Servier – Phlebolymphology

Chairpersons: A. K. KAKKAR (UK), S. NOVO (Italy)

Venous thromboembolism in medical patients: burden of the disease

The incidence of venous thromboembolism (VTE) in the USA is 117/100000. There are 107 000 new cases of deep venous thrombosis per year. More than 70% of pulmonary emboli are diagnosed at autopsy, and approximately 80% of DVT cases are clinically asymptomatic. Epidemiological data have shown that the risk of VTE in medical patients is comparable to the risk in surgical patients. The incidence of VTE in patients with ischemic stroke is 11% to 75%, in patients with myocardial infarction 17% to 34%, and in the intensive care 25% to 42%. The risk factors for the development of deep venous thrombosis are determined both by the patients’ characteristics and by the clinical settings, and also by the fact that there is still a low rate of patients receiving prophylaxis. According to Aujesky and Rahim, the rates amount to 22% to 33%. The reasons for underuse of thromboprophylaxis are: lack of awareness of the guidelines, lack of outcome expectancy, concern about bleeding, and difficulty in defining medical patients at risk. To improve patient selection, individual risk assessment and clinical decision support tools should be used. The Medenox study has shown that the most important risk factors for venous thromboembolism are: chronic respiratory failure, age over 75 years, chronic heart failure, obesity, varicose veins, cancer, history of VTE, and hormone therapy.
The authors concluded that the medical inpatients can be at substantial risk for venous thromboembolism, and they should be assessed for risk of venous thromboembolism based on the acute clinical condition and on the concomitant presence of predisposing risk factors.

State-of-the-art thromboprophylaxis in medical patients

Venous thromboembolism is a common, potentially life-threatening complication in acutely ill medical patients. In the absence of thromboprophylaxis, the risk of deep venous thromboembolism ranges from 5% to 26%. The risk of DVT in patients with spinal cord injury range from 5% to 100%. A recent survey (Baglin et al 1997) reported that without prophylaxis, up to 1 in 20 hospitalized medical patients with multiple clinical problems develops fatal pulmonary embolism. There are several methods of DVT prophylaxis in medical patients: unfractionated heparin, low-molecularweight heparins, new antithrombotics, oral anticoagulants, antiplatelet therapy, mechanical compression, and early ambulation. Several trials and meta-analyses have clearly demonstrated the prophylactic beneficial role of UFH and LMWHs with a significant 50% reduction of VTE. Two important double-blind randomized placebocontrolled clinical trials validated the use of LMWHs in the medical patients. In the Medenox Study prophylaxis with enoxiparine 40 mg once daily for 6 to 14 days reduced the risk of VTE by 63%. This was achieved without a significant increase in adverse events such as hemorrhage or thrombocytopenia. Patients immobilized with severe cardiopulmonary, infectious, or rheumatic disease are at significant risk of VTE. In the Prevent Study (still unpublished) the administration of dalteparin 5000 UI daily subcutaneously was associated with a risk reduction of VTE of 45% in acutely ill patients with a low risk of bleeding.
The authors mentioned new antithrombotics: ximelagatran, an oral direct thrombin inhibitor but currently not evaluated in medical patients, and fondaparinux, an indirect (AT III-dependent) antifactor Xa inhibitor that is in one trial being used in medical patients (Artemis study).

Optimizing management of the medical patient in the future

In venous thromboembolism (VTE) prophylaxis in medical patients there are still unresolved issues:
1. Patient selection: identifying those who benefit most from thromboprophylaxis
2. Dosing of heparins
3. Duration of treatment It is still difficult for clinicians to assess which medical patients should be given thromboprophylaxis. The risk assessment model (RAM) does not exist for medical patients. Data from the Medenox study has enabled us to identify patients at a very high risk of VTE who benefit most from thromboprophylaxis, such as elderly people or patients suffering from congestive heart failure in the worst functional class.
Also, as mentioned above, the dosing of heparins is a matter of controversy. The Prevent and Artemis Studies have demonstrated that high prophylactic doses of dalteparin or fondaparinux reduced the burden of VTE risk but there are still topical issues:
• do we have to use high prophylactic doses (eg, dalteparin 5000UI and fondaparinux 2.5 mg) also in the common practice for the low-risk patients?
• are lower dosages possibly ineffective?
The optimal duration of thromboprophylaxis in medical patients remains an unresolved issue. Several studies underline the fact that the risk of VTE of medical patients is likely to be sustained as in high-risk surgery where a prolonged prophylaxis with low-molecular weight heparins has proven to be benefit. The ongoing Exclaim study (Extended Clinical Prophylaxis with Enoxaparin in Acutely Ill Medical Patients) with 5800 medical patients at 450 sites worldwide may determine whether a 4-week course of 40 mg enoxaparin would be better than the current practice of 1 week to 10 days of enoxaparin administration.

SYMPOSIUM IUA/EVF (EUROPEAN VENOUS FORUM)

Chairpersons: J. FAREED (USA) A. NICOLAIDES (Cyprus)

Pentasaccharides and melagatran

Heparin is effective in reducing the incidence of deep vein thromboses (DVT) in elective hip surgery and many other situations.
If we have to propose a new drug to take the place of heparin, it should be better, safer, cost-effective, and if possible oral.
Since the clinical use of unfractionated heparin (UH), many new drugs have been synthesized, with more specific action. Many low-molecularweight heparins (LMWH) that are more effective than UH in some situations are now in use, and they show no clinically relevant differences.
Among the new synthesized pentasaccharides, fondaparinux, melagatran, and, ximelagatran are now in clinical use. They have been compared in various settings with placebo, LMWH, and oral anticoagulants. In general they have proved themselves to be at least as effective as LMWH.

Venous thromboembolism in patients with cancer

It is a well-known fact that venous thromboembolism (VTE) is much more frequent in cancer patients. Cancer patients who are surgical candidates may benefit from prophylactic therapy. Randomized, well-conducted studies have shown that low doses of unfractioned heparin and LMWH give very similar results, stand shoulder to shoulder, and can both be used for prophylaxis.
Prolonging prophylaxis for 4 weeks after operation offers a significant reduction of VTE when compared with 1-week therapy. A different subgroup of patients is acutely ill patients that are not surgical candidates, and in this group of high-risk patients LMWH seems to be the best option, and greatly reduces the frequency of DVT. One study has shown that low-dose warfarin can reduce the number of VTE episodes in cancer patients on palliative therapy.
The use of central venous catheters (CVC) is widespread in cancer patients, and these devices have been shown to be associated with in situ thrombosis in a high number of cases. Warfarin or LMWH can reduce the number of these episodes.
However, quite recently the improvement of the CVC material and construction, together with better catheter care, has much reduced the number of thromboses, and at the moment we are not sure if prophylactic therapy is warranted in cancer patients with CVC, and if so, what type of treatment should be used. There have been some reports that therapy with LMWH can improve the overall mortality of cancer patients, as well as reduce the number of VTE. To assess this survival benefit, a number of studies such as CLOT, SCLC, and MALT have been conducted.
Although there is a benefit for the general population, this is maximal mainly in the patients with a better prognosis.

Extended prophylaxis

That patients undergoing major orthopaedic surgery are at an increased risk of developing deep vein thrombosis (DVT) is a well-known fact, and prophylaxis is commonly used, but it is less clear for how long these patients have an increased risk of developing thrombosis.
In total hip replacement (THR) giving prophylaxis for 1 to 2 weeks and then continuing prophylaxis for 3 to 4 weeks reduced DVT by half, when compared with a group of patients treated with placebo during the second period.
A metanalysis showed that in such an approach the number needed to treat (NNT) is 45, which means that we have to treat 45 patients to avoid one DVT, with a number needed to harm (NNH) of 862, which means that we will have one bleeding in 862 patients treated, with a gain times 40, which is a really good result.
On the contrary, data on total knee replacement (TKR) has failed to show a similar gain for extended prophylaxis for this subgroup of patients.
Hip fracture, an increasingly frequent disease with the growing elderly population, impairs venous function for a very long period of time, up to 6 weeks or more, and so benefits from long-term prophylaxis.

Treatment at home

Home treatment of venous thromboembolism (VTE) has been made possible by the introduction of low-molecular-weight heparins (LMWHs), which are safe and effective like unfractionated heparins (UH) but much simpler to use and without the need for specific laboratory monitoring.
This treatment can be offered to about 80% of deep vein thrombosis (DVT) patients, while about 20% still need to be hospitalized for medical or social reasons.
Of course the patients must be investigated for the presence of occult cancer, which can be found in up to 7% of patients with proximal DVT.
Patient with suspected recurrent DVT or pulmonary embolism (PE) should stay in the hospital. Even hospitalized patients should be mobilized as soon as possible.
One of the advantages of home therapy is the fact that at home the patient is much more free to move around, which actually helps clot lysis and prevent thrombus extension.

Duration of anticoagulant therapy

On anticoagulant therapy for deep vein thrombosis (DVT) one issue has been resolved: the INR in these patients must be maintained between 2.0 and 3.0, to give the best benefits. This regimen must be maintained for at least 3 months in patients with transient risk factors, like accidents In cancer patients with DVT, LMWH should be administered for 3 to 6 months.
Patients with thrombophilic states should be treated 6 to 12 months, or indefinitely, like the patients with idiopathic VTE, also, if there are recurrent episodes, patients should be treated for life with an annual review.
It is most important to listen to the patient, to talk to him or her, and to involve him or her in therapeutic decisions, to the degree that he feels is right for him or her.

The rationale for using aspirin in metabolic syndromes

The biosynthesis of thromboxane A2 is associated with several cardiovascular risk factors. Thromboxane- dependent platelet activity represents the mechanism that amplifies the consequences of vascular acute occlusions and other longstanding metabolic disturbances. Aspirin reduces the level of thromboxane A2 diminishing the risk of metabolic disorders. The authors have demonstrated the reduction of thromboxane levels in patients with type 2 diabetic mellitus who take aspirin. The authors have demonstrated the reduction of thromboxane-dependent platelet activation in patients with hypercholesterolemia who are having the same treatment. The AHA has recommended the prescription of aspirin in several metabolic syndromes such as abdominal obesity, atherogenic dyslipemia, elevated blood pressure, insulin resistance, and glucose intolerance. The authors support the recommendation for aspirin in healthy women with android obesity, and suggest that low-dose aspirin may be an option in subjects who fail to lose weight. In conclusion, low-dose aspirin represents the best primary and secondary prevention strategy in metabolic syndromes characterized by high cardiovascular risk.

Meta-analysis of randomized trials of aspirin versus control in low-risk populations

The authors presented a meta-analysis of primary and secondary prevention trials of aspirin versus control for vascular events. This meta-analysis included 55 580 patients. The principal results of this work are the primary prevention is effective for vascular events and principally for cardiac events. Secondary prevention is not effective for the prevention of ischemic stroke and vascular death.
The authors recommend primary prevention with low doses of aspirin for patients at high risk of vascular events. In this group of patients thedecrease in vascular events is 10 times greater than in the patients with no preventative treatment. If the patients have a moderate risk of CHD events it is necessary to evaluate the risk of hemorrhagic bleeding. If the risk of bleeding is low, they must take long-term aspirin therapy. The patients with moderate cardiovascular risk and high risk of bleeding and the patients with low cardiovascular risk for ischemic events do not need primary prevention with aspirin.

Aspirin resistance

The doses normally used in all international guidelines represents a 3- to 10- fold excess over the minimum amount of the drug necessary and sufficient to fully inactivate platelet COX-1. There exists an aspirin resistance whose origin is not clear but whose incidence is very low. The European Society of Cardiology Task Force on Antiplatelet Agents and The American College of Chest Physicians Consensus Conference on Antithrombotic Therapy recommend that no test of platelet function be performed to assess the antiplatelet effect of aspirin in the individual patient. Like the other treatments to prevent artherothrombosis, antithrombotic, lipid-lowering, or antihypertensive agents, failure can occur with aspirin, but there is no scientific basis to change therapy in the case of a treatment failure. The author maintains that there is no controlled evidence that changing therapy is a more effective strategy than maintaining an evidencebased therapy. The real incidence and the importance of aspirin resistance must be evaluated with new studies. This studies must include a sufficient number of patients to correctly evaluate the sensitivity and specificity of aspirin resistance, which until now no published studies have done.

Determinants of the risk of upper gastrointestinal bleeding complications

The author describes the incidence of upper gastrointestinal bleeding complications in patients with treatment with nonaspirin, nonsteroidal antinflamatory drugs (NA-NSAIDs) and in patients in treatment with aspirin. In general, the risk of bleeding increase with age, and higher in patients with previous hemorrhagic episodies. The risk of bleeding of patients with NA-NSAIDs is fourfold compared with nonusers, and this risk increases with dose. Once treatment is stopped the risk quickly returns to baseline. There are several differences with aspirin. The risk of bleeding with aspirin is only twofold with respect to nonusers. Another difference is that the risk does not increase with the dose, and there are no differences between doses of 75, 150, and 300 mg a day. The risk is higher during the first month of treatment, and after this remains constant. It seems that the new cyclo-oxygenase-2 selective NA-NSAIDs (coxibs) would be half of that observed among NA-NSAIDs users and the same is true for the aspirin risk.

ORAL COMMUNICATIONS

Carotid and femoral artery intimal-medial thickness as an
early predictor of arterial occlusive disease in patients with
diabetes

The aim of this study was to evaluate the influence of risk factors of atherosclerosis by measuring the intima-media thickness (IMT) in the common carotid artery (CCA) and in the common femoral artery (CFA).
The greatest increase in IMT was observed in diabetes patients, and then in patients with peripheral arterial disease. There are no differences between insulin and non-insulin-dependent diabetes.
This is a useful method to detect patients with arterial asymptomatic pathology, and it could be used to follow the progression of subclinical atheroclerosis.

Endothelium-dependent vasodilatation predicts restenosis
after coronary stenting

This is a small-group study on the relationship between endothelium-dependent vasodilatation and restenosis after coronary stenting. The authors demonstrate statistical differences in the index of vasodilatation measured in the brachial artery during hyperemia in patients after coronary stenting. The patients with a lower index of vasodilatation have a higher risk of coronary postangioplasty restenosis. There are no differences if the index of vasodilatation is calculated after administration sublingual nitrates.
Probably the in-stent restenosis is mainly due to intimal hyperplasia, but endothelial dysfunction may have a role in predisposing the mechanisms to intimal proliferation after coronary stenting.

Does peripheral vasomotion reflect coronary vasomotion?

The authors wished to demonstrate the relationship of endothelial-independent vasomotor function to nitrate, measured in the brachial artery with ultrasounds, and in the coronary artery measured with magnetic resonance angiography (MRA).
This study demonstrates that there are differences in the index of vasodilatation between the coronary and the brachial artery. This lack of correlation could express the impossibility of comparing the coronary bed with the peripheral bed. In any case the small group of patients in this study does not allow the authors to establish definitive conclusions.