well as symptomatic deep venous thrombosis or pulmonary embolism, fatal pulmonary embolism, overall mortality, and the development of the postthrombotic syndrome when available.
A. Comerota (USA) presented the methodology of the 2012 American College of Chest Physicians (ACCP) consensus. Panel members have changed from the previous guidelines. In this edition, methodologists, health economists, “frontline” clinicians, and experts have worked together.
Conflict-of-interest (COI) statements have an important role, to avoid circumstances (financial or intellectual) that might influence recommendations. For example, panelists with COI participated in discussions, but were excluded from voting on final recommendations.
Another difference was the use of electronic (rather than paper) publication and communication, which needed less time, was more easily searchable, had links to additional sources, was less expensive and more environmentally friendly, and led to a yearly review of the evidence.
For most of items, the evidence is only 1B or 2B, with no 1A-level evidence. Changes in recommendations from the previous version were provided as examples. For example, anticoagulation alone over catheter-directed thrombolysis, operative venous thrombectomy, or systemic thrombolytic therapy (grade 2C), or recommendations against the use of vena cava filters in addition to anticoagulation in patient with acute deep venous thrombosis (grade 1B).
A. Kakkar (UK) commented on the differences between the guidelines from both sides of the Atlantic using aspirin as an example. Harmonization of the way the evidence is assessed is necessary.
W. Leong (Canada) highlighted the limitations of guidelines in relation to ethnic diversity (pharmacogenetics) and differences in local standards of care (in developed or third-world countries, public or private health care, or in countries with no health care institutions, primary or secondary care, and professional types of qualification).
C. Carter (USA) presented the global issues of venous thromboembolism (VTE). Venous thromboembolism is the first cause of potentially preventable deaths in hospitalized patients and venous thromboembolism management is rated as the most effective patient safety practice for hospitals. He posed the question of how to improve their use of prophylaxis. Measures to increase adherence to guidelines could include professional public reporting, accountability for patient safety, or not covering the additional cost incurred for hospital-acquired venous thromboembolism in selected patients.
V. Kakkar (UK) made a historical review of the anticoagulant treatment of deep vein thrombosis (DVT), which included the burden of venous thromboembolism (VTE), its current therapy, the newer anticoagulants, and unresolved issues.
The burden of thromboembolism is 300 000 deaths due to pulmonary embolism (PE) in the USA and 370 000 PE-related deaths per year in 6 European countries. The cost per VTE in Australia in 1 year is 1.5 million AUD (753 000€).
Appropriate initial treatment of DVT leads to prevention of fatal PE, reduced morbidity associated with acute leg or lung thrombus, prevention of recurrent VTE, and prevention of long-term sequelae.
It is important to consider venous thromboembolism as a chronic disease rather than an acute illness, with a high risk of recurrence during the first 6 to 12 months after an acute episode, and with a cumulative rate of recurrence of about 25% at 5 years and 30% at 20 years. This recurrence is associated with a higher likelihood of postthrombotic syndrome and recurrent PE, which is fatal in about 4% to 9% of patients.
Vitamin K antagonists have been the most used alternative but have an unpredictable dose-response and need to be monitored to achieve therapeutic levels (international normalized ration [INR] of 2.0-3.0). Moreover, they have an important burden of complications (bleeding, drug interactions, and food effects). The duration of therapy depends on the causes and risk factors and varies from 3 months if risk factors are limited, to 6 months in first idiopathic VTE events, and 12 months in case of thrombophilia. High-risk patients with recurrent VTE or cancer may need lifelong treatment.
The new anticoagulants are expected to play an important role in treatment. They could provide similar or better therapeutic results with less complications and easy control (simple, single oral therapy administered in fixed-dose regimens for the initial and long-term treatment of DVT and PE). The likelihood of having improved benefit-risk profiles and efficacy in reducing the long term sequelae needs to be addressed.
J. Fareed (USA)
The new oral anticoagulants seem to be very promising in comparison with warfarin. They differ from warfarin in many aspects—they work as direct inhibitors of specific coagulation factors, have an immediate onset of action, a fixed dosage, are eliminated from the body in 12 hours, have minimal drug and food interactions, and there is theoretically no need for laboratory monitoring. Nevertheless, warfarin has been used for 60 years in clinical practice while there is no experience with the long-term use of these new substances. Two main classes are the most developed—thrombin inhibitors (dabigatran etexilate) and factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, etc…). All of them are candidates for use in several clinical situations—thromboprophylaxis in surgical (especially orthopedic) and medical patients, prophylaxis of stroke in atrial fibrillation, treatment of venous thromboembolism, and as part of the treatment of acute coronary syndrome. For these indications, they are undergoing or have even undergone phase 3 clinical studies and some of them have already been approved for clinical practice. Both dabigatran and rivaroxaban have obtained approval for thromboprophylaxis after major orthopedic surgery and for atrial fibrillation. However, dabigatran has failed to get FDA approval for acute coronary syndrome. Rivaroxaban seems very promising in the treatment of venous thromboembolism, with proven efficacy even in the initial phase of treatment, thereby giving the opportunity to avoid parenteral anticoagulation. Moreover, the extension of therapy with rivaroxaban beyond 6 to 12 months significantly reduced the rate of venous thromboembolism recurrence. Apixaban was recently evaluated by the FDA for atrial fibrillation but the decision was postponed as more data on clinical efficacy and safety is required. Edoxaban has been approved in Japan for atrial fibrillation and is currently being evaluated for further indications.
In conclusion, in spite of the advantages of the new oral anticoagulants, there are also some crucial safety issues—the absence of specific antidotes, no anticoagulant effect in case of missed doses, no test to monitor the anticoagulant effect and its intensity, difficulties in modulating dosage, relatively high
discontinuation rates due to gastrointestinal distress, a reported 0.2% increase in the incidence of myocardial infarction, and a considerable increase in cost.
C. Carter (USA) said that preapproval clinical trial safety data is not a substitute for postapproval safety monitoring. The APPRAISE 2 trial (apixaban vs placebo) was stopped prematurely due to an excess of clinically important bleeding in the apixaban arm without a counterbalancing reduction in ischemic events (7048 patients; median follow-up, 3.5 months; 412 primary events [44%]).
Many questions emerged following the ATLAS-51 trial (rivaroxaban 2.5 mg and 5 mg vs placebo + acetyl salicylic acid 75 mg). Rivaroxaban was effective in reducing the risk of the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in men and women but increased the risk of the primary end point in subjects with a history of ischemic stroke/transient ischemic attack. Rivaroxaban increased the risk of noncoronary artery bypass grafts–related thrombolysis in myocardial infarction and major bleeding in all subgroups except those with a history of chronic heart failure receiving rivaroxaban 2.5mg. Those at higher risk of bleeding were subjects >75 years of age, subjects weighing <60 kg or >90 kg, subjects with moderate renal impairment, and women.
In Japan, the occurrence of a number of cases of fatal hemorrhage in patients receiving dabigatran for the prevention of stroke and systemic embolism resulted in a strengthening of the advice for prescribers. These patients were all older than 75 years, with renal impairment and additional risk factors for bleeding, including concomitant medication.
From 2006 to 2012, the FDA submitted thousands of adverse event reports, a quarter of which were for dabigatran as well as generic and/or brand name drugs containing the same primary active ingredients (6090 gastrointestinal signs and symptoms, of which 4324 gastrointestinal hemorrhages).
We are in the early stage of market approval for the newer anticoagulants. Structured, well-conducted postapproval outcome research is desperately needed.
W. Leong (Canada) focused his presentation on the various safety aspects of treatment with the new oral anticoagulants.
It is difficult to verify patient compliance. Patients who use the new oral anticoagulants discontinue their medication in larger numbers than those treated with warfarin because of gastrointestinal symptoms. The administration of 2 daily doses favors forgetfulness by the patient. Forgetting more than one dose can put the patient at prothrombotic risk. A “bad” warfarin patient will be a very “bad” dabigatran (rivaroxaban or apixaban) patient.
Some drug interactions often remain unknown. Pantoprazole reduces the plasma dabigatran concentration by up to 30%.
The combined use of dual antiplatelet therapy with warfarin is mandatory in certain thrombotic risk situations. In patients with atrial fibrillation the use of warfarin + aspirin + clopidogrel is associated with a more than 3-fold increased risk of nonfatal and fatal bleeding and this will probably also apply to the new the new anticoagulants. These strategies determine the potential increase in severe or moderate hemorrhagic events and even life-compromising events. There are insufficient studies to recommend a strategy at this point.
Monitoring is not recommended nor is it clinically useful for the new oral anticoagulants. However their anticoagulant effect must be controlled and there is no test to assess their effect or therapeutic range.
In renal failure their dose should be reduced or they should be discontinued. Nevertheless, there are no studies that clearly indicate the dose to use in these circumstances. If the partial thromboplastin time (PTT) of a dabigatran patient is>90 sec and his/her international normalized ratio (INR) is >1.5 there is a suspicion of overdosage or accumulation.
A survey from the Australian Government’s Department of Health and Ageing reported that some bleeding adverse events occurred during the transition from warfarin to dabigatran. Many adverse events occurred with the reduced dosage regimen. For dabigatran, the most common type of serious bleeding was gastrointestinal bleeding.
Another survey from the Institute for Safe Medication Practices reported 932 serious adverse events (120 deaths, 25 cases of permanent disability, 543 cases requiring hospitalization) in patients using dabigatran. In the USA, from 2007 to 2009, 100 000 elderly patients were hospitalized per year for adverse drug reactions and the most commonly implicated medication was warfarin.
There is no evidence of an antidote for dabigatran, rivaroxaban, or apixaban. There is limited evidence with reversal strategies for rivaroxaban and dabigatran, in particular the use of plasma clotting factors to reverse the anticoagulant effect of rivaroxaban and the use of hemodialysis to remove dabigatran from the blood.
D. Hoppensteadt (USA) proposed to measure the effects of the oral anti-Xa agents (rivaroxaban and apixaban) and an anti-IIa agent (dabigatran) using the currently available assays (prothrombin time (PT), activated partial thromboplastin time [aPTT], amidolytic activity, Technothrombin thrombin generation assay) and a newly developed prothrombinase-induced clotting time assay (PiCT) in order to identify a clinically suitable test for monitoring the anticoagulant effects of these agents.
In the PT assay, responses showed assay-dependent variations: each reagent exhibited its own specific sensitivity to the different anticoagulants. Dabigatran produced the strongest anticoagulant activity whereas apixaban was relatively weaker. aPTT was relatively more sensitive to dabigatran and rivaroxaban while apixaban showed weaker anticoagulant responses with all reagents.
Amidolytic anti-IIa and Xa assays revealed the product-specific inhibition of these enzymes. Apixaban showed a relatively lower anti-Xa activity compared with rivaroxaban.
In the PiCT test, all agents exhibited a concentration-dependent anticoagulant effect. The one-stage PiCT test showed the highest sensitivity to all 3 agents and was the only test where apixaban exhibited significant anticoagulant responses. The sensitivity limit of this assay was higher than for the other tests. In the thrombin generation assay, all agents showed a concentration-dependent inhibition of thrombin generation in both platelet-poor plasma and platelet-rich plasma. The relative inhibition in platelet-poor plasma was greater than in platelet-rich plasma.
These studies show that the PT and aPTT reagents exhibit wide variations and varying degrees of sensitivity to the new oral anticoagulants. The one- stage PiCT assay shows a higher sensitivity to all of the agents studied compared with the other clot-based tests and its use should be validated in clinical trials. The amidolytic anti-Xa and anti-IIa assays are relatively specific and are not affected by endogenous factors whereas the thrombin generation assays provide an overall anticoagulant/antithrombin potential test of plasma.
M. Tangelder (The Netherlands)
TB-402 is derived from an antibody that arose spontaneously during the treatment of hemophiliac patients and partially inhibits factor VIII (FVIII) activity. FVIII is an acute-phase protein with elevated activity after surgery; it is associated with a high risk of thrombosis. A partial inhibitor of FVIII activity may be an effective anticoagulant preserving partial coagulation activity.
The author presented the results of phase 1 and 2 trials investigating the use of a single dose of TB-402 for the prevention of venous thromboembolism (VTE) in patients after total knee and hip replacement.
Phase 1 trial: After total knee replacement, 316 patients were treated with a single dose of either TB-402 at a dose of 0.3 mg/kg, 0.6 mg/kg, or 1.2 mg/kg or enoxaparin 40 mg for at least 10 days.
Phase 2 trial: Prior to total hip replacement, 632 patients were treated either with a single dose of TB-402 (25 mg or 50 mg) 2 to 4 hours postoperatively, or rivaroxaban 10 mg for 20 to 35 days.
The primary efficacy outcome for both groups was total VTE. The safety outcome was the presence of major and nonmajor clinically relevant
TB-402 was more effective than enoxaparin for the prevention of VTE (patients with a VTE, pooled data for TB-402, 21.7%; enoxaparin, 39.7%). The 0.3-mg/kg and 0.6-mg/kg doses had a bleeding risk comparable with that of enoxaparin, whereas the 1.2-mg/kg dose had a higher bleeding risk.
TB-402 is approximately as effective as rivaroxaban in preventing VTE after total hip replacement. No dose-response effect was found for the 25-mg and 50-mg doses. The bleeding risk with TB-402 is 4 to 5 times higher than for rivaroxaban. Based on these results, the further development of TB-402 was stopped.
J. Fletcher (Australia)
The aim of this study was to establish the incidence of venous thromboembolism (VTE) in 366 patients undergoing elective spinal surgery. A venous duplex ultrasound was performed preoperatively, within 1 week postoperatively, and after 4 to 6 weeks. The median duration of the operation was 2.4 (0.6-3.5) hours. Mechanical prophylaxis was used in all patients and pharmacological prophylaxis in 48% of patients (low-dose unfractionated heparin in 27%, low-molecularweight heparin in 25%). VTE incidence was 3.5% (in-hospital, 1.6 %; out-ofhospital, 1.9 %). The incidence of nonfatal pulmonary embolism was 0.6%. The risk of major bleeding increased 2.5 fold for every hour increase in the duration of the operation. Preoperative venous scans showed a high incidence (20%) of superficial thrombophlebitis in the small saphenous vein, which is likely to be related to preoperative immobility and lying supine due to back pain. In conclusion, vigorous perioperative mechanical prophylaxis minimizes VTE risk. The combined use of mechanical and pharmacological prophylaxis was safe and effective. The bleeding risk was related to the duration of the operation and not to the use of pharmacological prophylaxis.
A. Kakkar (UK)
The author examined trials from the last 40 years that dealt with thrombo – prophylaxis in surgical procedures. Low-dose unfractionated heparin proved its efficacy in the prophylaxis of postoperative venous thromboembolism (VTE) and against fatal pulmonary embolism (PE) in the 1970s. In the 1980s, low-molecularweight heparin (LMWH) demonstrated its efficacy (versus placebo) in preventing VTE after major surgery. The effective once-daily dose of LMWH for thromboprophylaxis in cancer surgery was established in 1995. Cancer operations have a higher risk of VTE and fatal PE. The @RISTOS study showed that VTE risk persists in cancer surgery patients and among them, 40% of VTEs were observed more than 21 days after cancer surgery. In ENOXACAN II, 332 patients undergoing cancer surgery received enoxaparin for 1 week followed by enoxaparin or placebo for another 21 days. At each follow-up, prolonged thromboprophylaxis was associated with a 60% reduction in the risk of DVT. Similar results were obtained in the FAME trial. In conclusion, primary prophylaxis is mandatory for surgical patients. There is increasing evidence of the benefits of extended postdischarge LMWH. VTE remains a serious disease in surgical cancer patients.
J. Maly (Czech Republic)
Pulmonary embolism (PE) has long been considered a reason for hospitalization and its home treatment is relatively new and controversial. This possibility was first mentioned in 2003 by the British Thoracic Society, and then later on in 2008 by the European Society of Cardiology. The recent guidelines for antithrombotic therapy, published by the American College of Chest Physicians (ACCP) this year mentioned the possibility for outpatient treatment of PE in carefully selected patients.
Outpatient treatment may be understood as management of the patient on an outpatient-basis since the very beginning, or, more often, as an early discharge after a short hospital stay. Suitable patients are those with low-risk PE. In fact, many patients with deep vein thrombosis (DVT) have silent PE, and in many cases, this is not treated in hospital. In the first published studies of outpatient PE treatment, the exclusion criteria were chest pain, hypotension, and noncompliance. In the most recent studies, a more sophisticated selecting system was used. For example, one Dutch study used NT-proBNP as a risk marker with a cut-off value <500pg/ml for outpatient treatment. Up to 45% of patients were treated as outpatients and during the 3 months of follow-up, there were no cases of death, bleeding, or recurrence in this group. Another study—“OTPE”—used PESI (pulmonary embolism severity index), a semiquantitative risk scoring system to select patients with low-risk PE for home treatment and with this approach, the authors confirmed the noninferiority of outpatient treatment. Besides NT-proBNP and PESI, there are more useful biomarkers and scoring systems—troponin I or T or simplified PESI. In conclusion, outpatient treatment of PE is possible in low-risk patients with nonmassive PE. It is feasible and safe in selected patients. Validated methods for risk assessment and selection of patients are available. The new anticoagulants may in the future broaden the potential for the home treatment of PE but no data are available so far for this indication. It is likely that up to 50% of PE patients will be candidates for the home treatment of PE.
D. Wagner (USA)
Neutrophils release extracellular fibers composed of DNA, thereby forming a network called neutrophil extracellular traps (NETs). NET formation is induced by an infection and NETs should bind pathogens. However, NETs can bind platelets, which consequently become activated. In patients with deep vein thrombosis (DVT), an elevated level of circulating DNA was found in plasma, and this level correlated with the level of von Willebrand factor. This concept has been further investigated in experimental models of thrombosis. In the baboon thrombus, nuclear and extranuclear DNA was found. In a mouse model of thrombosis, venous flow restriction induced secretion from Weibel-Palade bodies and plateletleucocyte adhesion.
It may be hypothesized that besides plasmin, DNAse and ADAMTS13 (von Willebrand factor cleaving protease) may be necessary for the lysis of thrombus.
Thrombotic thrombocytopenia purpura (TTP) is an example of thrombotic microangiopathy. NETs could be involved in its pathogenesis. Plasmatic DNA levels increase with TTP and decrease after plasma exchange therapy.
In conclusion, NET formation is a stimulus for platelet adhesion and thrombus formation. A better understanding of the interrelated pathogenesis of inflammation and thrombosis may improve the management of thrombosis.
S. Coccheri (Italy)
According to the Euro Heart Survey, 30% of the patients with atrial fibrillation (AF) are undertreated, which doubles their risk of stroke. The results of the new oral anticoagulants (dabigatran at higher and lower doses, rivaroxaban, apixaban) in AF patients proved their noninferiority and even their superiority to warfarin. In addition, the results of studies in patients with venous thromboembolism (VTE) seemed promising, and even offered the possibility of treating VTE orally since the very beginning (shown for rivaroxaban). However, there are some concerns about safety in clinical practice. In comparative studies, intracranial bleeding was reduced with the newer anticoagulants compared with warfarin but gastrointestinal bleeding was slightly higher. In patients with renal impairment their dose must be reduced and there are very little or no data for very old patients. In addition, there are no tests available to precisely measure the anticoagulant effect. Problems may thus arise in emergency situations. So far, only one of the newly developed new anticoagulants (betrixaban) has a specific antidote.
In conclusion, patients must be carefully selected before treatment with new oral anticoagulants and they should remain under surveillance. Further registries and observational studies are necessary.
D. Hoppensteadt (USA).
Defibrotide was developed 40 years ago. It is an agent with multiple actions: downregulation of thrombomodulin, vasodilatation at the microvascular level, release of TFPI (tissue factor pathway inhibitor), modulation of platelets and leucocytes, inhibition of factor Xa, and profibrinolytic effect. There are various potential indications of defibrotide: periphery artery disease, deep vein thrombosis, microangiopathy, and post–bone marrow transplant vasculopathy. Additional indications may include sepsis-associated coagulopathy, heparin-induced thrombocytopenia, ischemic stroke, senile dementia, and venoocclusive disease. It is effective in the pathology of arteries and veins as well as the microvasculature.
C. Carter (USA).
Generic low-molecular-weight heparins (LMWH) may lead to potential cost savings. However, these drugs are used in critically ill patients and great care must be taken to avoid possible complications: bleeding, allergic reaction, a drop in platelet count, skin reaction, or even new thrombosis. In previous years, more than 1800 reports of adverse events caused by generic LMWHs were reported due to heparin contaminants (contamination of the raw heparin stock, respectively).
In various countries, there are different drug regulatory rules. A generic drug must usually prove “biosimilarity,” which means that it must prove the absence of a clinically meaningful difference. The two main regulatory authorities in the world are the Food and Drug Agency and the European Medicines Agency. Following the scandal with contaminated heparin preparations, the rules have been changed; more evidence is required regarding the physical and chemical characteristics of the products, their bioavailability, efficacy, and safety. However, differences remain between the rules of the different regulatory authorities.
In conclusion, regulatory authorities should harmonize the approval process for complex biological drugs such as LMWH.
I. Elalamy (France)
Heparin-induced thrombocytopenia is a paradoxical syndrome. This term may include heparin-induced thrombocytopenia as wells as heparin-induced thrombus generation or heparin-induced thrombosis. Its incidence is approximately 10 times higher after unfractionated heparin than after low-molecular-weight heparin (LMWH). Clinical manifestations include white (arterial) clots, deep vein thrombosis (DVT) or extension of DVT in spite of therapy, livedo reticularis, phlegmasia, ischemic gangrene, and bilateral adrenal hemorrhagic infarction. Heparin-induced skin necrosis is quite rare. The diagnosis of heparin-induced thrombocytopenia is difficult. Timing the kinetics of platelet count is very important—the drop usually occurs 5 to 15 days after heparin or LMWH has been started. A special scoring system was proposed to assess the pretest probability. Laboratory tests include immunologic and functional assays. ELISA tests have a very high sensitivity but a low specificity. An immunochromatographic method is rapid and permanently available and is specific for IgG isotypes. Functional assays are not well standardized and are only performed in expert laboratories.
If heparin-induced thrombocytopenia is clinically suspected, heparin therapy must be suspended and immediately substituted with alternative anticoagulants (lepirudin, argatroban, fondaparinux); a survey of platelet count recovery and of the clinical signs of heparin-induced thrombocytopenia is recommended (4 “S”: suspicion – suspension – substitution – survey).
M. K. Jezovnik and P. Poredos (Slovenia)
Atherosclerosis and venous thromboembolism (VTE) were historically considered to be separate clinical entities. However, the concept of “white and red clot” is an oversimplification. Aspirin also works, to some degree, in venous thrombosis, while anticoagulants are being used in arterial diseases. In both arterial and venous thrombosis, the pathogenesis includes damage of the vessel wall, formation of thrombus, action of platelets, and coagulation factors. Autopsy findings have also proved the association of VTE with arterial diseases. In clinical studies, VTE was associated with a higher risk of subsequent cardiovascular events. There are also some common risk factors for both arterial and venous thrombosis.
This study evaluated the association between signs of preclinical atherosclerosis and VTE. In VTE patients, morphological, laboratory, and functional markers of preclinical atherosclerosis were measured (intima-media thickness in common carotid and femoral artery, inflammatory markers, markers of endothelial dysfunction, flow-mediated dilatation in brachial artery).
The authors found a significantly higher prevalence of the markers of preclinical atherosclerosis in VTE patients. The interrelation of both processes may be explained by the systemic inflammatory response.
W. Rakke (Germany)
Biological medicine uses active substances that are made by or derived from a living organism. Biosimilar products are products that are similar to original products of biological origin. They are not generic products and their immunogenic risk cannot be determined by pharmaceutical tests.
Heparin is sourced mainly from porcine intestinal walls. Due to this chemical heterogeneity, conventional pharmacokinetic studies cannot be performed. The essential requirements for generic LMWHs (European Medicines Agency guideline) are the following:
• Nonclinical studies.
• In vivo studies evaluating anti Xa and anti IIa.
• Toxicological studies that should last at least 4 weeks, with special emphasis on the determination of the effects on blood coagulation and homeostasis and on the potential development of osteoporosis.
Data on local tolerance can be collected as part of a repeat-dose toxicity study. A biosimilar medicinal product should show equivalent efficacy and safety to a reference product approved in the EU. The chosen reference product must be a medicinal product authorized in the European Community. Although it is generally expected that generic medicinal products are cheaper than the originals, the major problem of biosimilars is their development cost.
A. Comerota (USA)
Deep vein thrombosis (DVT) may have very important sequelae and may lead to valvular dysfunction, ambulatory venous hypertension, obstructive iliac lesion, calf muscle pump dysfunction, venous claudication, ulcerations. The risk of recurrence is high. Anticoagulation treatment alone does not always solve the problem. Venous thrombectomy can be an option.
Catheter-directed thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life as evidenced in a cohort study including 98 patients (68 treated with thrombolysis, 30 treated with anticoagulation alone) followed up for 16 to 22 months, using a validated health-related quality of life questionnaire. There was a significantly better improvement in health distress, postthrombotic symptoms, physical functioning, and stigma in the thrombolysis group compared with the heparin group (Comerota, J Vasc Surg 2000). In 2012, the same group found that postthrombotic morbidity correlates with residual thrombus following catheter-directed thrombolysis for iliofemoral deep vein thrombosis.
In the Scandinavian Randomized Trial, 63 patients with iliofemoral deep venous thrombosis were followed up at 6 months, 5 years, and 10 years and valve patency, postthrombotic morbidity, and complications were reported. The interventional approach showed a significant improvement on these criteria.
Another randomized trial was carried out in 35 eligible patients followed up for 6 months, of which 18 underwent thrombolysis and 17 had anticoagulation treatment alone (Eisharawy, Eur J vasc Endovasc Surg 2002). Patients with patent veins and normal valve function did not have postthrombotic syndrome and had a significantly reduced risk of recurrence.
In 2012, The Lancet published a randomized trial with a long-term outcome that compared additional catheter-directed thrombolysis (CDT) versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVen study). In 20 Norwegian Hospitals, Enden et al, treated 209 patients aged 18 to 75 years (101 catheter-directed thrombolysis). The follow-up of 24 months was achieved in 189 patients. Patients were assessed with the Villalta scale at 24 months and iliofemoral patency was assessed at 6 months. Both were significantly better in the catheterdirected thrombolysis group (66% vs 47% patency, and 41% vs 56% postthrombotic syndrome). The authors concluded that postthrombotic syndrome is directly associated with patency of the iliofemoral venous segment.
The presence of a residual “thrombus” on ultrasonography when warfarin is discontinued is associated with a substantially increased risk of recurrent thrombosis (Prandoni, Arch Int Med 2002). In a systematic review (Russell, Am J Med 2005) the quantitative assessment of thrombus burden predicted the outcome of treatment for venous thrombosis. The authors estimated that if residual thrombus is <50%, recurrence is 5%; however, when residual thrombus is >50%, recurrence can reach 50%.
In conclusion, iliofemoral DVT is associated with substantially increased postthrombotic morbidity if it is treated with anticoagulation alone. Catheterdirected thrombolysis for acute iliofemoral DVT is highly successful and is associated with a low risk of major bleeding.
M. K. Jezovnik (Slovenia)
The diagnosis of superficial vein thrombophlebitis is established primarily on the basis of clinical signs. Nevertheless, clinical examination does not always reveal the true extent of superficial thrombophlebitis (ST), because clinical signs and symptoms of inflammation usually underestimate the true extent of the thrombus (Cochrane Database of Systematic Reviews 2012, Eur J Vasc Endovasc J 2005, Ann Int Med 2010, Fam Pract 2004, VASA 2004).
It has been established that up to 40% of patients with ST have concomitant DVT at the time of diagnosis. Up to 25% of concomitant DVT is not contiguous with ST but is in the contralateral limbs and in around 15% of patients there is propagation of ST to DVT. In addition, in 20% to 33% of patients, asymptomatic pulmonary embolism (PE) is present, while symptomatic PE is present in 2% to 13% of patients.
Venous ultrasonography can be used to objectively confirm the diagnosis of ST. Ultrasonographic investigation should be performed in patients with a clinical diagnosis of ST in the lower limb if SVT is above the knee, in case of edema of the whole leg, and in those with risk factors for venous thromboembolism.
Patients with isolated ST below the knee associated with varicose veins and with no risk factors for venous thromboembolism may not need ultrasonographic evaluation.
Duplex sonography–lead direct visualization of the thrombus inside the superficial venous system (homogeneous intraluminal material, increased venous diameter, and lack of compression) can show the relationship of the thrombus to the deep venous system and the simultaneous involvement of the deep venous system. This is useful for differential diagnosis (cellulitis, erythema nodosum, panniculitis, and lymphangitis).
V. Stvrtinova (Slovakia)
The Consensus Proposal from the Central European Vascular Forum for Diagnosis and Treatment in Superficial Thrombophlebitis was published in Acta Phlebologica (2011) and can be summarized as follows:
• Recommendation nº1: Look carefully for risk factors of superficial thrombosis, especially for cancer, systemic disease, and thrombophilia.
• Recommendation nº2: Clinical investigation may underestimate the real extension of superficial thrombophlebitis, and does not give enough information on the status of the deep venous system; therefore, after clinical investigation it is important to perform duplex ultrasound investigation of the superficial and deep venous system too. In many cases, superficial thrombophlebitis (ST) is a banal condition, which resolves spontaneously. However, in recent years, a large number of deep venous thromboses concomitant with ST have been found due to systematic ultrasound investigation of the venous system.
• Recommendation nº3 Duplex ultrasound investigation should be done bilaterally—on both lower limbs—not only on the limb affected by ST.
• Recommendation nº4: It is necessary (mandatory) to perform duplex ultrasound investigation immediately after the clinical diagnosis of ST in the case of ST localized on the trunk of the greater saphenous vein, 10 cm or less from the sapheno-femoral junction, or on the trunk of the small saphenous vein, 10 cm or less from the sapheno-popliteal junction.
• Recommendation nº5: All patients with superficial thrombophlebitis should be treated with compression therapy.
• Recommendation nº6: In all cases of ST, immediate mobilization with elastic compression is necessary (mandatory). Patients should not to be confined to bed. Confinement to bed favors progression of the thrombus in both the superficial and the deep venous system.
• Recommendation nº7: Patients with ST, with an inflamed and thrombosed superficial vein larger than 5 cm on duplex ultrasound investigation should receive anticoagulant treatment with fondaparinux 2.5 mg for at least 45 days or with LMWH for 4 weeks. The dosage and duration of anticoagulation treatment depends on the concomitant diseases and other risk factors for VTE.
There are multiple drugs involved in the treatment of ST: anticoagulants, nonsteroidal anti-inflammatory drugs, topical local anti-inflammatory treatment (gel, cream, spray), venoactive drugs (in patients with varicose ST), antibiotics (in patients with septic ST), or corticosteroids (in patients with vasculitic and autoimmune syndromes), but evidence is lacking to support the choice of the best therapeutic option, dosage, or duration. Low-molecular-weight heparins are used in therapeutic or prophylactic dosages and with a duration ranging from 10 to 20 or 30 days. The Calisto study has showed that treatment with fondaparinux for 45 days is more effective than placebo (relative risk ratio, 85%) in reducing systematic thromboembolism and complications or death.
H. Partsch (Austria)
The main question is whether compression therapy can decrease the incidence of deep venous thrombosis, thrombus extension, and pulmonary embolism (objective signs), or pain (subjective symptoms). There are no randomized controlled trials that answer this question, because up to now trials have compared anticoagulation vs no anticoagulation. All trials included the use of stockings (not standardized) and there are no published studies comparing compression vs no compression. For this reason, further studies exploring these aspects are needed.
2.2. Chronic venous disease
M. Koster (Switzerland)
Venous insufficiency is a major health problem. In some patients, peripheral venous pressure measurement may be useful but due to its invasive nature (puncture of the superficial vein of the dorsal foot), it is not routinely performed. The authors tested a noninvasive method using compression ultrasound. They compressed the great saphenous vein above the medial ankle and compared the pressure necessary to fully compress the vein lumen in the supine position, at rest, and during a standardized Valsalva maneuver. They compared the results obtained in a group of patients with venous insufficiency and in 20 healthy controls. They excluded patients with a history of prior deep vein thrombosis. In the healthy subjects, no pressure difference was found at rest and during Valsalva maneuver. On the contrary, in patients with venous insufficiency the pressure was significantly higher during the maneuver. The authors concluded that compression ultrasound seems to be a promising method for noninvasive peripheral pressure measurement in patients with venous insufficiency. The research is ongoing.
In the discussion, H. Partsch commented on a possible disadvantage of the method: it does not enable continuous pressure measurement and only assesses reflux and not obstruction.
2.2.2. Conservative treatments
P. Carpentier (France) introduced the session by emphasizing the special place of edema in the clinical, etiological, anatomical, pathophysiological (CEAP) classification1 and the Vein-Term definitions.2 In these classifications, edema is at the turning point of the progression of chronic venous disease (CVD), being placed between the early stages and the occurrence of skin complications.
In the Venous Clinical Severity Score (VCSS), edema is also considered as a valuable sign that can progress with chronic venous disease severity and change with treatment. Therefore, edema assessment is part of the global sensitivity to clinical changes of the VCSS.
According to a further analysis of the Basel study database, there is a close relationship between the presence of edema and venous symptoms (unpublished results).
Achieving a comprehensive understanding of venous edema is challenging for various reasons. The first reason is a pathophysiological one. The molecular mechanisms leading to venous edema remain to be fully elucidated. Second, edema measurement is far from being straightforward, since many assessment methods have been tried but none, except the water displacement method, is validated. Until now, the “water boot” method remains the gold standard for edema assessment, despite the large variability in repeated measurements reported in the previous trials using this method. Third, treatment of edema and its associated symptoms is also challenging, as explained by F. A. Allaert (France) who presented a study of the efficacy of a 28-day treatment with ruscus extracts on venous symptom improvement and venous refilling time amelioration. Venous symptoms were assessed on a visual analogue scale (VAS) and daily activities were assessed with VCSS. Venous refilling time was measured using mercury strain-gauge plethysmography, and reflux was measured with duplex scan. Women aged from 18 to 50 years, assigned to the C2s or C3s classes of the CEAP classification, with no history of deep venous thrombosis, and no heart and/or kidney failure, were enrolled in the study. The study design was open and aimed at assessing clinical and plethysmographic parameters before and after treatment. A total of 65 patients, aged 38.1 ± 7.4 years, who had chronic venous disease for a mean of 22.8 years entered the study. A significant improvement in leg heaviness, pain, paresthesia, cramps, impatience, and pruritus was seen after treatment. Daily activities increased. With ruscus treatment, there was a correlation between improvement of symptoms and plethysmographic parameters, which increased from 11.7 s ± 4.0 to 13.8 s ± 4.4 (P<.0001).3
J. Chudek (Poland) reported that many chronic venous disease patients do not accept compression therapy. Previous epidemiological surveys have showed that less than 30% of patients with CVD accept to wear a compression device. In Poland, only 28% of women and 20% of men comply with compression therapy. In the US, the figures are almost the same with 27% of patients accepting to wear compression stockings.4 The main reasons for noncompliance in the US were ranked as follows: not helpful, problems of arthritis, sweating, itching, not cosmetic, and high cost. In Poland, the reasons ranked differently: high cost, sweating, itching, not cosmetic, ulcer exudation, and difficulty to apply. Whatever the reason for noncompliance to compression therapy, those patients have to be treated and therefore, pharmacotherapy with venoactive drugs (VADs) is an alternative. It is also possible that patients are not adherent to VAD treatment. This was the aim of a survey performed between 2008 and 2009 in Poland, which enrolled 5134 patients compliant to compression therapy and 4663 who did not accept this type of therapy. It appeared that patients who were noncompliant to compression therapy used VADs significantly less frequently. Obesity, male gender, older age, and the presence of comorbidities influenced nonadherence to VADs.
A new concept of compression therapy consisting in a progressive compression with higher pressure at the calf level (26 mm Hg) than at the ankle (10 mm Hg)— in contrast with the ‘degressive’ classical compression—was presented by P. Carpentier (France). The efficacy of this new device on edema reduction was tested in a multicenter, randomized, double-blind study enrolling C3 patients with pitting edema and reflux and/or obstruction demonstrated with duplex scan. Its aim was to evaluate leg volume reduction between 7 and 30 days of “degressive” therapy, together with the subsequent volume control over a 3-month follow-up period. Leg volume was measured by water displacement. Patients in the treatment group used the “degressive” compression therapy and were compared with those wearing stockings as close as possible to ‘placebo compression’ in the control group. A total of 89 patients (29 men and 60 women), aged 62.1 ± 14.1 years, with a mean body mass index (BMI) of 30 were enrolled in the study. No statistical difference was seen between the groups in terms of age, gender proportion, BMI, weight, leg pain, and heaviness. A significantly higher decrease in leg volume was shown at day 7 in the treatment group over the control one (difference, 388 ml) and the volume steadily decreased over the 3-month follow-up period in both groups. Volume reduction was not negligible in the control group. Volume reduction was most important when edema was substantial at day 0, VAS was high, and treatment took place in summer. Why did the control group improve so much? Could it be due to the placebo effect, the stimulation of physical activity (showing the importance of the calf muscle pump in edema reduction)? Or perhaps because placebo compression was not just “placebo,” which may partly explain the results. In conclusion, “progressive” stockings are able to rapidly (1 week) decrease edema.
G. Mosti (Italy) explained that “progressive” compression therapy may also help prevent edema. In 30 volunteers who mainly stood or sat for their entire work shifts, leg volume was assessed by water displacement at baseline—early in the morning—and at the end of the work shift, on 2 consecutive days. On one day, classical compression therapy was applied on one leg and a “progressive” compression on the contralateral leg. On another day, no stockings were applied and the legs were left without therapy. Both legs and day sequences were randomized. No difference in leg volume (assessed as the difference between volume after wearing the stockings and baseline, and after wearing the stockings and no stockings) was seen between classical compression and “progressive” compression therapy. Occupational edema (assessed as the difference between leg volume at the end of the working shift and the morning) was significantly more reduced with “progressive” compared to classical compression therapy (-82% versus -69% respectively). “Progressive” compression therapy is more effective than classical compression in preventing occupational edema. Redistribution of leg fluid might be one of the explanations for the more effective edema reduction observed with “progressive” stockings.
– Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg. 2004;40:1248-1252.
– Eklof B, Perrin M, Delis K , Rutherford R. Updated terminology of chronic venous disorders: the Vein Term Transatlantic Interdisciplinary Consensus Document. J Vasc Surg. 2009;49:498-501.
– Allaert FA, Hugue C, Cazaubon M, Renaudin JM, Clavel T, Escourrou P. Correlation between improvement in functional signs and plethysmographic parameters during venoactive treatment (Cyclo 3 Fort). Int Angiol. 2011;30(3):272-277.
– Raju S, Hollis K, Neglen P. Use of compression stockings in chronic venous disease: patient compliance and efficacy. Ann Vasc Surg. 2007;21:790-795.
C. R. Lattimer (UK)
Compression therapy is recommended after DVT but the class of compression and its length are not perfectly known. A longer and stronger compression could be the best but this remains to be confirmed. The aim of this study was to evaluate the effect of different classes of compression stockings on hemodynamics in postthrombotic syndrome patients.
A total of 40 legs with postthrombotic syndrome were tested with class-1, class- 2, above-the-knee, and below-the-knee stockings. Duplex ultrasound and air plethysmography investigations were performed.
Hemodynamics were improved in 70% of the legs, irrespective of the class or length of stockings. The legs with the most severe reflux at baseline had the greatest reduction in the venous filling index. A better hemodynamic assessment method might help identify the most appropriate level of compression.
G. Mosti (Italy), H. Partsch (Austria)
It is reported that 16% of venous ulcers are associated with arterial disease. Until now, the treatment of venous ulcers involved compression therapy but this was not recommended for arterial disease due to impairment of arterial inflow. The authors reported their experience in the treatment of mixed ulcers with compression therapy and defined the range of optimal compression pressure.
In 25 patients with mixed ulcers, they assessed skin flow in the peri-wound area and plantar surface of the first toe, toe pressure with laser-Doppler flowmetry, and venous pumping function (ejection fraction) with strain gauge plethysmography. They applied different ranges of pressure (baseline to 40-50 mm Hg). Patients presented a low mean ankle brachial pressure index (ABPI) (0.57 ± 0.09) and in 16 patients claudication occurred when walking less than 100 meters.
They observed that external compression of up to 40 mm Hg increases arterial flow and venous ejection fraction and concluded that compression therapy could be applied even in patients with arterial disease.
– Mayrovitz HN. Clin Physiol. 1998;18(2): 117-124.
– Most G, Partsch H. Phlebology. 2008;23:287-294.
– Most G, Partsch H. J Vasc Surg. 2010; 52:925-931.
A. ten CATE-HOEK (The Netherlands)
Post-thrombotic syndrome (PTS) arises in 20% to 50% of patients after deep venous thrombosis, impairs quality of life, and increase costs. The origin of PTS is an increase in venous pressure due to obstruction or reflux after valve damage during recanalization. The prevention of recurrent DVT is based on the appropriate duration of anticoagulation and in some cases on the use of catheter-directed thrombolysis in the acute phase. The arbitrary duration of compression is usually of 2 years, started 10 days after diagnosis. The aim of this report was to determine the optimal duration of compression.
The authors concluded that 6 months of compression is sufficient to prevent PTS and that compression must be applied as soon as the diagnosis is made. In some cases, compression must be maintained for a prolonged period, depending on the Villalba score.
– Phillips II. J Vasc Surg. 2007;43:116A-122A.
H. Partsch (Austria)
The essential determinants of the efficacy of compression therapy are the pressure exerted and the elastic property of the material used. The main difference between the use of stockings and compression is the stiffness of bandages.
Computed tomography scan pictures showed that a minimum of 83 mm Hg elastic compression is needed to occlude the great saphenous vein in the thigh, whereas only 20 mm Hg is enough to compress the deep venous system in the calf.
The main aims of compression therapy are edema reduction and improvement of venous hemodynamics. Less pressure is needed to reduce edema and more pressure is needed to reduce the diameter of the leg veins in the upright position.
The author prefers using inelastic high pressure bandages in patients with longstanding leg ulcers and after endovenous or surgical abolition of venous reflux, deep venous thrombosis, or superficial thrombophlebitis, and for the initial treatment of lymphedema.
Compression stockings are preferred to maintain the good results achieved after inelastic high pressure bandages.
– Partsch B. Phlebology. 1992;7:101-104.
– Partsch H. Vasa. 1984;13:58-64.
– Partsch H. Int Angiol. 2010;29(5):408-410.
– Damstra R. J Vasc Surg. 2009;49(5):1256-1263.
2.2.3. Nonconservative treatments
S. Kaspar (Czech Republic)
Endovenous laser therapy is not commonly used to treat severely dilated veins because of possible failure.
In this study, the author reported 224 procedures, performed either with Diode 980 or 1470 or Nd Yag 1320 nm lasers and under tumescent anesthesia. The treated great saphenous veins (GSV) and small saphenous veins (SSV) had diameters of more than 15 mm and more than 10mm, respectively. DVT and PE were not recorded during the follow-up (1 to 67 months). Bruising was found in 87% of cases and paresthesias (7%) were observed only after SSV treatment and resolved within 2 months. The total occlusion rate was 96%.
The author concluded that the procedure is safe and effective and could be performed even in severely dilated intrafascial veins. However, we should pay attention on how we perform tumescent anesthesia in order to decrease the risk of skin damage as well as nerves injuries, particularly in case of SSV treatment. Moreover, good compression and sufficient energy delivery are required to achieve good occlusion rates.
J. Marusiak (Czech Republic)
This retrospective study analyzed the results of stripping and radiofrequency ablation in 180 patients with varicose vein disease. Both groups were treated under general or spinal anesthesia, which was associated with local tumescent anesthesia only for the radiofrequency ablation group. Hematoma, paresthesia, infection, cosmetic results, and recurrence were analyzed. There were no statistical differences between the two groups concerning the number of complications and the rate of clinical or hemodynamic recurrence but the authors concluded that radiofrequency ablation is less painful and achieves a better quality of life.
It would have been interesting to compare cosmetic and quality of life results of two different surgical techniques but because of the use of tumescent local anesthesia in the radiofrequency ablation group no conclusions can be made for this study. We know that tumescent local anesthesia reduces hematoma and bruising, reduces pre- and postoperative pain, and has an impact on peri- and postoperative QOL.
T. King (USA)
There are some controversies about the impact on health-related quality of life (QOL) of the concomitant or delayed treatment of symptomatic varicose veins during endovenous thermal ablation (ETA) for saphenous vein reflux. In this prospective comparative study, 156 patients were treated with ETA for great saphenous vein reflux. In group 1, 78 patients received delayed adjunctive treatment with foam and liquid sclerotherapy 4 to 6 months after ETA and in group 2, 78 patients received the same adjunctive treatment but simultaneously to ETA. The demographics, sapheno-femoral junction size, CEAP class, and Aberdeen Varicose Vein Questionnaire (AVVQ) score at baseline were similar in the 2 groups. In Group 2, the AVVQ scores were improved at 3 and 6 months and for group 1 the improvement was remarkable after undergoing delayed treatment. The author therefore concluded that there is no benefit in delaying adjunctive treatment for the management of residual symptomatic varicose veins after ETA.
This is in total accordance with the randomized controlled study of Carradice et al, which has shown that 66% of patients treated with ETA alone required secondary procedures on residual varicose vein tributaries after one year whereas only 0.04% of patients who had concomitant phlebectomy treatment required secondary procedures. Moreover, quality of life in the concomitant treatment group was much better. We should never forget that patients come for the treatment of their varicose veins and not for the treatment of great saphenous vein reflux and we should pay much more attention to the patients’ requests.
– Carradice D. Br J Surg. 2009;96:369-375.
S. Kaspar (Czech Republic)
Laser ablation of the anterior accessory great saphenous vein (AAGSV), small saphenous vein (SSV), or Giacomini vein (GV) are infrequent and rarely reported. The author reported his experience on the laser ablation of 142 SSV, 115 AAGSV, and 6 GV using 980- or 1470-nm diode or 1470-nm Nd YAg laser. Patients were assessed clinically and with duplex ultrasound. No severe complications were reported, some bruising resolved spontaneously, and transient paresthesia was observed in 7% of patients of the SSV group. The total occlusion rate was good.
The author concluded that endovenous laser therapy is safe and effective and could be routinely performed on AASV, SSV, and GV, which is not actually the case.
The use of tumescent local anesthesia could also decrease the risk of skin and nerve damage.
T. King (USA)
In a meta-analysis, the incidence of deep venous thrombosis after endovenous laser ablation (EVLA) was reported to range from 0% to 5.7%. In this retrospective case study, the author wanted to assess the immediate risk of venous thromboembolism (VTE) after EVLA for chronic venous disease.
A duplex ultrasound was performed 3 to7 days after 21 041 EVLA procedures and venous thromboembolism was found in only 0.29% of the cases while deep venous thrombosis was found in 44%, superficial thrombophlebitis in 23%, and pulmonary embolism in 11%.
The author concluded that there is a low incidence of venous thromboembolism after EVLA. He also concluded that thrombotic risk has a low level of predictability. Further studies are therefore required to determine predictive factors.
Venous Forum (AVF)
P. Glovicski (USA)
Why new guidelines? Because in these new guidelines, the evaluation process was perfected, the pathogenesis clarified, and the treatment revolutionized. The author reported the top 10 recommendations of the SVS and AVF guidelines.
1) The CEAP classification should be used to describe the severity of venous disease (grade 1B).
2) Patient evaluation should include duplex ultrasound scanning of the deep and superficial veins (duration of reflux > 0.5 s in superficial veins and >1.0 s in deep veins (grade 1A).
3) Compression therapy is suggested for patients with varicose veins (grade 2C).
4) The guidelines recommend against compression therapy as the primary treatment of varicose veins if the patient is a candidate for saphenous vein ablation (grade 2C).
5) Compression therapy should be used as the primary treatment in varicose ulcers (grade 1B).
6) For the treatment of an incompetent saphenous vein, endothermal ablation is recommended over high ligation and stripping (grade 1B).
7) Foam is an option for saphenous vein ablation (grade 2C).
8) Phlebectomy or sclerotherapy are recommended for varicose tributaries (grade 1B).
9) The guidelines are against the selective treatment of perforating veins in patients with simple varicose veins (grade 1B)
10) To decrease the recurrence of ulcers, ablation of the incompetent varicose vein should be performed (grade 1A)
The author concluded that the best treatment should be based not only on guidelines but also on physician experience and patient preferences.
B. B. Lee (USA)
Arteriovenous malformation is one of various types of congenital vascular malformations with highly destructive potency. Arteriovenous malformations represent 10% to 20% of all congenital vascular malformations.
The classification of the embryologic subtypes of arteriovenous malformation distinguishes between truncular and extratruncular malformations in order to identify the risk involved in their clinical management (Hamburg Classification). Infiltrating extratruncular lesions are the most dangerous primitive type of congenital vascular malformations.
An early and aggressive approach is recommended after adequate diagnosis and proper classification of arteriovenous malformations.
R. Matassi (Italy)
Clinical examination alone does not give sufficient data for the complete diagnosis of arteriovenous malformations in the majority of cases. Therefore, the first noninvasive exam to be performed is a duplex scan, which should give data about flow (high flow, low flow, or no flow).
Plan radiography is the second less invasive exam; it gives information on the presence or absence of phleboliths.
Magnetic resonance imaging gives information on the site of the arteriovenous malformation, the presence of infiltration lesions, and vessel morphology. Computed tomography is less clear except for the study of the main vessels.
Angiography is performed to confirm diagnosis or an indication for endovascular treatment.
P. Burrows (USA)
Primary embolization of arteriovenous malformations cures 40% of cases. Its symptoms can be controlled and palliated.
The best timing for endovascular treatment is in Schöbinger stage II or early stage III. Arterial embolization with tissue adhesives and arterial coils achieves proximal occlusion of the feeding arteries and is unlikely to produce good long-term results. Supraselective intranidal embolization with ethanol can produce better results and can occasionally be curative. It must be performed in stages, often for many months, to achieve closure.
I. Baumgartner (Swizerland)
The majority of arteriovenous malformations are extratroncular. To achieve good results the nidus should be targeted.
Ethanol induces protein denaturation with subsequent wall denaturation. It provides the best outcome with minimal recurrence. The treatment should be performed precisely into the nidus either by direct puncture or transcatheter techniques. Multiple sessions are required. Preferably use 60% ethanol for lesions that are superficial and close to the nerves. Additional coil embolization may also be used. Steroids should be dispensed intravenously before and after treatment. Repeat sessions with single injections over several months are mandatory.