Servier – Phlebolymphology

Venous thromboembolism and guidelines

Prophylaxis and treatment of venous thromboembolism (VTE)?
Moderators: MM Samama (France), A Katsamouris (Greece)
Participants: MM Samama (France),W Leong (Canada), J Walenga (USA), J Fareed (USA)

Regarding prophylaxis and treatment of venous thromboembolism (VTE) in special populations, MM Samama in his presentation focused on pregnant women with confirmed VTE or at risk of VTE. It is well known that pulmonary embolism is a major cause of maternal mortality. Moreover in pregnancy the risk of VTE is 5- to 10-fold higher than in the non-pregnant population, the risk being much higher after delivery. Therefore, there is a need for clinical vigilance when there is a suspicion of VTE in pregnant women. There are no randomized clinical trial data on this subject, and the recommendations from the American College of Chest Physicians (ACCP) are scarce. The new ACCP 2008 guidelines recommend the following:

• For women receiving anticoagulation for the management of VTE who become pregnant, vitamin K antagonists have to be replaced by unfractionated heparin (UFH) or low molecular-weight heparin (LMWH) (grade 1A)
• For lactating women using warfarin or UFH who wish to breastfeed it is recommended to continue these medications (Grade 1A).
• For pregnant women it is suggested LMWH over UFH for the prevention and treatment of VTE (grade 2C), but a switch to UFH 4 weeks before delivery is required, as noted by MM Samama. For prevention, the prophylactic and intermediate dose (the prophylactic dose given twice daily) should be used, depending on the patient’s risk level. In acute VTE, the body weight-adjusted therapeutic dose (full dose) of LMWH or adjusted iv or sc dose of UFH (with activated partial thromboplastin time within therapeutic range) should be used for at least 5 days (Grade 1A). After the initial therapy, sc LMWH or UFH should be continued throughout pregnancy (Grade 1B) or at least 3 months.. The question when to reduce the full dose of LMWH if VTE occurs in the 2nd or 3rd month of pregnancy remains unanswered. Anticoagulation should be continued for at least 6 weeks postpartum (for a minimum total duration of therapy of 6 months) (Grade 2C).
• Regarding prevention it is crucial to find out whether the patient had prior episodes of VTE (0,1, =,>2 ) or not, and if so whether it was provoked or unprovoked, whether the patient has primary or secondary thrombophilia or other risk factors such immobilization, obesity, older age, twin pregnancy, cesarean section, etc. Even the thrombophilic states do not have the same risk: AT deficiency, homozygous thrombophilias and combined thrombophilias are considered high risk, heterozygous PC deficiency is deemed intermediate risk, and PS deficiency, heterozygous FII G20210A status, and heterozygous FV Leiden status are low risk. ACCP 2008 guidelines suggest that a thrombosis risk assessment be carried out in all women undergoing cesarean section to determine to need for prophylaxis (Grade 2C). In patients without other risk factors undergoing Cesarean section, only early mobilization is recommended (Grade 1B). In the presence of at least one risk factor in addition to pregnancy and cesarean section, pharmacologic (UFH or LMWH) or mechanical (graduated compression stockings or intermittent pneumatic compression) prophylaxis is recommended while in hospital following delivery (Grade 2C). In patient with high risk and cesarean section it is suggested to combine the pharmacologic prophylaxis with the use of graduated compression stockings or intermittent pneumatic compression or both, which can be extended following discharge from the hospital (Grade 2C). The other recommendations for prevention vary regarding the presence of one or more episodes of prior VTE, transient or permanent risk factors, and the presence of thrombophilic states at different risk levels. In women with lower risk, antepartum prophylactic or intermediate dose of LMWH/UFH or clinical surveillance is recommended throughout pregnancy, plus postpartum anticoagulation. For higher risk patients, antepartum prophylactic or intermediate dose LMWH/UFH (Grade 2C) is recommended in addition to postpartum prophylaxis. For pregnant women with very high risk, the recommendation is for antepartum prophylactic, intermediate or adjusted dose LMWH/UFH followed by postpartum anticoagulation (Grade 2C). For pregnant women receiving long-term anticoagulants for prior VTE, the recommendation is for either adjusted-dose LMWH or UFH, 75% of adjusted dose LMWH or intermediate dose LMWH throughout pregnancy followed by resumption of long-term anticoagulants postpartum (Grade 1C). For all pregnant women with previous deep vein thrombosis (DVT), the use of graduated compression stockings is suggested both antepartum and postpartum (Grade 2C). For pregnant patients with thrombophilia but no prior VTE, physicians are advised not to use routine pharmacologic antepartum prophylaxis (but in antithrombin deficiency antepartum and postpartum prophylaxis is recommended), but postpartum prophylactic anticoagulants are recommended.

In conclusion, MM Samama said that treatment of pregnant women with confirmed VTE is well documented, although appropriate dose regimens and the optimal duration of treatment is still disputed. Individual decisions and clinical judgment are also necessary.

W Leong from Canada talked about outpatient management of deep vein thrombosis. She presented a functional model of outpatient treatment based on the activities of an anticoagulation clinic, a medical day-car clinic, and an emergency department. About 40% of their patients are treated as outpatients. She presented the indications and contraindications and stressed the usefulness of the guide-book given to the patients. The number of outpatient treatments is continuously increasing with increasing use of LMWH in daily practice. Clinical follow-up is crucial. Treatment failure in generally is due to LMWH underdosage, administration for less than 5 days, subtherapeutic international normalized ratio, noncompliance, and inappropriate follow-up. Finally, J Fareed presented two lectures about the role of new anticoagulants in the management and prophylaxis of venous thromboembolism. The main question he posed was: will they replace heparins and oral anticoagulants? Despite progress in the science, he said, none of these new drugs (oral dabigatran, an anti-IIa, and fondaparinux, an anti-Xa, and oral apixaban and rivaroxaban) will ever match the various pharmacological effects of heparins. There is a major thrust in the development of orally bioavailable anti-Xa and anti-IIa agents, which are slated to replace oral anticoagulants. Both anti factor-Xa and anti-IIa agents have been developed for oral use and have given impressive clinical results. However, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons the FDA in USA did not approve oral Ximelagatran for several indications. Fondaparinux (a synthetic pentasaccharide) also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower.

IUA guidelines on venous thromboembolism and beyond – Part A
Moderators: VV Kakkar (UK), A Comerota (USA)
Participants: A Nicolaides (Cyprus), S Kakkos (UK), M Samama (France), J Fletcher (Australia), H Gibbs (Australia)

In the first lecture A Nicolaides presented interesting evidence on venous thromboembolism (VTE) prevention. The cross-sectional international study ENDORSE evaluated VTE prophylaxis (according to the ACCP 2004 guidelines) in hospitalized patients in 32 countries. The results showed a great variance between countries in application of prophylactic measures and proved that quite a high proportion of hospitalized patients at risk for VTE do not receive prophylaxis (59% of surgical and 40% of medical patients at risk). Implementation of prophylaxis in every day practice is necessary. Every admitted patient should be assessed for the VTE risk. It is also important to educate the public about VTE risk and prevention.

In 2006 the IUA released the last VTE prophylaxis guidelines (updated every 4 years). According to the risk stratification (low, moderate, and high), the appropriate prophylaxis is recommended and the strength of recommendation is graded based on the level of existing evidence. Duration of VTE prophylaxis is an unresolved issue but the recent EXCLAIM study has produced the evidence of substantial risk reduction (44%) with extended prophylaxis (with enoxaparin) in medical patients.

S Kakkos summarized the results of a review assessing the efficacy of combined modalities in venous thromboembolism (VTE) prophylaxis. He performed the database search of randomized controlled trials, controlled clinical studies and other studies, comprising 9998 patients in a variety of specialties. Pharmacological intervention (heparin, low-molecular-weight heparin [LMWH] or warfarin) and a mechanical method (intermittent pneumatic leg compression used together were more efficient in preventing deep vein thrombosis (DVT) as well as symptomatic pulmonary embolism (PE). These results support the use of combined prophylactic modalities in a subgroup of high-risk patients, based on thorough individual risk assessment. However, this topic deserves further research, including cost-effectiveness studies.

M Samama concentrated on prophylaxis in two special patient populations – patients with cancer and with myeloproliferative disease (MPD). Cancer patients have a 4-fold higher VTE risk, but the mechanism of this association is still not fully understood. VTE prophylaxis in cancer is strongly recommended, especially in immobilized patients and in patients undergoing surgery. In the treatment of VTE, the benefit of long-term dalteparin has been proved in the CLOT study. Cancer patients are a very heterogeneous group and the risk assessment should take into account age and comorbidities, additional risk factors (chemotherapy, radiotherapy, some inherited thrombophilic disorders), primary site of the cancer, and its stage.

MPD represents 4 entities – chronic myeloid leukemia, polycythemia vera, essential thrombocythemia , and primary myelofibrosis. In the last three diseases, and especially in polycythemia vera, a recently discovered the JAK2 mutation plays a substantial role. MPD represents a hypercoagulable state and is frequently associated with splanchnic vein thrombosis. Therefore, every patient with splanchnic vein thrombosis should be tested for the JAK2 mutation, which may uncover occult MPD. Whether the JAK2 mutation modifies VTE risk and prognosis in MPD is not known and research is ongoing.

In patients with essential thrombocythemia, aspirin is efficient in VTE prophylaxis. J Fletcher presented the Australian and New Zealand VTE prophylaxis guidelines (created by the Australian and New Zealand Thrombosis Working Party and based on the IUA and ACCP guidelines) and how the aim is to improve their application in clinical practice. The recommendations are summarized and distributed them as booklets, seminars and workshops are organized, and medical record alerts are implemented, etc. The initiative is intended to increase awareness of VTE and its prophylaxis among government officials, healthcare professionals, medical organizations, as well as the public. An analysis of VTE cases in Australia in 2008 revealed the substantial cost burden of the disease (not only health expenditure but also lost productivity, lost wellbeing, and other factors were taken into account). It is necessary to achieve mandatory VTE risk assessment in hospital-admitted patients as well as to check adherence to the evidence-based guidelines.

H Gibbs reported on venous thromboembolism (VTE) prevention in medical patients. VTE treatment is not always fully successful and the consequences could be serious or even fatal. However, the efficacy of VTE prophylaxis is very well documented (according to three recent meta-analyses with heparin and LMWH) and so it is crucial to optimize prophylaxis, especially in hospitals. It is reasonable to use heparin, LMWH, or fondaparinux in medical patients. There is a lack of data about the efficacy of mechanical methods (graduated compression stockings) in medical patients (the only evidence is for patients with an ischemic stroke), so they can only be recommended for patients with a contraindication to anticoagulant therapy. The risk assessment and choice of appropriate prophylaxis is necessary. Prophylaxis is usually continued until discharge or until the resolution of the acute condition. However, the recent EXCLAIM study has provided evidence of the benefit of extended VTE prophylaxis in some groups of medical patients. Prolonged duration of VTE prophylaxis should be considered, especially in patients with marked immobility, advanced age, cancer, or a history of VTE. Though effective prophylaxis reduces VTE incidence by 50% to 90%, it is still underused in practice (as shown in the recent ENDORSE study). Multiple strategies should be applied to improve implementation of prophylaxis guidelines (education, reminders, audit, and feedback)

IUA guidelines on venous thromboembolism and beyond – Part B
Moderators: J Fletcher (Australia), M de Castro Silva (Brazil)
Participants: A Comerota (USA), E Ascher (USA), VV Kakkar (UK), R Hull (Canada), J Fareed (USA)

In his very interesting presentation about aggressive management of ilio-femoral deep vein thrombosis (DVT), A Comerota highlighted that the 2004 ACCP guidelines do not explicitly recommend clot removal in proximal DVT, but this will change in the 2008 ACCP recommendations, which will be published this month. Recent studies show a clear benefit of clot removal in ilio-femoral DVT, in which efficient anticoagulation and elastic stockings are frequently not sufficient to prevent recurrence and sequelae or to improve quality of life. In the new guidelines, two strategies of venous thrombus removal in acute proximal DVT will be implemented. The first one is catheter-directed thrombolysis with many newer facilities and devices (modern catheters, ultrasound accelerated devices, ultrasoundguided venous access, aspiration, etc.). The case control and cohort studies available in this field since 2001 show relatively low bleeding complication (<5%, with much lower intracranial bleeding). The method has a significantly higher patency rate and valve function preservation than anticoagulation and elastic compression alone. The second strategy includes venous thrombectomy with creation of an arteriovenous fistula, especially in patients who have contraindications for thrombolysis. Studies have also shown a better patency rate, lower incidence of post-thrombotic syndrome, and better valvular function preservation. The importance of routine chest, abdominal, and pelvic CT scan in ilio-femoral DVT patients because of high rate of subsequent malignancy was also stressed.

E Ascher dealt with the controversial issue of superficial thrombophlebitis (SVT). He posed several questions: Is there a correlation between SVT and deep vein thrombosis (DVT)? Does SVT correlate with hypercoagulable states? Does SVT correlate with pulmonary embolism (PE)? How should it be treated? His answers showed that the SVT is not as benign a clinical entity as the medical community believes. The SVT patient may have a hypercoagulable state, parallel DVT, or PE, or a combination thereof. According to a recent meta-analysis, the incidence of DVT in SVT patients is 6% to 44%, the incidence of asymptomatic PE is 20% to 33% and of symptomatic PE 2% to 13%. Up to 25% of DVT cases are noncontiguous, suggesting the presence of systemic predisposing factors. The same conclusion is suggested by the incidence of primary thrombophilias in SVT patients, which varies between 38% and 50% in different studies. The incidence of PE in SVT patients varies between 0% and 33%, and is mostly clinically silent. For proximal great saphenous vein thrombosis anticoagulation, elastic stockings and mobilization are more effective for prevention of DVT and PE, whereas surgery (crossectomy) with or without stripping is only superior in symptomatic relief. The speaker didn’t highlight the potential etiologic, prognostic, and therapeutic differences between non-varicose and varicose-superficial vein thrombophlebitis. More studies are needed for clearer recommendations.

VV Kakkar in his partly historical review talked about half a century of challenges in VTE prophylaxis. In the 1960s, the problem was defined: incidence, natural history of VTE, and identification of high-risk group of patients. The low fixeddose unfractionated-heparin era was in the 1970s. In the 1980s, low-molecularweight heparin (LMWH) was developed with more clinical trials proving the efficacy and safety of LMWH in both prophylaxis and treatment of DVT and PE. Eventually it became evident that there is a need for prophylaxis in medical patients also. Today’s challenges are: why does prophylaxis still fail frequently? Are the available guidelines followed? What would be the ideal guidelines? How can the implementations of guidelines be improved? The answers need more public awareness, well-defined strategies from health authorities, and more welldesigned studies, of course.

R Hull raised the main question of when to start and finish thromboprophylaxis. Prevention started perioperatively (shortly before or soon after surgical intervention) seems to be the best choice, the decision depending on the patient’s risk-benefit ratio.

J Fareed summarized the newer anticoagulants (anti-Xa and antithrombin inhibitors) pointing out that heparins will remain in the landscape of VTE patient management. Since VTE has a multifactorial etiology, heparins due to their various pharmacologic effects remain the standard therapy. For this reason monotherapy (anti-Xa and anti-IIa inhibitors) at this moment have a reduced but well-defined area of indication, especially in management of heparin-induced thrombocytopenia (parenteral antithrombin agents) or in orthopedic prophylaxis (parenteral pentasaccharides). The oral anti-Xa and anti-IIa are promising agents, but at this moment they are not a replacement for warfarin.

Superficial thrombophlebitis: a significant subset of venous thromboembolic disease
Moderators: I. Quere (France), K. Katsenis (Greece)
Participants: M.A. Sevestre-Pietri, G. Boge, I. Quere, P. Carpentier, G. Pernod (France)

MA Sevestre-Pietri presented the results of the OPTIMEV study. A total of 8253 patients with suspected venous thromboembolism (VTE) were investigated by Duplex scan, computer tomography, and lung scan. The diagnosis was confirmed in 2795 cases (33.9%). Superficial thrombophlebitis (ST) was found in 595 cases, ST and pulmonary embolism (PE) were noted in 32 cases, and ST and deep venous thrombosis (DVT) in 174 cases. Among ST risk factors, the greatest were varicose veins (odds ratio [OR]=5.5; 95% CI) and hormone therapy (OR=2.7; 95% CI). G. Boge et al presented the results of the POST study, which estimated risk factors for VTE in patients with isolated ST. A total of 810 patients with symptomatic ST were separated into 2 groups. First group included 210 patients with deep vein thrombosis (DVT) or symptomatic pulmonary embolism (PE) or both. The second group included 600 patients with isolated ST. Analysis of patients with ST and VTE revealed the following risk factors: current hospitalization or bedridden for more 3 days in previous 20 days (odds ratio [OR]=15.1), history of autoimmune disease (OR=6.5), absent of the varicose veins (OR=4.5), age above 75 years (OR=3.1), history of VTE (OR=2.2). Interestingly, there was no significant relation with traditional risk factors of VTE (active cancer, cardiac or respiratory insufficiency, permanently restricted mobility, previous surgery, infection, long-haul travel, pregnancy). Traditional risk factors were found in the group of patients with isolated ST, such as male sex (OR=3.10), history of VTE (OR=2.6), and cardiac or respiratory insufficiency (OR=2.5). Absence of varicose veins and venous insufficiency was a risk factor too (OR=2.2). I Quere confirmed the relation between ST and cancer.

Malignant neoplasms were found in 3.8% cases of isolated ST and in 13.4% cases of ST and VTE (POST-study). The OPTIMEV study has demonstrated a relation between cancer and ST in 10.3% cases and between cancer and VTE in 20.7% cases. There is no consensus about optimal treatment of ST (G Pernod). Compression stockings and LMWH are most commonly used for treatment ST. Only two randomized, controlled trials have been devoted to efficacy of LMWH. The Stenox (2003) and Vessalio (2005) studies did not find significant differences between prophylactic and therapeutic dosages of LMWH in patients with ST. The international, multicenter, randomized, controlled trial CALISTO started recently and should provide answers to many problems of ST treatment.

Antithrombotic drugs

Generic antithrombotic drug development: what are the guidelines?
Moderators: G Rao (USA), W Raake (Germany)
Participants: J Fareed (USA), W Leong (Canada), W Raake (Germany), J Walenga (USA), R Hull (Canada)

As protection of the intellectual property rights of the companies who developed low-molecular-weight heparins (LMWHs) is expiring, concerns arise regarding generic LMWH products. The classic approach to generic development, in which the generic should be similar to the reference product with respect to active substance, content, pharmaceutical form, and bioequivalence, is not adequate for LMWH. LMWHs are biological products, whose active substance is derived from living organisms by chemical modification of the multicomponent mixture of glycosaminoglycans. These kinds of drugs are more difficult to characterize, due to the wide spectrum of molecules that they contain, and limited knowledge regarding the safety and efficacy of each fraction. That is why the regulatory authorities consider each available LMWH as a distinct drug. R Hull reviewed how LMWHs differ, and how these differences might affect patient outcomes. LMWHs are all derived from unfractionated heparin, which allows increased bioavailability, decreased protein and endothelium binding, and thus a more predictable effect, improved safety, and generally increased efficacy. However, because the manufacturing process differs, the molecular weight profile of the different branded LMWHs varies. This has an impact not only on the anti-Xa over anti-IIa ratio, but also on clearance: the lighter the molecules, the greater the renal clearance. This might have clinical implications, since renal impairment is very common in patients treated with LMWH. The risk of accumulation and hence of bleeding could vary amongst the different LMWHs. Another concern is the possibility of drug reversal in the case of bleeding. The proportion of the effect that is reversible is related to the proportion of anti-Xa activity and to the proportion of drug sulfation. These two parameters again differ amongst LMWHs.

This differentiation of LMWHs becomes crucial as we observe a paradigm shift towards a “first do not harm” perspective, and stresses the need for a thorough safety assessment in the development of generic drugs. Various attempts are being made to develop specific guidelines for biological medicine generics. W Raake presented the EMEA’s ongoing guideline development. In vitro and in vivo studies will be required, as well as a 4-week toxicity study. Due to possible molecular heterogeneity, pharmacodynamic and pharmacokinetic phase 1 studies will also be mandatory. Safety issues, mainly the risks of bleeding and of heparin-induced thrombocytopenia, will need to be addressed for each generic drug. On the other hand, reproduction, mutagenicity, or carcinogenicity studies will not be necessary. Moreover, demonstration of comparable efficacy and safety for example in surgery patients at risk for VTE may allow extrapolation for the other indications of the reference drug.

J Fareed reminded the audience that several generic versions of LMWHs exist in India and in South America. Some of them have been compared with the reference product and exhibited significant pharmacological differences despite chemical equivalence. J Walenga insisted on the need for immunogenic studies in this setting. In fact, the immunogenicity and the proportion of antibody subtypes produced could differ according to the composition of the preparation. A generic product that would have an identical composition, with the same proportion of the different oligosaccharides, should induce a similar quantitative and qualitative immunogenic response profile. Demonstration of this equivalence, however, will require clinical trials. Another concern is that LMWHs are able to bind to other endogenous proteins. This might result in the generation of neoepitopes, whose clinical implications are unknown until now. J Fareed and J Wallenga both reminded the audience of recent accidents reported after the use of a contaminant, hypersulfated chondroitin sulfate, in heparin preparation. These nonheparin glycosaminoglycans can also have an immunogenic effect. This further illustrates the need for strict control of the bioequivalence of all the agents used.

To conclude, because of their biological nature, developing generic LMWHs is particularly challenging. To ensure not only chemical similarity, but also comparable efficacy and safety, regulation authorities (EMEA, FDA) are currently developing specific guidelines that will include pharmacokinetic and pharmacodynamic studies, as well as safety and immunogenic studies. These requirements will, however, make the approval of a generic LMWH a very long, complicated and expensive process which could significantly decrease the cost-savings of such an approach.

From low-molecular-weight heparins to specific factor xa inhibitors.
Pharmacological and clinical issues
Moderators: G.T.Gerotziafas (France), MM Samama (France)
Participants: G.T. Gerotziafas (France), P Prandoni (Italy), A Kakkar (UK), J Walenga (USA), MM Samama (France)

After a short historical overview concerning discoveries of antithrombotic drugs and their clinical use, G.T. Gerotziafas concentrated on the explanation of the different mechanisms of action of some of the current antithrombotic drugs, as well as that of the recently developed agents, on the anti-IIa and anti-Xa effect, respectively. Thrombin (factor IIa) plays multiple roles in many processes beside coagulation, e.g. in the activation of protein C (natural inhibitor of coagulation), in fibrinolysis, inflammation, cell proliferation, and angiogenesis. Factor Xa has a central function in coagulation. In a free form it participates in the initiation phase of coagulation, while the prothrombinase-bound FXa plays an important role in the propagation phase.

In comparison with heparin (which is a mixture of different polysaccharide chains and possesses both anti-IIa and anti-Xa activities), low-molecular-weight heparins (LMWHs) have prevalent anti-Xa activity, with some preserved anti-IIa activity. More LMWHs are in clinical use, with different molecular weights, different anti- Xa/anti-IIa activity ratio, and different impact on thrombin generation. Therefore, they are not interchangeable.

It is also necessary to realize that there are differences between the two groups of new anti-Xa agents. Indirect inhibitors (eg, fondaparinux) inhibit only free FXa, while direct inhibitors (eg, rivaroxaban) inhibit both free and bound FXa. These two groups differ as to the mode of action, the mode of administration, and the impact on prothrombin time (PT) and activated partial thromboplastin time (aPTT).

Whether factor IIa or Xa is a better target remains an open question.

P. Prandoni reviewed evidence on the use of LMWH and pentasaccharides in the prevention and treatment of venous thromboembolism (VTE):

• • in the prevention in major orthopedic surgery, LMWH are superior to unfractionated heparin (UFH). Fondaparinux (a synthetic pentasaccharide) is even more effective than LMWH, without increased bleeding. The use of fondaparinux is safe also with the concomitant use of neuroaxial or peripheral anesthesia. Prolonging the prophylaxis with LMWH or fondaparinux further reduces VTE risk without increasing the risk of hemorrhage.
• • in general surgery, LMWHs are as effective and safe as UFH; fondaparinux is comparable to LMWH but probably more effective in cancer patients.
• • in medical patients the prophylaxis of VTE is underused in spite of the proven risk reduction with LMWH as well as with fondaparinux. In the EXCLAIM study, the postdischarge prolongation of prophylaxis with LMWH (for up to 4 additional weeks) was efficient in VTE reduction, but caused a small but significant increase in bleeding and therefore the extended prophylaxis should be reserved only for high-risk medical patients.
• • fondaparinux is as effective and safe as the conventional initial treatment of VTE with UFH or LMWH.
• • idraparinux, a new pentasaccharide with once-weekly dosing, was comparable to UFH or LMWH in the initial treatment of deep vein thrombosis with a trend to a better tolerability. However, it was inferior to a conventional initial treatment of primary pulmonary embolism (more symptomatic recurrent VTE observed in Van Gogh PE study). In the extension of the secondary VTE prophylaxis after the conventional 6-month anticoagulation, idraparinux resulted in fewer recurrent events than placebo, but increased rate of major bleeding. A new, potentially safer version of idraparinux (biotinylated idraparinux) is currently being tested.

G.T. Gerotziafas briefly considered oral specific factor Xa inhibitors ( rivarobaxan) and stressed the absence of dose-dependent efficacy in all Xa inhibitors. Rivarobaxan binds specifically at an active center of FXa. After repeated administration, no significant accumulation was observed. Rivaroxaban has proven more effective than LMWH in major orthopedic surgery. In vitro, even in a very low concentration, rivaroxaban suppresses thrombin generation.

M. M. Samama added a short comment. While we nowadays already have efficient anticoagulants available for VTE prophylaxis in orthopedic surgery, the main objective for the new drugs in this indication should be the decrease in bleeding risk.

J. Fareed presented the next lecture on behalf of J. Walenga. He stressed the polypathologic nature of the thrombotic process and the role of some of the existing as well as newly developed drugs (UFH, LMWH, ultra-LMWH, pentasaccharides, oral anti-Xa and anti-IIa agents, recombinant thrombomodulin and recombinant antithrombin).

• • The advantages of LMWH versus direct anti-Xa agents are lasting effect after subcutaneous or intravenous administration, multiple sites of action, and multiple indications.
• • The disadvantages of direct anti-IIa agents are their variability, delayed onset, and the suppression of the regulatory functions of thrombin.
• • Moreover, in both oral anti-IIa and anti-Xa agents, there are still concerns about potential hepatotoxicity and additional data from phase III clinical studies are needed.
• • These agents do not have any known antagonist and their long-term toxicity is not known.
• • So, the total conversion from heparin and LMWH to new anticoagulants is highly unlikely. However, the new agents may find their place in some special indications (heparin-induced thrombocytopenia; resistance to the conventional anticoagulant therapy; short-term prophylaxis; and stroke prevention in atrial fibrillation).

M. M. Samama concentrated on the action of anti-Xa agents and the possibility of their laboratory monitoring. It is necessary to distinguish between oral and parenteral, direct and indirect anti-Xa agents. In general, laboratory monitoring is not necessary. However, it may be useful for some special patient populations and in some special clinical settings. Therefore, appropriate coagulation tests should be available. Such a test should be available in any laboratory, 24 hours a day. He reported the results of his extensive research work in this field (published and unpublished). The possible coagulation tests studied are prothrombin time (PT), dilute PT, activated partial thromboplastin time (aPTT), Heptest, prothrombinase-induced clotting test (PiCT), thrombin generation test, anti-FXa test, and the Russell´s viper venom test (RVVT). Only some of these tests are potentially suitable for anti-Xa agents. A good practical option seems to be modified PT, RVVT for rivaroxaban, and maybe PiCT with some modification. Before the introduction of some of these tests to practice, standardization is needed and the research is ongoing.

Do low-molecular-weight heparins have a future in thrombosis management?
Moderator: A Kakkar (UK)
Participants: A Kakkar (UK), S Haas (Germany), J Arcelus (Spain)

A. Kakkar introduced the session with an interesting historical overview of some key publications from the last 50 years that have influenced the approach to the prevention and treatment of venous thromboembolism (VTE). The first evidence about the efficacy of the prophylaxis with anticoagulation in orthopedic surgery was published in The Lancet in 1959. At that time, the diagnosis of postoperative VTE was based only on clinical symptoms, but later on the imaging method (radiolabeled fibrinogen scanning) demonstrated the high incidence of postoperative VTE (Lancet, 1961). Low-dose unfractionated heparin (UFH) proved to be efficient in the prophylaxis of postoperative VTE in the 1970s.

The advent of low-molecular-weight heparin (LMWH) was in the 1980s. In 1986 the first evidence was published about the efficacy of LMWH (versus placebo) in the prevention of VTE in major orthopedic surgery.

Later on, a meta-analysis clearly demonstrated that prophylaxis with heparins is efficient in reducing postoperative pulmonary embolism (PE) including fatal PE, but does not increase fatal bleeding. In the mid 1990s, LMWH proved at least as effective as heparin in the initial treatment of VTE, with potentially better safety (fewer bleeding complications).

S. Haas summarized current knowledge of LMWHs, which have become the golden standard in a variety of conditions because of the convincing evidence of their efficacy in:

• VTE prevention:
– in major orthopedic surgery (no increase in bleeding risk was found; better efficacy than UFH was proven; better efficacy of prophylaxis prolonged to 4-5 weeks after surgery)
– in general surgery (better efficacy of prolonged prophylaxis)
– in medical patients (similar efficacy as UFH, but less major hemorrhage)
– in patients with ischemic stroke (better efficacy than UFH; the large body of evidence proved consistent benefit across multiple comorbidities)

• the initial treatment of VTE (LMWHs are at least as good as UFH and cause fewer bleeding complications; there is evidence of their efficacy even in proximal DVT and in PE which facilitates the outpatient management of VTE)
• the treatment of VTE in cancer patients (better efficacy in long-term secondary prevention of VTE was shown in the CLOT study; a potential favorable effect on survival was shown in CLOT and also some other studies, probably due to the pleiotropic effect of LMWH)
• the treatment of acute coronary syndrome (the meta-analysis significantly favors LMWH over UFH)

In the patients with renal impairment, LMWHs should be used cautiously respecting the recommendations about dose reduction according to creatinine clearance. For obese patients, LMWH in prophylactic indications should be given without any special dose adjustment (the exception may be bariatric surgery for which there is evidence of the benefit of a doubled prophylactic dose).

Taking into account the unresolved issues regarding new antithrombotic drugs and the above mentioned evidence, LMWHs will definitively survive for many more years, at least in acute indications.

J.I. Arcelus concentrated on the new oral antithrombotic agents. In spite of having quite safe and effective antithrombotic drugs available, there is still a need to develop new and better ones. The new oral agents may have potential advantages but are still far from being ideal anticoagulants. They target only one coagulation factor – either factor Xa or thrombin (factor IIa). Dabigatran, an oral anti-IIa agent, has low bioavailability, interacts with pantoprazol, and is of limited use in renal insufficiency. Rivaroxaban, a direct anti-Xa agent (inhibits both free and clotbound factor Xa), has high bioavailability, interacts with food and drugs, and its excretion is both urinary (66%) and biliary (30%). Both drugs have been tested in phase III clinical trials (in VTE prophylaxis in patients with total hip replacement (THR) and total knee replacement (TKR), compared with enoxaparin) and the results can be summarized as follows:
• dabigatran is as effective as enoxaparin, without significantly increased bleeding risk
• rivaroxaban is more effective, but there is a tendency to more bleeding complications
So the conclusion is that the new oral anticoagulants are at least as effective as enoxaparin in prophylaxis after THR and TKR and could be promising due to greater convenience (oral administration is better accepted by patients), but before a definitive conclusion is drawn more experience is needed, ie, broader population of treated patients.

Will heparins and oral anticoagulant drugs survive? Newer developments in anticoagulation
Chairman: D Hoppensteadt (USA)
Lecture by J. Fareed (USA)

Many new anticoagulant drugs are being developed with a view to potentially replacing the two old agents, heparin and warfarin. These two anticoagulants have their limitations, but both have been used for many years and are of proven efficacy and relative safety in the treatment and prevention of thrombosis. As thrombosis involves a variety of pathologic processes, it requires multidrug therapy. The new anticoagulant drugs have various mechanisms of action: they inhibit thrombin (factor IIa) or factor Xa or tissue factor or influence thrombin generation. There are 22 oral anti-Xa agents under development, the most advanced being rivaroxaban (recent application to the EMEA for approval in deep vein thrombosis (DVT) prophylaxis after orthopedic surgery) and apixaban.

The parenteral anti-Xa agents are pentasaccharides: fondaparinux (already approved for several indications) and idraparinux, a new generation drug, with a very long half-life.

Of anti-IIa inhibitors, development is most advanced in dabigatran, an oral direct anti-IIa inhibitor (already approved by EMEA for DVT prophylaxis after orthopedic surgery), but many other anti-IIa inhibitors are under development. The previously introduced ximelagatran is no longer used because of several cases of severe hepatotoxicity.

There are also parenteral anti-IIa inhibitors—hirudin, hirulog, and argatroban— approved by the FDA exclusively for cases of heparin-induced thrombocytopenia. The new anticoagulants are currently being evaluated in a number of clinical trials, in the indication of DVT (with or without pulmonary embolism) therapy, DVT prophylaxis, and stroke prevention in atrial fibrillation. They differ in their pharmacokinetic properties.

In spite of some possible advantages, there are several reasons why these new agents are unlikely to totally replace heparin, low-molecular-weight heparin (LMWH), and warfarin in a near future.

• • All the oral agents cross the placental barrier.
• • None of the new drugs have multiple therapeutic effects and none induces the release of endogenous mediators, such as tissue factor pathway inhibitor (TFPI), which is induced by heparin and LMWH. That is why the therapeutic spectrum of the new drugs is much narrower than that of the older ones.
• • There are great concerns with both anti-IIa and oral anti-Xa agents regarding hepatotoxicity and rebound effect and additional data may be needed to demonstrate their safety in this sense in phase III trials.
• • The other problem is the lack of any potential antagonist.
• • There is also no knowledge of the long-term toxicity of the new anticoagulants.

The possible perspective is the continuing use of heparin and related drugs, probably in an expanded range of indications, and introducing new anticoagulants just for special indications, while paying further attention to safety issues.

Thrombocytopenia, bleeding

Moderators: J Fareed (USA), R Hull (Canada)
Participants: J Fareed (USA), J Walenga (USA), I Elalamy (France), H Gibbs (Australia)

Update on the detection, prevention and management of patients with heparin-induced thrombocytopenia
Chairman: J Fareed (USA)
Lecture by J Walenga (USA)

Heparin-induced thrombocytopenia (HIT) is a rare but severe adverse effect of heparins (both unfractionated and low-molecular-weight). J Walenga reminded the audience that HIT is an immune-mediated response to heparin, often but not always resulting in thrombocytopenia. The pathophysiology is complex and involves antibodies directed against the complex formed between heparin and platelet factor 4 (PF4). She emphasized that HIT gives much more than a “justplatelet” response. It also has important pro-inflammatory effects, and induces activation of leukocytes, endothelial cells, platelets, and the formation of cellular micro particles. The result is the most important procoagulable state known, with an increase thrombin generation. The risk of thrombosis is very high (more than 50% if untreated), often leading to severe arterial as well as venous thrombosis, amputation, and death. As stressed by I Elalamy, a sudden decrease in platelet count in patients treated with heparin, either at prophylactic or therapeutic dose, should prompt the suspicion of HIT. The threshold over which a HIT should be suspected varies according to the clinical setting: a 30% to 50% decrease in platelet count. The timing is also important, as thrombocytopenia develops after day 5 of treatment. It may be observed earlier, during the first hours of treatment, in the case of exposure to heparin in previous weeks. Some cases of delayed onset, even two weeks after heparin is stopped, have also been described. In surgical patients, transient thrombocytopenia is often seen in the immediate postoperative period. In this particular setting, from a low level the platelet count increases again after 3 or 4 days. A discontinuation in the platelet increase curve should prompt the suspicion of HIT. Finally, some patients can even have no thrombocytopenia. In fact, some antibodies have a procoagulant effect without a decrease in the platelet count. That’s why HIT should be suspected in patients developing thrombosis during heparin treatment.

All panelists confirmed that all types of heparins should immediately be withdrawn as soon as the diagnosis is suspected. Moreover, H Gibbs stressed that stopping heparin is not enough, and that it is mandatory to start the patient on an alternative anticoagulant (the risk of major thrombotic events in patients not started on an alternative anticoagulant is higher than 50% over the following weeks). Physicians should not await diagnostic confirmation to make this substitution. J Walenga went over the different therapeutic options. Danaparoid is a nonheparin antithrombotic with multiple sites of action and an anti-inflammatory effect. It has a good safety profile, with a risk of bleeding lower than that observed with direct thrombin inhibitors. Other advantages are the subcutaneous route of administration and that there is no need for monitoring. A cross-reaction with anti heparin-PF4 antibodies is rare but possible, and should be suspected in the case of worsening thrombosis, or if platelet count does not recover after a few days, although I Elalamy reported that in this case, use of a subtherapeutic dose should be suspected and is more likely than a cross-reaction. Its renal clearance is also a limitation in patients with renal failure. Two direct thrombin inhibitors, argatroban and lepirudin, are also available. Argatroban has the advantage of its rapid reversibility in the case of bleeding. Dose should be adjusted in patients with liver dysfunction. Lepirudin is eliminated by the kidneys, and dose adjustment is required in renal failure patients. Another specific issue is the high rate of antibodies generated that may lead to an anaphylactic response in patients previously exposed to lepirudin. New anticoagulant drugs have been used in case reports or series, mainly fondaparinux and bivalirudin, but not enough evidence is yet available to support their use in this setting.

Unfortunately, because of the heterogeneity of the antibodies produced, there is no simple diagnostic test. J Walenga reminded the audience of the importance of not missing a patient with HIT because of the severe complications. Also, the diagnosis must be confirmed, given the specific risks associated with anticoagulant management and the consequences for further medical management. I Elalamy presented the current diagnostic strategies for HIT. The clinical probability can be assessed using the 4Ts model, which is based on criteria related to the Thrombocytopenia, the Timing of events, the presence of a Thrombosis, and of a possible oTher explanation for the thrombocytopenia. If the clinical probability is low, the diagnosis can be ruled out, and the heparin treatment resumed if a sensitive test (ELISA or ID-PaGIA test) is negative. If the result is positive, or if the clinical probability is high, a more specific test will confirm the diagnosis. However, because of antibody heterogeneity, a cautious interpretation of the results is required. It may be interesting to perform different tests, and to repeat them over time. In fact, some of them are based on the detection of IgG antibodies, which may appear only after several days. The panelists also recommended a multi-disciplinary approach to diagnosis, in order to “build a likelihood” of HIT. Future research will focus on the role and prognosis of nonfunctional antibodies, on new diagnostic tests, and on the evaluation of the new anticoagulant drugs in this clinical setting.

Current approach in the management of bleeding
Moderators: D Hoppensteadt (USA), MM Samama (France)
Participants: D Hoppensteadt (USA), MM Samama (France), J Caprini (USA), G Rao (USA), J Fareed (USA), J Fletcher (Australia)

This session focused on the management of bleeding, either in patients on antithrombotics or during the postoperative period. J Fareed stated in the introduction that the ideal hemostatic agent should work within minutes, stop the inappropriate hemorrhage without clotting working vessels, have no side effects, and be inexpensive. Unfortunately, such an agent is not available. Bovine thrombin, recombinant thrombin, and human thrombin are, however, widely used, in more than 5% of all surgical procedures in the USA. Other options include recombinant activated factor VII, which was primarily developed for the treatment of patients with anti-factor VIII antibodies, aprotinin, recombinant tissue factor pathway inhibitor (TFPI), and desmopressin (DDAVP), whose effect is to release von Willebrand factor.

MM Samama focused on the management of bleeding related to antithrombotic drugs. He reminded the audience that not all bleeding in this setting is related to an overdose, and that half of the bleeding episodes occur in patients with an international normalized ratio within target. For patients on vitamin K antagonist, the recently published 8th ACCP guidelines recommend for bleeding associated with an elevated international normalized ratio intravenous vitamin K (10 mg), and either fresh frozen plasma, prothrombin complex, or recombinant factor VIIa. For heparins, if protamine sulfate is able to fully reverse their anti-IIa activity, only about one half of their anti-Xa activity is antagonized. This means that not all bleeding episodes on LMWHs (whose anti-Xa activity is stronger than that of UFH) may be controlled by protamine sulfate. This is a limitation of the use of LMWH. However, MM Samama stressed that the absence of an antidote is a common characteristic of all the so-called “new anticoagulants” (apixaban, bivalirudin, dabigatran, fondaparinux, hirudin, rivaroxaban). He cited the exception of idraparinux, a pentasaccharide administered subcutaneously once weekly. The development of this drug has been hampered by an increased risk of intracerebral hemorrhage observed in phase 3 trials. This, along with its long half-life, was a major concern. A biotin component has been successfully added to the molecule, without modifying its pharmacologic properties, but allowing its rapid reversal by the use of avidine.

In terms of the management of surgical bleeding, beyond the technical causes and their management (inadequate vessel repair, occult or unrecognized unrepaired injury to the vascular system either remote or in the operative field), J Caprini stressed the importance of pre-operative assessment of bleeding risk. A thorough history taking and physical examination should be performed, including familial and personal history of bleeding or easy bruising, with a focus on previous surgery, childhood trauma, and gynecological bleeding in women. Patients’ current medications are of primary importance, including over-the-counter medications (NSAIDs and anti-histamine, in particular). The comorbidities also play a role: malignancy, sepsis, chronic medical disorders, and collagen vascular disease. After surgery is performed, any bright red blood at any site should prompt a basic clinical and laboratory assessment: body temperature, complete blood count, platelet count, prothrombin time, partial thromboplastin time. J Caprini and other panelists and attendees also voiced their interest in the bleeding time in such a context. If all these tests are normal, an urgent surgical re-exploration should be considered. One of the frequent causes of bleeding after surgery is disseminated intravascular coagulation, whose management mainly relies on cause eradication (tumor, infection, abrupt placenta removal), and sometimes on the use of low doses of heparin.

G Rao reviewed the different topical hemostatic agents, such as oxidized cellulose, gelatin sponge, microfibrillar collagen, bovine thrombin, fibrin sealants (whose structure is similar to that of fibrin strands in a plasma clot), biological glue and nonbiological glue. G Rao also went over the different hemostatic agents currently used in battle fields by the US army and marines. Uncontrolled hemorrhage is the leading cause of death in this context. Two new approaches have been developed: the use of a granular mineral zeolite, and of a mix of powdered human fibrinogen, thrombin, and factor XIII. Although promising, these have never been formally tested in trauma or surgical patients, nor are they approved for this indication. Finally, J Fareed summarized the evidence on two recent controversies. The first one was following the report of anti-factor V antibody development in patients treated with bovine thrombin. The manufacturing process has been improved since, and this has been shown to decrease the level of detectable factor V. He then addressed the controversy on the off-label use of recombinant activated factor VII. He reminded the audience that outcome studies have shown no improvement in prognosis when this drug is used for the treatment of hemorrhagic stroke. There are also concerns about its strong procoagulant effect, which could lead to an increased risk of undesirable thrombotic events, highlighting the risks of its offlabel prescription.

Among future perspectives, the management of bleeding on new anticoagulant drugs needs to be addressed. Further studies should also focus on the estimation of bleeding risk, and on the off-label use and efficacy monitoring of recombinant activated factor VII.