Prophylaxe und Therapie venöser Thromboembolien bei Tumorerkrankungen

Venous thromboembolism (VTE) is a common complication in patients with cancer. Because of their improved subcutaneous bioavailability and reliable antithrombotic efficiency low-molecular-weight heparins (LMWH) are preferably used for prevention and treatment of cancer-related VTE. Thromboprophylaxis with LMWH is well established in patients undergoing cancer surgery and hospitalized cancer patients, while outpatient prophylaxis remains contentious. LMWH are recommended over unfractionated heparins and vitamin K antagonists for initial treatment and secondary prophylaxis (3–6 months) after cancer-related VTE. Long-term secondary prophylaxis should be considered for patients with ongoing active malignancy and low bleeding risk. Due to absence of clinical studies in cancer patients, the use of novel oral anticoagulants is currently not recommended.     

Long-term administration of a low-molecular-weight heparin contributed to successful treatment in a patient with primary mediastinal large B-cell lymphoma and venous thromboembolism

The case of a 16-year-old girl with primary mediastinal large B-cell lymphoma who had thrombosis in the brachiocephalic, subclavian, and internal jugular veins at presentation is reported. MACOP-B chemotherapy plus radiation therapy could be the first-line strategy, but MACOP-B increases the risk of thrombosis. Although an effective method for initial treatment of venous thromboembolism (VTE) in cancer patients has not been established, recent studies revealed that the administration of a low-molecular-weight heparin (LMWH) was effective for secondary prevention of VTE. Therefore, the patient in this case was treated with MACOP-B plus rituximab followed by radiation therapy, and an LMWH was administered through the course of treatment. She achieved complete remission and never suffered from VTE. This case suggests that long-term administration of an LMWH contributes to the primary improvement and secondary prevention of VTE even in patients who are at high risk for thrombosis.     

Approach to Venous Thromboembolism in the Cancer Patient

Venous thromboembolism (VTE) is frequently encountered in cancer patients, acts as an important cause of morbidity and mortality, and may be a predictor of worse prognosis. In cancer patient who have a poor life expectancy, preventing death from pulmonary embolism is the mainstay of treatment. Patients who present with severe hypotension or other clinical manifestations suggestive of critical pulmonary embolism and do not have contraindications to thrombolysis should promptly be administered thrombolytic drugs. Except for selected cases requiring aggressive therapy, treatment of VTE in patients with cancer should not differ from that of patients without malignancy; the initial treatment should be conducted with adjusted dose of unfractionated heparin (UH), fixed dose of low-molecular-weight heparins (LMWH), or fondaparinux. LMWHs and fondaparinux have the potential to greatly simplify the initial treatment of VTE, making the management of the pathology feasible in an outpatient setting for selected patients. Traditionally, in cancer as well as in non-cancer patients, UH or LMWH or fondaparinux are overlapped by oral anticoagulation, targeted to reach an International Normalized Ratio (INR) between 2.0 and 3.0, and then followed by oral anticoagulants. However, during oral anticoagulant therapy, cancer patients exhibit a two- to fourfold higher risk of recurrent VTE and major bleeding complications when compared to non-cancer patients. Studies performed during the current decade have demonstrated that LMWHs offer several advantages in terms of efficacy in preventing VTE recurrences without increasing the bleeding risk. According to International Guidelines, the long-term administration of LMWH should be considered an alternative to anti-vitamin K drugs in patients with advanced disease and in those with conditions limiting the use of oral anticoagulants. The targeted policy is to administer LMWH at full therapeutic doses for the first month of treatment and then 75% of the initial dose for at least the following 5 months of therapy. Prolongation of anticoagulation should be considered for as long as the malignant disorder is active. In patients with acute deep venous thrombosis and contraindications to anticoagulation, vena cava filters should be considered. If anticoagulation is temporarily contraindicated, retrievable filters should be considered. Only patients who are actively bleeding or who are at extremely high risk for bleeding should receive a filter without anticoagulation coverage.     

Use of low molecular weight heparin for medical prophylaxis by European geriatricians

PURPOSE: Many hospitalised elderly patients are at increased risk of venous thromboembolism (VTE). The aim of this study was to assess the rate and duration of medical utilization of low molecular weight heparin (LMWH) for VTE prevention by European geriatricians. METHOD: A questionnaire was sent to 94 geriatricians of the European Academy for Medicine of Ageing (EAMA), to be filled out for each patient older than 65 years of their institutions who received LMWH during 1 day of December 2000. RESULTS: In the 37 centers that participated (representing 11 different European countries) 2912 patients were present on the day of the study: 857 patients in acute care, 367 in rehabilitation care, 1568 in long-term care and 141 in day hospital. Prophylaxis by LMWH was given to 284 medical patients (9.75%, mean age 82.2 years). Use of LMWH was more frequent in acute and rehabilitation care (22.4% and 9.8%) than in long-term care (3.1%). The main risk factors in patients with LMWH prophylaxis were: bedridden (53%), infectious disease (18%), heart failure (17.6%), venous insufficiency (17.6%), paralysis of lower limbs (16.6%), recent stroke (15%) and malignancy (10%). The duration of the treatment for VTE prophylaxis exceeded 30 days in 51 patients (12%) and one year in 15 patients (3.3%). CONCLUSION: In Europe, VTE prophylaxis by LMWH is widely used in elderly medical patients without specific guidelines in this population. Further studies are necessary to evaluate the appropriate duration of prophylaxis in very prolonged immobilization.     

Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer

Anticoagulation is used to treat venous thromboembolism (VTE) in cancer patients, but may be associated with an increased risk of bleeding. VTE recurrence and major bleeding were assessed in cancer patients treated for VTE with the most currently prescribed anticoagulants in clinical practice. Newly diagnosed cancer patients (first VTE 1/1/2013‐05/31/2015) who initiated rivaroxaban, low‐molecular‐weight heparin (LMWH), or warfarin were identified from Humana claims data and observed until end of eligibility or end of data availability. VTE recurrence was a hospitalization with a primary diagnosis of VTE ≥7 days after first VTE. Major bleeding events on treatment were identified using validated criteria. Cohorts were compared using Kaplan–Meier rates at 6 and 12 months and Cox proportional hazards models. Cohorts were adjusted for their differences at baseline. A total of 2428 patients (rivaroxaban: 707; LMWH: 660; warfarin: 1061) met inclusion criteria. Patient characteristics were well balanced after weighting. There was a trend for lower VTE recurrence rates in rivaroxaban users compared to LMWH users at 6 months (13.2% vs. 17.1%; P = .060) and significantly lower at 12 months (16.5% vs. 22.2%; P = .030) [HR: 0.72, 95% CI: (0.52‐0.95); P = .024]. VTE recurrence rates were also lower for rivaroxaban than warfarin users at 6 months (13.2% vs. 17.5%; P = .014) and 12 months (15.7% vs. 19.9%; P = .017) [HR: 0.74, 95% CI: (0.56‐0.96); P = .028]. Major bleeding rates were similar across cohorts. This real‐world analysis suggests cancer patients with VTE treated with rivaroxaban had significantly lower risk of recurrent VTE and similar risk of bleeding compared to those treated with LMWH or warfarin.     

Cancer and venous thromboembolism: prevention, treatment and survival

Venous thromboembolism (VTE) occurs frequently in patients with cancer. It can be difficult to manage, sometimes delay cancer therapy and predicts for a worse prognosis. Hence, effective methods to prevent and treat VTE can reduce morbidity and mortality. Prophylaxis with anticoagulants is recommended for patients hospitalized for surgery or medical conditions, but is not routinely administered in the ambulatory setting. Traditional anticoagulation with a heparin followed by vitamin K antagonist therapy for cancer patients with acute VTE is associated with a high frequency of treatment failure and bleeding complications. Low molecular weight heparins (LMWHs) have simplified and improved the management of VTE, and recent studies suggest these agents may improve survival in patients with limited or early stage disease. This brief review will provide an update on the primary prevention and treatment of VTE and discuss the evidence for the survival advantage associated with LMWH use in patients with malignancy.     

Treatment of venous thromboembolism in cancer patients

Venous thromboembolism (VTE) is a common complication in patients with malignant disease. Its management remains challenging because patients with a cancer-associated thrombosis are at higher risk of recurrent VTE than are noncancer subjects with thrombosis and also have a greater risk for anticoagulant-associated bleeding complications while receiving therapy to prevent recurrent VTE. Recently, anticoagulant strategies based on the administration of low-molecular-weight heparin (LMWH) rather than vitamin K antagonists for up to 6 days to prevent recurrent VTE have been evaluated. These studies indicate that LMWH is associated with a lower rate for recurrent VTE and similar rates of bleeding when compared with oral anticoagulant therapy. Chronic exposure to LMWH may also prolong survival of cancer patients.     

Emerging strategies in the prevention of venous thromboembolism in hospitalized medical patients

Venous thromboembolism (VTE) remains a significant cause of morbidity and mortality in hospitalized patients with acute medical illness. The high prevalence of VTE in this patient population, its clinically silent nature, and associated morbidity and mortality indicate that prophylactic therapy is appropriate in those determined to be at increased risk. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have been shown to reduce the incidence of VTE and are the primary therapies used for prophylaxis in these patients. Although both UFH and LMWH have received grade 1A recommendations for the prevention of VTE in at-risk medical patients in the 2004 American College of Chest Physicians consensus conference statements, LMWH has advantages over UFH in its once-daily dosing scheme, reduced incidence of major and minor bleeding events, and reduced incidence of heparin-induced thrombocytopenia. Fondaparinux is a novel antithrombotic agent characterized by specificity for factor Xa and a lack of platelet interaction. A recent clinical trial in hospitalized patients with acute medical illness found that fondaparinux significantly reduced the incidence of both VTE and fatal pulmonary embolism compared with placebo, without increased major bleeding. Despite the availability of effective thromboprophylactic therapies, VTE prophylaxis continues to be underutilized in hospitalized medical patients.     

Treating patients with venous thromboembolism: initial strategies and long-term secondary prevention

Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a candidate for both acute and chronic therapy. The Thrombin Inhibitor in Venous Thromboembolism (THRIVE) clinical trial program has demonstrated that this agent has a favorable benefit-risk profile compared with standard therapy for the initial treatment (6 months) and secondary prevention (up to 18 months) of VTE. However, in a substantial proportion (6 to 13%) of patients given extended ximelagatran therapy, elevated serum transaminase enzymes developed, typically in the first 2 to 4 months of treatment. Even though these elevations usually abated without clinical sequelae whether or not treatment was continued, their clinical relevance remains unclear. In addition, locally reported coronary events occurred more frequently in ximelagatran-treated patients during the initial 6 months of treatment, the reason for which is yet unclear. The consistent anticoagulant response and fixed oral dosing without coagulation monitoring allows ximelagatran to overcome many of the limitations inherent to current treatment options for VTE treatment and secondary prevention, provided the problem of liver enzyme elevation and coronary events is resolved.     

Venous thromboembolism in cancer patients: expanding horizons

Venous thromboembolism (VTE) and particularly idiopathic VTE may be paraneoplastic phenomena. The merits of screening patients with idiopathic VTE for occult cancer are still under debate, and randomized studies are required to establish its potential cost-effectiveness. Cancer and its related surgery greatly increase the risk of VTE. Thromboprophylaxis using agents such as low-molecular-weight heparin (LMWH) has proved to be safe and effective in reducing the incidence of postoperative VTE. The ENOXACAN II study has shown that prolonging the standard 1-week regimen of the LMWH enoxaparin to 4 weeks may further reduce the incidence of postoperative VTE. Enoxaparin has also shown potential benefits in the secondary prevention of VTE and the reduction of bleeding complications. Emerging data indicate that LMWH may improve survival rates in cancer patients with VTE, making this a very important area for future research.     

The prevention of pregnancy‐related venous thromboembolism

Pregnancy‐related venous thromboembolism (VTE) remains one of the leading causes of maternal mortality and morbidity in the developed world. There is a lack of high‐level data surrounding the use of thromboprophylaxis in pregnancy. In the UK, following the publication of the first Royal College of Obstetricians and Gynaecologists (RCOG) guideline for VTE prophylaxis during pregnancy and the puerperium in 2004, a fall in maternal deaths secondary to VTE was observed during the subsequent triennium (2006–2008). For the first time since 1985, VTE was no longer the most common cause of maternal death. Low‐molecular‐weight‐heparin (LMWH) is generally the agent of choice for thromboprophylaxis in this setting, and is considered safe and efficacious. The accurate risk stratification of women in order to allow the targeted provision of thromboprophylaxis is challenging. A number of international guidelines support risk assessment for pregnancy‐related VTE and the provision of LMWH for those who are deemed at sufficiently high risk. This review describes the importance of VTE in pregnancy and the puerperium, the part played by different risk factors and the role of thromboprophylaxis in this group of patients.     

Is recurrent venous thromboembolism after therapy reduced by low-molecular-weight heparin compared with oral anticoagulants?

PURPOSES: To evaluate whether the incidence of recurrent venous thromboembolism (VTE) events after therapy differs for patients treated with long-term low-molecular-weight heparin (LMWH) or oral anticoagulant therapy (OAT). METHODS: All randomized studies were searched through computerized queries of MEDLINE, the Cochrane Controlled Trials Register, the American Society of Hematology abstract database, and the American Society of Clinical Oncology abstract database. RESULTS: Eleven studies including 2,907 patients were identified. Seven studies evaluated a period of 3 to 9 months after cessation of the allocated treatment: 5.4% of patients in the LMWH group vs 4% in the arm allocated to OAT had an episode of recurrent symptomatic VTE. Combined analysis showed a nonsignificant trend in lowering recurrent symptomatic VTE in favor of OAT (relative risk [RR], 1.29; 95% confidence interval [CI], 0.82 to 2.02; p = 0.27). By contrast, during active treatment, a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT was registered (RR, 0.63; 95% CI, 0.47 to 0.83; p = 0.001). Regarding cancer patients only, 37 of 569 patients (6.5%) in the LMWH group had recurrent symptomatic VTE vs 69 of 546 patients (12.6%) in the OAT group, with a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH (RR, 0.52; 95% CI, 0.35 to 0.76; p = 0.001). CONCLUSIONS: Despite the significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT during treatment, patients treated with long-term LMWH do not seem to have more frequently recurrent VTE events compared with OAT after cessation of therapy. The significant difference favoring LMWH over OAT among all patients receiving treatment comes mostly from studies enrolling cancer patients.     

Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis

BACKGROUND: Venous thromboembolism (VTE) remains a major cause of morbidity following stroke. The optimal form of pharmacologic prophylaxis following stroke is unknown. METHODS: We identified randomized trials comparing unfractionated heparin (UFH) to low-molecular-weight heparin (LMWH) for VTE prevention in ischemic stroke patients. We focused on the risk for VTE, pulmonary embolism (PE), bleeding, and mortality as a function of the type of agent used for prophylaxis. Findings were pooled with a random-effects model. RESULTS: We identified three trials including 2,028 patients. Two of the studies were blinded, two studies relied on enoxaparin, while one study utilized certoparin. In two studies, UFH was administered three times a day, while it was administered twice daily in the remaining study. The use of LMWH was associated with a significant risk reduction for any VTE (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.41 to 0.70; p < 0.001). Limiting the analysis to proximal VTEs also indicated that LMWHs were superior (OR with LMWH vs UFH, 0.53; 95% CI, 0.37 to 0.75; p < 0.001). LMWH use led to fewer PEs as well (OR, 0.26; 95% CI, 0.07 to 0.95; p = 0.042). There were no differences in rates of overall bleeding, intracranial hemorrhage, or mortality based on the type of agent employed. Restricting the analysis to the reports employing enoxaparin did not alter our findings. CONCLUSIONS: The prophylactic use of LMWH compared to UFH following ischemic stroke is associated with a reduction in both VTE and PE. This benefit is not associated with an increased incidence of bleeding. Broader use of LMWH for VTE prevention after ischemic stroke is warranted.     

Cancer and thrombosis

The risk of venous thromboembolic events (VTE) in patients with cancer is well established. Malignancy screening in patients who present with their first episode of VTE is recommended only if the history or physical findings are suggestive of an underlying problem, however. Thrombotic events remain a significant cause of death in cancer patients and their treatment remains a major challenge in the management of cancer. Low-molecular-weight heparins are safe, effective options for treatment and prophylaxis and may prolong survival in this patient population. It remains to be seen, however, if this treatment will influence cancer outcomes.     

Anticoagulants in Pregnancy

Venous thromboembolic (VTE) complications are a leading cause of maternal mortality in the developed world. To reduce the incidence of VTE in pregnancy, and improve outcomes, a wider understanding of the risk factors involved and a better identification of women at risk of thrombosis coupled with effective thromboprophylaxis and treatment of VTE are required. As coumarin is unsuitable for use in pregnancy because of problems with embryopathy and risk of fetal bleeding, anticoagulation therapy in pregnancy centres on the use of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH). There is now extensive experience of the safety and efficacy of LMWH in pregnancy. LMWH's, such as enoxaparin and dalteparin, have clinical and practical advantages compared with UFH in terms of improved safety (significantly lower incidence of osteoporosis and heparin induced thrombocytopenia), and patient convenience with once daily dosing for the majority of women. Such therapy is not restricted only to prevention and treatment of VTE but is now being assessed in additional clinical situations such as the prevention of pregnancy complications.     

Treatment modalities in cancer-associated venous thromboembolism (VTE)

Anticoagulation is the cornerstone of cancer-associated VTE treatment, including vitamin K antagonists (VKA), unfractionated heparin (UFH), fondaparinux, low-molecular-weight heparins (LMWH) and direct oral anticoagulants (DOACs). The goals of anticoagulant therapy in cancer patients with cancer-associated thrombosis (CAT) are to improve symptoms, reduce risk of recurrent VTE or fatal pulmonary embolism (PE), and decrease the risk of post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension. Although LMWH have been the standard of care for a long time for VTE treatment in cancer patients, showing superiority over the classic VKA, in the recent years the landscape of anticoagulant therapy has significantly changed with the inclusion of DOACs in this population.     

Prevention of deep vein thrombosis in cancer patients

Venous thromboembolism (VTE) in patients with cancer follows an aggressive course, and it is often resistant to traditional regimens of pharmacological prophylaxis and treatment. Anticoagulant-related bleeding is also common and can complicate VTE treatment as well as cancer therapy. Consequently, the most effective approach to reducing the burden of VTE and its associated morbidity and mortality is to provide appropriate prophylaxis. Few clinical trials have focused on the prevention of VTE in this high-risk patient population, and they consistently demonstrate the efficacy and safety of anticoagulant prophylaxis in reducing thrombotic complications. Currently, low-molecular-weight heparins and oral vitamin K antagonists are the most commonly used anticoagulants for primary prevention in patients with cancer, but compliance with consensus guidelines is poor. Novel anticoagulants with a convenient and favorable risk/benefit profile may help to improve prophylaxis utilization and treatment. This review will provide a summary of the evidence on the primary prevention of VTE in patients with cancer.     

Malignancy and thrombosis: a double-sided clinical relationship

Venous thromboembolism (VTE) is the second most common cause of mortality in cancer patients and also points towards unfavourable prognosis. In about 10% of patients with idiopathic VTE there is underlying malignancy. However, the efficacy of extensive tumour screening in those patients is not yet established. Numerous plasmatic and cellular components contribute to the phenomenon of hypercoagulability in cancer patients, including Cancer Procoagulant and activation of coagulation with high levels of coagulation factors. Cancer surgery carries an increased risk compared to non-cancer patients necessating more intensive and longer thromboprophylaxis in those patients. In medical patients active cancer is associated with increased risk for VTE. In the treatment of VTE, cancer patients have a significantly higher recurrence rate for VTE when treated with vitamin K-antagonists (VKA) compared to non-cancer patients. Compared to VKA the use of low molecular weight heparin for long-term secondary prevention is more effective than vitamin K-antagonists. Thus, there is a grade 1A recommendation to use low molecular weight heparin for cancer patients during the first 3-6 months of secondary prevention of VTE. Several studies indicate that low molecular weight heparin may also improve the prognosis of cancer patients quoad vitam, particularly for cancer patients at an earlier stage of disease; this needs to be confirmed in further studies.     

Venous thromboembolism and cancer: a systematic review

Venous thromboembolism (VTE) is a serious and potentially fatal disorder, which is often associated with a significant impact on the quality of life and on the clinical outcome of cancer patients. The pathophysiology of the association between thrombosis and cancer is complex: malignancy is associated with a baseline hypercoagulable state due to many factors including release of inflammatory cytokines, activation of the clotting system, expression of hemostatic proteins on tumor cells, inhibition of natural anticoagulants, and impaired fibrinolysis. Several risk factors, related to the patient, the disease, and the therapeutic interventions, have been identified as contributing to the occurrence of VTE. There is convincing evidence to recommend the use of heparins or fondaparinux for prevention of VTE in selected cancer patients, and, especially in some particular types of malignancies and cancer treatments. Management of VTE in patients with cancer is more challenging and bleeding complications associated with the use of anticoagulants are significantly higher in cancer patients than in those without malignancy. Important issues that need to be considered in all cases are interference with anticancer therapy, inconvenience of treatment, and impact on quality of life.     

Venous thromboembolism in abdominal cancer surgery

Venous thromboembolism (VTE) is recognized as a serious complication in both surgical and non-surgical patients. Cancer, particularly adenocarcinoma developing in the digestive organs, is one of the most potent risk factors for VTE, as first described by Trousseau in 1865. Cell membrane microparticles shedding from cancer cells play a critical role in venous clot formation through tissue factor (TF)-mediated activation of the coagulation system. Since recent prospective studies have demonstrated that VTE risk in Japanese surgical patients is comparable to that in Caucasians, perioperative thromboprophylaxis with anticoagulants is now considered essential in patients undergoing abdominal cancer surgery, in addition to mechanical thromboprophylaxis. Recent multi-center studies have also shown the efficacy and safety of enoxaparin, a low molecular weight heparin (LMWH), and fondaparinux, a synthetic Xa inhibitor, in VTE prevention after abdominal cancer surgery. Anticoagulants like LMWH are expected to exert not only thromboprophylactic but also antineoplastic effects.