Treatment Of Established Venous Thromboembolism Research Articles

Cancer-Associated Venous Thromboembolism-Diagnostic and Therapeutic Considerations: An Update Based on the Revised AWMF S2k Guideline.

Patients with cancer are prone to develop venous thromboembolism (VTE) with negative impact on quality of life, morbidity, and mortality. Treatment of established VTE is often complex in patients with cancer. Treatment of cancer-associated VTE (CAT) basically comprises initial and maintenance treatment, for 3 to 6 months, secondary preventions, and treatment in special situations. Therapeutic anticoagulation is the treatment of choice in CAT. In addition to the efficacy and safety of low-molecular-weight heparin (LMWH) that had been recommended for decades, direct oral anti-factor Xa inhibitors, a subgroup of direct oral anticoagulants (DOACs), demonstrated their advantages along with the accompanying concerns in several randomized controlled treatment trials of CAT. The latest guidelines, such as the German AWMF-S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," agree with each other on most aspects with respect to the treatment of CAT. Encompassing recent clinical studies, and meta-analyses, as well as the focus on some special management aspects of CAT, the objective of this review is to present a current overview and recommendations for the treatment of CAT.

Therapy for Cancer-Related Thromboembolism

Cancer is an independent and major risk factor for venous thromboembolism (VTE), defined by symptomatic or asymptomatic DVT, including catheter-related thrombosis (CRT), and/or pulmonary embolism (PE). Over the past 20 years, VTE has become the second cause of death in cancer patients, where it accounts for increased morbidity, mortality, and healthcare costs. Incidental VTE is increasingly diagnosed on systematic computed tomography in cancer patients, raising new questions in daily oncology practice. Risk factors for VTE in cancer include patient-, cancer-, and treatment-related parameters, which vary for a single patient throughout the course of cancer disease and necessitate repeated individual risk assessments. The use of biomarkers and risk assessment models allow identification of cancer patients at high risk for VTE. Anticoagulant therapy for the prophylaxis and the treatment of established VTE is efficient and relatively safe when contraindications are respected, but the variety of risk factors and the number of comorbidities remain major challenges for adequate VTE treatment in cancer patients. Several national guidelines for primary prevention and treatment of VTE in cancer patients were issued in the past 10 years. To homogeneize existing Clinical Practice Guidelines (CPGs), an international consensus working group released specific guidelines for the treatment and prophylaxis of VTE in cancer patients in 2013, so as to make each CPG easier to use at the national level. In cancer patients treated for VTE, the use of low-molecular-weight heparins (LMWHs) is preferred over other anticoagulants in most cases, and LMWHs were shown to be superior to vitamin K antagonists (VKAs). For the prophylaxis of VTE, LMWHs have been validated in surgical patients. For medical cancer patients, ongoing or recent clinical trials will inform our practice. However, several questions remain unanswered due to the number of comorbities in a single patient and expert opinion regarding special situations is required. Better adherence worldwide to CPGs necessitates adequate educational and active implementation strategies, which could substantially decrease the burden of VTE and increase survival in cancer patients.

The Therapeutic Management of Bleeding and Thrombotic Disorders Complicating CNS Malignancies

Patients with central nervous system (CNS) malignancies have a substantial risk for developing both thrombotic and bleeding disorders. The risk of venous thromboembolism (VTE) is substantially higher in these patients, both in the perioperative period and throughout their disease course. Patients with CNS malignancy harbor a latent hypercoagulability, which predisposes to VTE, as do postoperative immobility, hemiparesis, and other factors. The management of VTE in these patients is complex, given the significant morbidity and mortality associated with intratumoral hemorrhage. In the past, the perceived risk of intracranial hemorrhage limited the use of anticoagulation for the management of VTE with many favoring nonpharmacologic methods for prophylaxis and treatment. Inferior vena cava (IVC) filters have since lost favor at many centers given significant complications, which appear to be more frequent in patients with CNS malignancy. Recent studies have demonstrated safe and efficacious use of anticoagulation in these patients with a low incidence of intracranial hemorrhage. Treatment of established VTE is now recommended in this population with many centers favoring low-molecular-weight heparin (LMWH) versus oral warfarin for short- or long-term treatment. We advocate a multimodality approach utilizing compression stockings, intermittent compression devices, and heparin in the perioperative setting as the best proven method to reduce the risk of VTE. In the absence of a strict contraindication to systemic anticoagulation, such as previous intracranial hemorrhage or profound thrombocytopenia, we recommend LMWH in patients with newly diagnosed VTE and a CNS malignancy.

New oral antithrombotics: focus on dabigatran, an oral, reversible direct thrombin inhibitor for the prevention and treatment of venous and arterial thromboembolic disorders

Venous thromboembolism, presenting as deep vein thrombosis or pulmonary embolism, is a major challenge for health care systems. It is the third most common vascular disease after coronary heart disease and stroke, and many hospitalized patients have at least one risk factor. In particular, patients undergoing hip or knee replacement are at risk, with an incidence of asymptomatic deep vein thrombosis of 40%–60% without thromboprophylaxis. Venous thromboembolism is associated with significant mortality and morbidity, with patients being at risk of recurrence, post-thrombotic syndrome, and chronic thromboembolic pulmonary hypertension. Arterial thromboembolism is even more frequent, and atrial fibrillation, the most common embolic source (cardiac arrhythmia), is associated with a five-fold increase in the risk of stroke. Strokes due to atrial fibrillation tend to be more severe and disabling and are more often fatal than strokes due to other causes. Currently, recommended management of both venous and arterial thromboembolism involves the use of anticoagulants such as coumarin and heparin derivatives. These agents are effective, although have characteristics that prevent them from providing optimal anticoagulation and convenience. Hence, new improved oral anticoagulants are being investigated. Dabigatran is a reversible, direct thrombin inhibitor, which is administered as dabigatran etexilate, the oral prodrug. Because it is the first new oral anticoagulant that has been licensed in many countries worldwide for thromboprophylaxis following orthopedic surgery and for stroke prevention in patients with atrial fibrillation, this compound will be the main focus of this review. Dabigatran has been investigated for the treatment of established venous thromboembolism and prevention of recurrence in patients undergoing hip or knee replacement, as well as for stroke prevention in atrial fibrillation patients with a moderate and high risk of stroke.

Anticoagulation in the Treatment of Established Venous Thromboembolism in Patients With Cancer

Cancer-associated thrombosis is a frequent and costly complication in patients with cancer. Significant morbidity and mortality not only result from thrombotic events, but may also occur as a result of the therapeutic interventions. The established treatment for cancer-associated thrombosis is anticoagulant therapy. Of the few options available, low molecular weight heparin (LMWH) is the preferred agent because of its efficacy, safety, and convenience. Alternatives to LMWH have undesirable limitations and have demonstrated poorer efficacy and safety in the oncology population. Treatment of recurrent thrombosis, patients with concurrent bleeding issues, role of vena cava filter insertion, and duration of therapy are all areas in need of urgent research. Treatment of cancer-associated thrombosis remains a challenging task and is limited by the paucity of evidence-based data. Research is urgently needed to advance current practice and improve patient care.

Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study

Venous thromboembolism (VTE) is common in patients with terminal cancer. Current treatment practice with warfarin has a high incidence of complications, including bleeding, poor control and recurrent VTE. Long-term low-molecular-weight heparin (LMWH) therapy is safer and more efficacious in this patient group, but there are concerns that daily therapy may have a negative impact on quality of life. A qualitative study was carried out to determine whether LMWH was acceptable in palliative care patients, both in the community and in-patient units. Forty palliative care patients receiving LMWH for VTE were interviewed. Participants found LMWH to be an acceptable intervention, allowing them freedom from blood tests and optimism regarding their care. It was considered a preferable therapy to warfarin, which had a negative impact on participant's quality of life. The findings of this study support the use of LMWH, first line in the treatment of established VTE in the palliative care setting.

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.

Screening for subclinical deep-vein thrombosis.

Most episodes of venous thromboembolism (VTE) are clinically silent; symptomatic events are merely the tip of the thromboembolism iceberg.1 The subgroup of events that evolve to develop clinical manifestations cannot accurately be predicted, and sudden death from pulmonary embolism (PE) may be the presenting feature. Consequently, various thromboprophylactic strategies are used to minimize the incidence of VTE in high‐risk cohorts (Table 1). While all of these reduce the frequency of deep‐vein thrombosis1 (DVT), a reduction in overall mortality has only been convincingly demonstrated with heparin.2 However, despite optimal prophylaxis, venographically‐demonstrated DVTs still supervene in an important minority.1,3–,6 Moreover, not all high‐risk patients receive heparin, either because of contraindications, or because evidence of sustained benefit is lacking, as in acute ischaemic stroke.7 Given that the treatment of established VTE is highly effective,8 the concept of screening for subclinical DVT with initiation of treatment in selected cases, both in conjunction with optimal prophylaxis and in subgroups that do not receive heparin, also warrants consideration. However, there is much uncertainty about which, if any, subgroups should be screened, and whether this would have an important impact on clinical outcomes. In addition, it is unclear which screening tool should be used as all current modalities have shortcomings, in that they are either invasive, imperfectly sensitive or insufficiently evaluated. In this review, we discuss the clinical relevance of asymptomatic DVT, the potential benefits of early diagnosis and treatment, and the diagnostic tools available for this purpose, as well as highlighting important areas requiring further research. View this table: Table 1 Prevalence of DVT in the absence of heparin prophylaxis in high‐risk patient groups2,9,,10 The prevalence of DVT in high‐risk cohorts such as general surgical, stroke and orthopaedic patients ranges from 19% to 84% (Table 1) in the absence …

Venous thromboembolism after acute stroke.

Treatment for venous thromboembolism (VTE) is highly effective in preventing morbidity and mortality, yet pulmonary embolism (PE) accounts for up to 25% of early deaths after stroke. This is because the current diagnostic paradigm is reactive rather than proactive: the clinician responds to VTE when it becomes symptomatic, in the expectation that initiation of treatment will prevent progression to more serious manifestations. This approach is flawed, because sudden death from PE is frequently unheralded and nonfatal symptomatic pulmonary emboli are often unrecognized or misdiagnosed. Morbidity and mortality from PE could be reduced either by more effective thromboprophylaxis or earlier diagnosis and treatment of established VTE. The fact that early use of short-term, low-dose, unfractionated heparin (UFH) is not associated with sustained, clinically meaningful benefit suggests that a fundamental change in the diagnostic approach to VTE is needed, one which requires a greater appreciation that clinically apparent events are merely the tip of the thromboembolism iceberg. Research into a strategy of screening for subclinical VTE in these patients is needed, with a view to identifying a subgroup at risk of progression to symptomatic and life-threatening events, in whom outcome might be improved by anticoagulation.

Low-Molecular-Weight Heparins and New Strategies for the Treatment of Patients with Established Venous Thrombosis

Unfractionated heparin is the commonest treatment for established venous thromboembolism. While this treatment undoubtedly reduces mortality and morbidity there are problems associated with its use. It does not always prevent thrombus propagation or embolisation, the low bioavailability results in a frequent failure to achieve therapeutic heparin levels in vivo and the variable sensitivity of the partial thromboplastin time to the heparin effect may result in inappropriate heparin dosage. The low-molecular-weight heparins have high predictable bioavailability and can be administered as weight-calculated fixed-dose regimens for the treatment of established venous thromboembolism. While statistically significant clinical results are awaited, there is increasing evidence for the superior benefit-risk ratios for these agents compared to unfractionated heparin. In routine practice, the frequent failure to achieve a therapeutic intensity of anticoagulation is currently the main reason for adopting low-molecular-weight heparins for first-line treatment of venous thromboembolism. Cost analysis studies based on total health care costs may support the use of these drugs, because savings from the abolishment of laboratory monitoring, improved clinical outcome and shorter inpatient stay may prove treatment with low-molecular weight heparin to be more cost-effective than treatment with unfractionated heparin.

MANAGEMENT OF VENOUS THROMBOEMBOLIC DISEASE: The Impact of Low-Molecular-Weight Heparin

Prophylaxis for DVT unequivocally is beneficial in patients identified to be at high risk. Heparin prophylaxis with subcutaneous low-dose UFH is adequate in some clinical settings but less effective in others. LMWH preparations are effective and safe as prophylaxis in certain medical patients as well as in general surgery and elective hip replacement. Efficacy and safety are demonstrated in the therapy of established venous thromboembolism. Subcutaneous administration of LMWH once or twice daily may prove more convenient from both the patient and nursing viewpoint, particularly in the treatment of established DVT. Monitoring is not necessary when using LMWH preparations as prophylaxis, and a fixed-dose without weight adjustment has been used in most prophylaxis trials. When treating established DVT, less monitoring is likely to be required than currently is the case with UFH. Although the cost of LMWH preparations is greater than that of UFH, the decrease in the occurrence or recurrence of thromboses that has been demonstrated in some trials might prove an effective balance. Future avenues to explore include discovery of better means to standardize the LMWH preparations and determination of the efficacy and safety of LMWH in specific populations, such as those in intensive care units, cancer patients, nursing home patients, and outpatients in general. Although cost-benefit is favorable thus far, meticulous assessment in other settings may enhance the acceptance of these agents. Long-term follow-up could be helpful in determining the relative effect of different heparin preparations on the frequency of postphlebitic syndrome. Comparison of different LMWH fractions may follow, as well as further investigations of newer ultra-low-molecular-weight agents. One LMWH preparation (enoxaparin) already has been approved in the United States for prophylaxis in the setting of elective hip replacement; and dalteparin has been approved here for use as DVT prophylaxis in patients undergoing abdominal surgery when there appears to be a significant risk of thromboembolism. It is likely that LMWH preparations will become even more widely used in North America and that the approved indications will expand to include prophylaxis in numerous settings and the treatment of established venous thromboembolism.