[Bridging anticoagulation in patients receiving vitamin K antagonists : Current status]. / Überbrückende Antikoagulation bei Patienten unter Vitamin-K-Antagonisten : Eine Bestandsaufnahme.

Approximately 30% of patients receiving oral anticoagulation using vitamin K antagonists (VKA) require surgery within 2 years. In this context, a clinical decision on the need and the mode of a peri-interventional bridging with heparin is needed. While a few years ago, bridging was almost considered a standard of care, recent study results triggered a discussion on which patients will need bridging at all. Revisiting the currently available recommendations and study results the conclusion can be drawn that the indications for bridging with heparin must nowadays be taken more narrowly and considering the individual patient risk of bleeding and thromboembolism. Bridging with heparin is only needed in patients with a very high risk of thromboembolism. This overview aims to give guidance for a risk-adapted peri-interventional approach to management of patients with a need for long-term anticoagulation using VKA.

[Bridging anticoagulation in patients receiving vitamin K antagonists : Current status]. / Überbrückende Antikoagulation bei Patienten unter Vitamin-K-Antagonisten : Eine Bestandsaufnahme.

Approximately 30% of patients receiving oral anticoagulation using vitamin K antagonists (VKA) require surgery within 2 years. In this context, a clinical decision on the need and the mode of a peri-interventional bridging with heparin is needed. While a few years ago, bridging was almost considered a standard of care, recent study results triggered a discussion on which patients will need bridging at all. Revisiting the currently available recommendations and study results the conclusion can be drawn that the indications for bridging with heparin must nowadays be taken more narrowly and considering the individual patient risk of bleeding and thromboembolism. Bridging with heparin is only needed in patients with a very high risk of thromboembolism. This overview aims to give guidance for a risk-adapted peri-interventional approach to management of patients with a need for long-term anticoagulation using VKA.

Diagnosis and treatment of superficial vein thrombosis.

Superficial vein thrombosis (SVT) is a common disease, characterized by an inflammatory-thrombotic process in a superficial vein. Typical clinical findings are pain and a warm, tender, reddish cord along the vein. Until recently, no reliable epidemiological data were available. The incidence is estimated to be higher than that of deep-vein thrombosis (DVT) (1/1000). SVT shares many risk factors with DVT, but affects twice as many women than men and frequently occurs in varicose veins. Clinically, SVT extension is commonly underestimated, and patients may have asymptomatic DVT. Therefore, ultrasound assessment and exclusion of DVT is essential. Risk factors for concomitant DVT are recent hospitalization, immobilization, autoimmune disorders, age > 75 years, prior VTE, cancer and SVT in non-varicose veins. Even though most patients with isolated SVT (without concomitant DVT or PE) are commonly treated with anticoagulation for a median of 15 days, about 8% experience symptomatic thromboembolic complications within three months. Risk factors for occurrence of complications are male gender, history of VTE, cancer, SVT in a non-varicose vein or SVT involving the sapheno-femoral junction (SFJ). As evidence supporting treatment of isolated SVT was sparse and of poor quality, the large, randomized, double-blind, placebo-controlled CALISTO trial was initiated assessing the effect of fondaparinux on symptomatic outcomes in isolated SVT. This study showed that, compared with placebo, 2.5 mg fondaparinux given for 45 days reduced the risk of symptomatic thromboembolic complications by 85% without increasing bleeding. Based on CALISTO and other observational studies, evidence-based recommendations can be made for the majority of SVT patients. Further studies can now be performed in higher risk patients to address unresolved issues.

International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.

BACKGROUND: Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. OBJECTIVES: To establish a common international consensus addressing practical, clinically relevant questions in this setting. METHODS: An international consensus working group of experts was set up to develop guidelines according to an evidence-based medicine approach, using the GRADE system. RESULTS: For the initial treatment of established VTE: low-molecular-weight heparin (LMWH) is recommended [1B]; fondaparinux and unfractionated heparin (UFH) can be also used [2D]; thrombolysis may only be considered on a case-by-case basis [Best clinical practice (Guidance)]; vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients [Guidance]. For the early maintenance (10 days to 3 months) and long-term (beyond 3 months) treatment of established VTE, LMWH for a minimum of 3 months is preferred over vitamin K antagonists (VKA) [1A]; idraparinux is not recommended [2C]; after 3-6 months, LMWH or VKA continuation should be based on individual evaluation of the benefit-risk ratio, tolerability, patient preference and cancer activity [Guidance]. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA to LMWH when treated with VKA; (ii) increase in LMWH dose when treated with LMWH, and (iii) VCF insertion [Guidance]. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started 12-2 h preoperatively and continued for at least 7-10 days; there are no data allowing conclusion that one type of LMWH is superior to another [1A]; there is no evidence to support fondaparinux as an alternative to LMWH [2C]; use of the highest prophylactic dose of LMWH is recommended [1A]; extended prophylaxis (4 weeks) after major laparotomy may be indicated in cancer patients with a high risk of VTE and low risk of bleeding [2B]; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy [Guidance]; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated [2C]. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux [1B]; for children and adults with acute lymphocytic leukemia treated with l-asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients receiving chemotherapy, prophylaxis is not recommended routinely [1B]; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic [1B] or lung [2B] cancer treated with chemotherapy and having a low risk of bleeding; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low-dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear [2C]. Special situations include brain tumors, severe renal failure (CrCl<30 mL min(-1) ), thrombocytopenia and pregnancy. Guidances are provided in these contexts. CONCLUSIONS: Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority.

International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer.

BACKGROUND: Although long-term indwelling central venous catheters (CVCs) may lead to pulmonary embolism (PE) and loss of the CVC, there is lack of consensus on management of CVC-related thrombosis (CRT) in cancer patients and heterogeneity in clinical practices worldwide. OBJECTIVES: To establish common international Good Clinical Practices Guidelines (GCPG) for the management of CRT in cancer patients. METHODS: An international working group of experts was set up to develop GCPG according to an evidence-based medicine approach, using the GRADE system. RESULTS: For the treatment of established CRT in cancer patients, we found no prospective randomized studies, two non-randomized prospective studies and one retrospective study examining the efficacy and safety of low-molecular-weight heparin (LMWH) plus vitamin K antagonists (VKAs). One retrospective study evaluated the benefit of CVC removal and two small retrospective studies were on thrombolytic drugs. For the treatment of symptomatic CRT, anticoagulant treatment (AC) is recommended for a minimum of 3 months; in this setting, LMWHs are suggested. VKAs can also be used, in the absence of direct comparisons of these two types of anticoagulants in this setting [Guidance]. The CVC can be kept in place if it is functional, well-positioned and non-infected and there is good resolution under close surveillance; whether the CVC is kept or removed, no standard approach in terms of AC duration has been established [Guidance]. For the prophylaxis of CRT in cancer patients, we found six randomized studies investigating the efficacy and safety of VKA vs. placebo or no treatment, one on the efficacy and safety of unfractionnated heparin, six on the value of LMWH, one double-blind randomized and one non randomized study on thrombolytic drugs and six meta-analyses of AC and CVC thromboprophylaxis. Type of catheter (open-ended like the Hickman(®) catheter vs. closed-ended catheter with a valve like the Groshong(®) catheter), its position (above, below or at the junction of the superior vena cava and the right atrium) and method of placement may influence the onset of CRT on the basis of six retrospective trials, four prospective non-randomized trials, three randomized trials and one meta-analysis. In light of these data: use of AC for routine prophylaxis of CRT is not recommended [1A]; a CVC should be inserted on the right side, in the jugular vein, and distal extremity of the CVC should be located at the junction of the superior vena cava and the right atrium [1A]. CONCLUSION: Dissemination and implementation of these international GCPG for the prevention and treatment of CRT in cancer patients at each national level is a major public health priority, needing worldwide collaboration.

[New oral anticoagulants and chronic kidney disease]. / Neue orale Antikoagulanzien und Niereninsuffizienz.

The prevalence of atrial fibrillation and venous thromboembolism will rise over the next decades due to foreseeable demographic developments. Anticoagulation treatment for these patients will become increasingly challenging due to the rising prevalence of chronic kidney disease (CKD), which is associated with both an increased risk of bleeding and impaired efficacy of oral anticoagulation (OAC). New oral anticoagulants (NOAC) are excreted by the kidneys and may thus accumulate in patients with CKD leading to an increased risk of bleeding; therefore, the pharmacological properties of NOACs have to be considered in order to avoid serious complications. Analysis of the currently available evidence for patients with CKD provides important insights for everyday clinical practice.

[Recent advances in the treatment of superficial vein thrombosis and extracranial carotid artery stenosis]. / Neues zur Therapie oberflächlicher Venenthrombosen und extrakranieller Karotisstenosen.

Superficial vein thrombosis (SVT) occurs at least as frequent as deep vein thrombosis (DVT), and shares common risk factors with venous thromboembolism. The CALISTO trial was the first to provide specific recommendations for the pharmacologic treatment of SVT. Before treatment is initiated, an accompanying DVT must be excluded and the proximal extension of the SVT assessed. If the proximal extension of the thrombus is closer than 3 cm towards the deep vein system, it should be treated like DVT. Under certain conditions treatment with fondaparinux is indicated in acute symptomatic SVT. Furthermore, compression treatment is recommended. Extracranial carotid artery stenosis can be treated by either surgical thrombarterectomy or catheter based endovascular stent implantation. Trials comparing the two methods have not provided conclusive results on whether the two strategies are equally safe and effective. Considering the latest data from RCTs, careful patient selection (symptoms, comorbidities, age, anatomy, re-stenosis) including individual interdisciplinary discussion appears of ample importance. To date no information is available on whether patients with asymptomatic high grade carotid stenosis receiving "best medical therapy" should be considered for revascularisation in general or only in selected circumstances.

[Prophylaxis for thromboembolism in internal medicine and family practice]. / Thromboembolieprophylaxe in der Inneren Medizin und der hausärztlichen Versorgung.

Although up to 80% of fatal pulmonary emboli occur in nonsurgical patients, conclusive studies on the prevention of thrombosis have only become available in the last 10 years. Bedridden inpatients with acute medical diseases require pharmacologic prophylaxis for thrombosis with unfractionated or low molecular weight heparin or with fondaparinux. This also holds true for patients with underlying malignancies or those suffering from acute ischemic stroke or paretic leg. The challenges to thrombosis prophylaxis are posed by ensuring that uninterrupted prophylaxis is continued after hospital discharge in cases of persisting risk, determining the indications and applying thrombosis prophylaxis on an outpatient basis as well as the multimorbidity and often advanced age of the internal medicine patients. The last factor not only entails an elevated risk of thromboembolism but also an increased risk of hemorrhage, especially in patients with renal insufficiency or platelet inhibitors. Product-specific recommendations and restrictions on pharmacologic prophylaxis need to be considered. Thromboprophylaxis as applied in internal medicine and family practice represents an effective measure to prevent symptomatic and fatal thromboembolisms, but due to multimorbidity and polytherapy of medical patients it requires careful monitoring.

Thromboprophylaxis--key points for the angiologist.

The expertise and the advice of vascular specialists are important in diagnosis and treatment of venous thromboembolism (VTE) and equally important for thromboprophylaxis. Thus, vascular specialists are expected to have significant knowledge of the exposing and disposing risk factors for VTE. They are also expected to be familiar with the risk groups for VTE and the appropriate measures for thromboprophylaxis. Because different pharmacological prophylactic strategies are available, angiologists must be familiar with the properties, the specific labeling and the product information regarding their drugs of choice. Being familiar with the pharmacological profile and the potential risk of impaired renal function due to drug accumulation is essential for angiologists, both for the treatment and prophylaxis of VTE. Appropriate time intervals between application of thromboprophylaxis and spinal or epidural anaesthesia should be observed. This is also important for the recently available oral thrombin- and factor Xa-inhibitors. Presently available data do not support routine pharmacological prophylaxis for patients in the low VTE-risk group. Rather, individual risk benefit assessment is required in these patients. Patients with moderate or high VTE risk should receive pharmacological thromboprophylaxis. There is clear evidence and recommendation for prolonged administration of thromboprophylaxis over a 4-week period in patients following major orthopaedic surgery, such as hip replacement, hip fracture and in cancer surgery patients. Pulmonary embolism (PE) remains the most common preventable cause of death among hospitalized patients. Therefore, angiologists have a central role in ensuring adequate and consistent implementation of thromboprophylaxis, which is the number one strategy to improve patient safety in hospitals.

[New anticoagulants]. / Neue Antikoagulanzien.

This review updates the latest developments concerning new anticoagulants. It describes potential targets in the coagulation pathway: inhibition of the initiation of coagulation, factor Xa and thrombin inhibitors. The focus is laid on substances in late development that already passed the phase II trial for venous thromboembolism (VTE)-prevention as "proof of concept". In the group of factor Xa inhibitors, the indirect inhibitor Fondaparinux has got approval for the indications prevention and therapy of VTE and acute coronary syndromes (OASIS 5 and 6). Rivaroxaban is the first direct factor Xa inhibitor that was admitted for approval in the indication VTE-prevention. The first trial of the program RECORD 1-4 was finished, trials for the indications therapy of VTE (EINSTEIN) and stroke prevention in atrial fibrillation (ROCKET AF) are in phase III. The use in acute coronary symptoms is - like apixaban - evaluated in phase II. The ADOPT trial with apixaban for VTE-prevention, as well as the BOTTICELLI trial for atrial fibrillation, have reached phase III. After the withdrawal of Ximelagatran, Dabigatran is the most developed direct thrombin inhibitor, being extensively studied in the comprehensive phase- III-program REVOLUTION and in approval for the indication VTE-prevention.

Fondaparinux: an update on new study results.

Fondaparinux (Arixtra) is the first selective factor Xa inhibitor approved for use in thromboprophylaxis after orthopaedic surgery. New recently completed trials have also demonstrated the potential of fondaparinux in the prevention of venous thromboembolism (VTE) in other surgical and medical settings and in the treatment of established VTE. In the randomized double-blind PEGASUS study in high-risk abdominal surgery patients, fondaparinux reduced the incidence of VTE from 6.1% with dalteparin to 4.6% (odds ratio reduction = 25.8%, P = 0.14), without increasing the bleeding risk. In the randomized double-blind ARTEMIS trial in acutely ill medical patients, fondaparinux reduced the incidence of VTE from 10.5% with placebo to 5.6% (odds ratio reduction = 49.5%, P = 0.029), without increasing the bleeding risk; there was no pulmonary embolism in the fondaparinux group compared with five, all fatal, in the placebo group (P = 0.029). In the two MATISSE trials, both the efficacy and safety of once daily fondaparinux were at least as good as enoxaparin in the treatment of deep-vein thrombosis (MATISSE-DVT) and unfractionated heparin in the treatment of pulmonary embolism (MATISSE-PE). In patients with coronary artery disease, promising results were obtained in phase II trials and large phase III trials are ongoing. In conclusion, fondaparinux may further improve and simplify the prevention and treatment of thrombosis in a large range of medical and surgical settings.

[Treatment of deep vein thrombosis. When to use which substance?]. / Therapie der Beinvenenthrombose. Wann welche Substanzen?

Current antithrombotic therapy of deep vein thrombosis (DVT) consists of an initial course of heparin, followed by the secondary prevention with oral anticoagulation (OAC). Low molecular weight heparin has several advantages over unfractionated heparin, however, renal insufficiency has to be observed to avoid accumulation. The synthetic pentasaccharide Fondaparinux is a factor Xa inhibitor, that will shortly be available for the initial treatment of DVT. Oral anticoagulation with vitamin K antagonists (VKA) is highly effective, the standard target INR is 2.0-3.0. For a first episode of DVT the duration of OAC usually is six months, but has to be adjusted according to the estimated risk for recurrence. Because of the narrow therapeutic window of VKA, low molecular weight heparins are increasingly being used for secondary prevention in patients with an increased risk for bleeding, mostly in 1/2-therapeutic dose. At present, several new antithrombotic agents are being studied and may become available shortly for DVT treatment.

[Therapy and secondary prevention of venous thromboembolism with vitamin K antagonists]. / Therapie und Sekundärprophylaxe der venösen Thromboembolie mit Vitamin-K-Antagonisten.

Oral anticoagulation with vitamin-K-antagonists is very effective in secondary prevention of venous thromboembolism. In Germany, most commonly Phenprocoumon is used, while most of the evidence-based data are available for Warfarin. The initial treatment of acute venous thromboembolism requires immediate anticoagulation with heparin and a subsequent overlapping treatment with oral anticoagulants. During this phase, anticoagulation may be unstable with increased risk for bleeding. An INR target range between 2 and 3 provides effective protection with minimal risk for major bleeding. The individual risk for bleeding may be estimated by a clinical score. Six months of oral anticoagulation is the standard duration for a first episode of venous thromboembolism, while recurrencies are treated for at least one to two years. The duration may be tailored to the individual patient according to underlying risk factors for recurrencies and for bleeding. Because of a plethora of practical problems and the narrow therapeutic window, there is a need for new antithrombotic agents. These may allow a longer duration of secondary prevention with improved protection against recurrencies without sacrificing safety.

[Stenting of the femoral artery: the angiologist's perspective]. / Stenting der Arteria femoralis aus angiologischer Sicht.

The percutaneous transluminal angioplasty of stenosis and short occlusions of the femoral artery is a well established, safe and effective treatment option. The additional placement of stents during angioplasty is associated with frequent and rapid restenosis due to intimal hyperplasia. Therefore, stent placement of the femoral artery is commonly recommended only for special circumstances, including PTA-induced dissection of the vessel wall, elastic recoil, and eccentric stenosis. Placement of stents near joints, e. g. in the common femoral artery or the popliteal artery should be avoided as it may lead to structural damage of the stents. The current angiological statement concerning stent implantation in the femoral artery may be revised if effective measures to inhibit intimal hyperplasia such as brachytherapy or sirolimus coated stents become available.

[Current management of thromboembolism in pregnancy and puerperium]. / Aktuelles Management der Thromboembolie in Schwangerschaft und Wochenbett.

Venous thromboembolism (VTE) remains the leading cause of maternal death. Today, various risk factors and conditions are known to increase the risk for VTE associated with pregnancy. Having identified the individual risk of a pregnant women, appropriate preventive measures can be taken. If VTE occurs during pregnancy, an appropriate immediate diagnostic work-up is essential in order to avoid further complications. For deep vein thrombosis (DVT) the diagnostic tool of choice is color-coded duplex-sonography, for pulmonary embolism (PE) perfusion/ventilation lung scan can be used. Integrating a detailed individual and family history, the presence of thrombophilia or other risk factors, a risk stratification can be undertaken. These risk categories are defined in the present paper and the appropriate treatment measures are described. As oral anticoagulants cross the placenta and may cause embryopathy in any trimester, oral anticoagulants should be avoided throughout pregnancy. Therefore, heparin is the anti-coagulant of choice for pregnant women, with low molecular weight heparins (LMWH) having distinctive pharmacological advantages over unfractionated heparins. Besides a potential for bleeding, the main side effects of heparin include heparin-induced thrombocytopenia which prompts for platelet monitoring, especially in the first weeks of heparin treatment, and, secondly, heparin-induced osteoporosis, which is a potential sequel of long-term heparin administration. Even though there are abundant reports in the literature on the use of LMWH in pregnant women, that show that they are safe and effective, LMWH are not specifically licensed for the use in pregnancy.

Involvement of erythrocyte aggregation and erythrocyte resistance to flow in acute coronary syndromes.

The objective of the study was to identify the relative importance of erythrocyte flow resistance and aggregation in acute and chronic coronary syndromes. 117 subjects in five groups were studied: (1) 34 patients shortly after acute myocardial infarction (AMI) before reperfusion therapy; (2) 27 patients with unstable and (3) 21 with stable angina pectoris (AP); (4) 14 age-matched control patients and (5) 21 healthy volunteers. Single erythrocyte transit times were measured using the Cell Transit Analyser. Shear dependent elongation and aggregation was measured by a modified computerized Myrenne aggregometer. Leukocyte count was increased in coronary artery disease (CAD), especially in acute syndromes (mean +/- SD for groups 1-5): 12.2 +/- 4.5; 10.0 +/- 5.4; 8.0 +/- 2.0; 8.0 +/- 3.7; 7.0 +/- 2.0 (pl(-1))). Platelets, hematocrit, fibrinogen, alpha2-macroglobulin did not differ between the groups. Plasma viscosity (mPas) was elevated in AMI and stable AP: 1.34 +/- 0.10; 1.30 +/- 0.09; 1.32 +/- 0.08; 1.27 +/- 0.07; 1.27 +/- 0.05. Erythrocyte filtrability was not different as was the shear dependent deformation. Aggregation parameters such as gammaTmin were elevated in CAD: 180 +/- 70; 159 +/- 60; 166 +/- 59; 115 +/- 43; 113 +/- 51 (s(-1)). Erythrocyte deformability, measured with two independent methods, does not appear to contribute to the pathophysiology of acute coronary syndromes. Erythrocyte aggregation and plasma viscosity were again found increased both in unstable and stable coronary disease. It is unlikely that increased red cell aggregation contributes to emergence of AMI.