Prevention of venous thromboembolism in cancer patients: current approaches and opportunities for improvement

Venous thromboembolism (VTE), a common complication in patients with cancer, is associated with increased risk of morbidity, mortality, and recurrent VTE. Risk factors for VTE in cancer patients include the type and stage of cancer, comorbidities, age, major surgery, and active chemotherapy. Evidence-based guidelines for thromboprophylaxis in cancer patients have been published: the National Comprehensive Cancer Network and American Society for Clinical Oncology guidelines recommend thromboprophylaxis for hospitalized cancer patients, while the American College of Chest Physician guidelines recommend thromboprophylaxis for surgical patients with cancer and bedridden cancer patients with an acute medical illness. Guidelines do not generally recommend routine thromboprophylaxis in ambulatory patients during chemotherapy, but there is evidence that some of these patients are at risk of VTE; some may be at higher risk while on active chemotherapy. Approaches are needed to identify those patients most likely to benefit from thromboprophylaxis, and, to this end, a risk assessment model has been developed and validated. Despite the benefits, many at-risk patients do not receive any thromboprophylaxis, or receive prophylaxis that is not compliant with guideline recommendations. Quality improvement initiatives have been developed by the Centers for Medicare and Medicaid Services, National Quality Forum, and Joint Commission to encourage closure of the gap between guideline recommendations and clinical practice for prevention, diagnosis, and treatment of VTE in hospitalized patients. Health-care institutions and providers need to take seriously the burden of VTE, improve prophylaxis rates in patients with cancer, and address the need for prophylaxis across the patient continuum.     

肿瘤患者静脉血栓栓塞抗凝出血与复发风险研究进展

肿瘤相关静脉血栓栓塞症(cancer-associated venous thromboembolism, CAVTE)为肿瘤患者在疾病进程中的常见并发症和死亡原因。其静脉血栓栓塞症(venous thromboembolism, VTE)复发和抗凝后严重出血的高风险可能会导致治疗延误和死亡率增加。目前, 国内外指南并未推荐对所有门诊患者直接进行一级预防, 但建议在化疗前评估发生静脉血栓栓塞的个体风险。本文对目前肿瘤患者静脉血栓栓塞抗凝出血与复发研究进展以及现行VTE防治指南和VTE风险评估模型进行综述。      

Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in patients with cancer. The risk of VTE varies over the natural history of cancer, with the highest risk occurring during hospitalization and after disease recurrence. Patient and disease characteristics are associated with further increased risk of VTE in this setting. Specific factors include cancer type (eg, pancreatic cancer, brain cancer, lymphoma) and the presence of metastatic disease at the time of diagnosis. VTE is a significant predictor of increased mortality during the first year among all types and stages of cancer, with metastatic disease reported to be the strongest predictor of mortality. VTE is also associated with early death in ambulatory patients with cancer. These data highlight the need for close monitoring, prompt treatment, and appropriate preventive strategies for VTE in patients with cancer. The American Society of Clinical Oncology and the National Comprehensive Cancer Network have issued guidelines regarding the prophylaxis and treatment of patients with cancer. This review summarizes the impact of VTE on patients with cancer, the effects of VTE on clinical outcomes, the importance of thromboprophylaxis in this population, relevant ongoing clinical trials examining the prevention of VTE, and new pharmacologic treatment options.     

肿瘤与静脉血栓栓塞症

 肿瘤患者有较高的静脉血栓发生率。研究发现,静脉血栓栓塞症（VTE）可增加肿瘤患者的死亡风险。VTE的发生机制与组织因子（TF）及癌促凝物质（CP）等因素密切相关。患者相关性因素、肿瘤相关性因素及治疗相关性因素均可导致患者VTE发生率增加。应重视对患者危险因素进行评估,对高危患者及早进行预防性抗凝治疗,在诊断VTE后应立即进行急性期治疗及慢性期维持治疗。     

Thromboprophylaxis with low‐molecular‐weight heparin in medical patients with cancer

Venous thromboembolism (VTE) is a frequent complication of cancer and cancer treatment and is associated with multiple clinical consequences, including recurrent VTE, bleeding, and an increase in the risk of death. Although the risks associated with VTE have been well recognized in surgical cancer patients, there is also considerable and increasing risk in medical cancer patients. VTE risk factors in medical cancer patients include the type and stage of cancer, major comorbid illnesses, current hospitalization, active chemotherapy, hormone therapy, and antiangiogenic agents. Low‐molecular‐weight heparins (LMWHs) are recommended commonly for the prevention of VTE in hospitalized cancer patients and in higher risk ambulatory cancer patients because of their favorable risk‐to‐benefit profile. These agents have demonstrated effectiveness in both the primary and secondary prevention of VTE in medical cancer patients. Extended‐duration anticoagulant therapy is often recommended to reduce the risk of VTE recurrence in patients with cancer. LMWHs are often used for long‐term prophylaxis because of a reduced need for coagulation monitoring, few major bleeding episodes, and once‐daily dosing. Despite clinical and practical benefits, a substantial proportion of medical cancer patients do not receive VTE prophylaxis. To improve the appropriate prevention and treatment of VTE in cancer patients, guidelines have been published recently by the American Society of Clinical Oncology and the National Comprehensive Cancer Network. Widespread dissemination and application of these guidelines are encouraged to improve the appropriate use of these agents and to improve clinical outcomes in medical cancer patients at risk for VTE and its complications. Cancer 2009. © 2009 American Cancer Society.     

Risk assessment models for cancer-associated venous thromboembolism

Venous thromboembolism (VTE) is common in cancer patients, and is associated with significant morbidity and mortality. Several factors, including procoagulant agents secreted by tumor cells, immobilization, surgery, indwelling catheters, and systemic treatment (including chemotherapy), contribute to an increased risk of VTE in cancer patients. There is growing interest in instituting primary prophylaxis in high-risk patients to prevent incident (first-time) VTE events. The identification of patients at sufficiently high risk of VTE to warrant primary thromboprophylaxis is essential, as anticoagulation may be associated with a higher risk of bleeding. Current guidelines recommend the use of pharmacological thromboprophylaxis in postoperative and hospitalized cancer patients, as well as ambulatory cancer patients receiving thalidomide or lenalidomide in combination with high-dose dexamethasone or chemotherapy, in the absence of contraindications to anticoagulation. However, the majority of cancer patients are ambulatory, and currently primary thromboprophylaxis is not recommended for these patients, even those considered at very high risk. In this concise review, the authors discuss risk stratification models that have been specifically developed to identify cancer patients at high risk for VTE, and thus might be useful in future studies designed to determine the potential benefit of primary thromboprophylaxis.     

The pathogenesis of venous thromboembolism in cancer: emerging links with tumour biology

Venous thromboembolism (VTE) is a frequent complication in individuals with cancer and is considered to be a cause of substantial mortality. Epidemiological studies identify malignancy as an independent VTE risk factor and show that cancer patients are at increased risk of both initial and recurrent VTE events. The risk due to cancer is compounded by the effects of chemotherapy and other treatments. The pathogenesis of cancer-associated VTE is complex involving multiple interactions between tumours and various components of haemostasis. The development of a systemic hypercoagulable state is considered a key pathogenetic feature and is attributed to tumour expression of tissue factor and other procoagulants, activation of vascular cells by tumour-derived cytokines and adhesive interactions between tumour cells and host cells. An increasing body of evidence indicates that the activation of haemostasis in malignant disease contributes to tumour growth and progression by stimulation of intracellular signalling pathways. The interaction of tissue factor, thrombin and other coagulation factors with protease activated receptor (PAR) proteins expressed by tumour cells and host vascular cells leads to the induction of genes related to the processes of angiogenesis, cell survival and cell adhesion and migration.     

Prediction and Prevention of Cancer‐Associated Thromboembolism

Venous and arterial thromboembolism are prevalent, highly burdensome, and associated with risk of worse outcomes for patients with cancer. Risk for venous thromboembolism (VTE) varies widely across specific cancer subpopulations. The ability to predict risk of cancer‐associated VTE is critical because an optimal thromboprophylaxis strategy is best achieved by targeting high‐risk patients with cancer and avoiding prophylaxis in patients with cancer at low risk for VTE. A validated risk tool for solid tumors has been available for a decade. Newer tools have focused on specific populations, such as patients with multiple myeloma. Emerging studies continue to optimize risk prediction approaches in patients with cancer. Recent randomized trials have specifically addressed risk‐adapted thromboprophylaxis using direct oral anticoagulants, and revised guidelines have included these new data to formulate recommendations for outpatient thromboprophylaxis. Implementation science approaches to enhance use of outpatient prophylaxis in the context of these guideline changes are under way. However, major knowledge gaps remain, including a lack of data for inpatient thromboprophylaxis in the cancer setting and a lack of formal tools for identifying risk of bleeding. This review describes optimal approaches to risk prediction and patient selection for primary pharmacologic thromboprophylaxis of cancer‐associated VTE, addresses barriers to implementing these practices, and highlights strategies to overcome them.Implications for PracticeRisk for venous thromboembolism (VTE) varies widely among patients with cancer. Individual risk can be determined using validated approaches. Inpatient and postsurgical thromboprophylaxis is more widely accepted. However, most patients with cancer develop VTE in the outpatient setting. Recent randomized trials have demonstrated benefit to risk‐adapted outpatient thromboprophylaxis. High‐risk patients may therefore be considered for outpatient thromboprophylaxis as recommended by recently updated guidelines. System‐wide implementation approaches are necessary to improve compliance with prophylaxis.     

The NCCN Clinical Practice Guidelines on Venous Thromboembolic Disease: strategies for improving VTE prophylaxis in hospitalized cancer patients

The risk for venous thromboembolism (VTE) is high in hospitalized cancer patients, and is associated with an elevated risk for recurrent thrombosis, bleeding complications, and use of health care resources. Thromboembolism is the second leading cause of death in hospitalized cancer patients. Thromboprophylaxis with unfractionated heparin or low-molecular-weight heparins has been clinically proven to reduce the risk for VTE and improve outcomes. However, VTE prophylaxis continues to be underprescribed in cancer patients. Recognizing the clinical burden of VTE in cancer patients, the National Comprehensive Cancer Network (NCCN) recently released guidelines for VTE prevention and management. These NCCN guidelines recommend evidence-based prophylactic anticoagulant therapy for all patients admitted to hospital with a diagnosis of cancer who do not have contraindications to anticoagulant use. However, there continue to be barriers to the implementation of clinical practice guidelines and appropriate use of VTE prophylaxis. Multifaceted active educational and electronic interventions are necessary to raise awareness and reduce the burden of cancer-associated thrombosis and its attendant consequences.     

Impact of Venous Thromboembolism on Mortality of Elderly Medicare Patients with Stage III Colon Cancer

Background. The improvement in survival rates for patients with colon cancer has shifted the focus from examining cancer-specific mortality to exploring all-cause mortality. Adverse events such as venous thromboembolism (VTE) affect overall survival times and the net clinical benefit of cancer management strategies. Methods. This retrospective study used Surveillance, Epidemiology and End Results (SEER) Medicare data to examine VTE incidence and mortality rates for elderly patients with stage III colon cancer who were diagnosed in 2004 or 2005 and followed through 2007. The impact of VTE on mortality was estimated using multivariable Cox proportional hazards regression. Results. In all, 20.7% of 4,985 elderly patients with stage III colon cancer had clinically diagnosed VTE following diagnosis. All-cause mortality risk was higher for patients with a VTE diagnosis (hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.04-1.27), greater comorbidity burden, more advanced tumor depth and nodal involvement within stage III, advanced age, and male sex; the risk was lower for patients treated with chemotherapy. VTE was associated with higher mortality hazards (HR: 1.41, 95% CI: 1.21-1.64) for patients treated with adjuvant chemotherapy but not for untreated patients. Conclusions. A new diagnosis of VTE significantly reduced survival rates for elderly patients with stage III colon cancer and further reduced survival rates for patients treated with chemotherapy. Improved prevention and management of VTE for elderly patients with stage III colon cancer who are at risk for VTE is warranted, particularly for patients treated with chemotherapy.     

The prophylaxis of venous thrombosis in patients with cancer undergoing major abdominal surgery: emerging options

Cancer is a risk factor for venous thromboembolism (VTE). This risk is amplified by treatment with chemotherapy, radiation, or surgery. Thus, patients with cancer undergoing major surgery should receive appropriate prophylaxis. Available agents include low-dose unfractionated heparin (LDUH), low-molecular-weight heparin (LMWH), and Factor Xa inhibitors. Recent data suggest that Factor Xa inhibitors are safe and effective for VTE prevention in patients with cancer undergoing abdominal surgery. Further study in this patient population is warranted.     

宫颈癌患者合并静脉血栓栓塞症的危险因素和治疗

目的:探讨宫颈癌化疗患者合并静脉血栓栓塞症的危险因素与治疗.方法:回顾性分析2010年至2015年我院158例宫颈癌化疗患者,按是否合并静脉血栓栓塞症(VTE)分成VTE组(n=40)与无VTE组(n=118),记录分析两组的性别、年龄、既往史、病例类型、肿瘤分期、血小板计数、血黏稠度、D-二聚体以及治疗措施.结果:VET组Ⅳ期:90.00%,血黏稠度增高:67.50%,D-二聚体增高:70.00%;无VTE组Ⅳ期:70.34%,血黏稠度增高:46.61%,D-二聚体增高:49.15%(均P<0.05).Logistic回归显示:肿瘤分期、D-二聚体水平以及血黏稠度与宫颈癌化疗患者发生静脉血栓高度相关,差异均有统计学意义(均P<0.05).40例宫颈癌化疗合并VTE患者2例并发大出血死亡;其余经溶栓、抗凝治疗后19例治愈,4例好转,总有效率为57.50%.结论:宫颈癌肿瘤分期晚、D-二聚体水平高以及血黏稠度高与宫颈癌化疗患者发生静脉血栓高度相关,为宫颈癌患者并发VTE的高危因素;及时评价宫颈癌化疗患者合并VTE的高危因素,及早抗凝治疗,可预防及减少并发VTE,同时提高治疗效果.     

Chronic lymphocytic leukaemia is a risk factor for venous thromboembolism

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in cancer patients. The literature is sparse on the incidence in the most common lymphoid malignancy, chronic lymphocytic leukaemia (CLL). We calculated the incidence rates for VTE in an unselected UK CLL clinic population at 1.45% per patient year. This represents a tenfold increase over previously published estimates of incidence in the general population and a twofold increase over that of the local hospital inpatient population. In our cohort, the risk of VTE was related to stage C disease. Clinicians should be aware that CLL patients are at risk of VTE.     

Estimated Glomerular Filtration Rate Is an Easy Predictor of Venous Thromboembolism in Cancer Patients Undergoing Platinum‐Based Chemotherapy

Background.

Reduced estimated glomerular filtration rate (eGFR) has been associated with increased venous thromboembolism (VTE) risk in the general population. VTE incidence significantly increases in cancer patients, especially those undergoing chemotherapy. Despite the evidence that a substantial number of cancer patients have unrecognized renal impairment, as indicated by reduced eGFR in the presence of serum creatinine levels within the reference value, chemotherapy dosage is routinely adjusted for serum creatinine values. Among chemotherapies, platinum-based regimens are associated with the highest rates of VTE. A cohort study was designed to assess the value of pretreatment eGFR in the risk prediction of a first VTE episode in cancer outpatients without previous history of VTE who were scheduled for platinum-based chemotherapy.

Methods.

Serum creatinine and eGFR were evaluated before the start of standard platinum-based chemotherapy in a cohort of 322 consecutive patients with primary or relapsing/recurrent solid cancers, representative of a general practice population.

Results.

Patients who experienced a first VTE episode in the course of chemotherapy had lower mean eGFR values compared with patients who remained VTE free. Multivariate Cox analysis demonstrated that eGFR had an independent value for risk prediction of a first VTE episode during treatment, with a 3.15 hazard ratio. Indeed, 14% of patients with reduced eGFR had VTE over 1-year follow-up compared with 6% of patients with normal eGFR values.

Conclusion.

The results suggest that reductions in eGFR, even in the presence of normal serum creatinine, are associated with an increased VTE risk in cancer outpatients undergoing platinum-based chemotherapy regimens. Determining eGFR before chemotherapy could represent a simple predictor of VTE, at no additional cost to health care systems.     

Cancer and thrombosis: managing the risks and approaches to thromboprophylaxis

Patients with cancer are at increased risk of venous thromboembolism (VTE) compared with patients without cancer. This results from both the prothrombotic effects of the cancer itself and iatrogenic factors, such as chemotherapy, radiotherapy, indwelling central venous devices and surgery, that further increase the risk of VTE. Although cancer-associated thrombosis remains an important cause of morbidity and mortality, it is often underdiagnosed and undertreated. However, evidence is accumulating to support the use of low-molecular-weight heparins (LMWHs) in the secondary prevention of VTE in patients with cancer. Not only have LMWHs been shown to be at least as effective as coumarin derivatives in this setting, but they have a lower incidence of complications, including bleeding, and are not associated with the practical problems of warfarin therapy. Furthermore, a growing number of studies indicate that LMWHs may improve survival among patients with cancer due to a possible antitumor effect. Current evidence suggests that LMWHs should increasingly be considered for the longterm management of VTE in patients with cancer.     

Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer

Venous thromboembolism (VTE) following breast cancer chemotherapy is common. Chemotherapy-induced alterations in markers of haemostasis occur during chemotherapy. It is unclear how rapidly this occurs, whether this is upregulated in patients developing VTE and whether changes predict for VTE. Markers of haemostasis, functional clotting assays and vascular endothelial growth factor were measured before chemotherapy and at 24 h, 4 days, 8 days and 3 months following commencement of chemotherapy in early and advanced breast cancer patients and in age- and sex-matched controls. Duplex ultrasound imaging was performed after 1 month or if symptomatic. Of 123 patients, 9.8% developed VTE within 3 months. Activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, fibrinogen, platelet count, VEGF and fibrinogen were increased in cancer. Fibrinogen, D-dimer, VEGF and tissue factor were increased, at baseline, in patients subsequently developing VTE. D-dimer of less than 500 ng ml(-1) has a negative predictive value of 97%. Activated partial thromboplastin time, PT and thrombin-antithrombin showed significantly different trends, as early as within 24 h, in response to chemotherapy in patients subsequently developing VTE. Markers of coagulation and procoagulants are increased, before chemotherapy, in patients who subsequently develop VTE. A group of patients at minimal risk of VTE can be identified, allowing targeted thrombopropylaxis to the higher risk group.     

Venous thromboembolism in oesophago-gastric carcinoma: incidence of symptomatic and asymptomatic events following chemotherapy and surgery

Venous thromboembolism (VTE) is a frequent cause of morbidity and mortality in patients with cancer and those having chemotherapy. However, the incidence of VTE during radical treatment for patients with oesophago-gastric cancer is poorly documented. The incidence of VTE was assessed in 200 consecutive patients with oesophago-gastric cancer having surgery with curative intent; 132 (66%) had neo-adjuvant chemotherapy, 37 (18.5%) had adjuvant chemotherapy and 64 (32%) had no chemotherapy. Patients received 40?mg of Enoxaparin subcutaneously daily during the peri-operative hospital stay. Asymptomatic VTE were detected by routine chest computed tomography (CT) pre and post surgery. Symptomatic patients with suspected VTE were investigated and treated as clinically appropriate. Twenty six patients (13%) developed VTE of which 14 (54%) were symptomatic; 12/26 (46%) VTE were detected pre-operatively, all during or after neo-adjuvant chemotherapy, and 14/26 (54%) post-operatively. There were two post-operative deaths caused by pulmonary emboli occurring at days 24 and 56 respectively despite peri-operative VTE prophylaxis. Multivariate analysis demonstrated that neo-adjuvant chemotherapy was the only factor that predicted pre-operative VTE (p?=?0.073) and any VTE (p?=?0.045). This study found a 13% incidence of VTE in patients undergoing therapy with curative intent for oesophago-gastric cancer and a statistically significant association between neo-adjuvant chemotherapy and VTE. Half of the patients with VTE were asymptomatic but two had fatal PE's. Current VTE prophylaxis regimens for this patient group may be inadequate.     

Risk of venous thromboembolism in people with lung cancer: a cohort study using linked UK healthcare data

Background:

Venous thromboembolism (VTE) is a potentially preventable cause of death in people with lung cancer. Identification of those most at risk and high-risk periods may provide the opportunity for better targeted intervention.

Methods:

We conducted a cohort study using the Clinical Practice Research Datalink linked to Hospital Episode Statistics and Cancer Registry data. Our cohort comprises 10 598 people with lung cancer diagnosed between 1997 and 2006 with follow-up continuing to the end of 2010. Cox regression analysis was performed to determine which demographic, tumour and treatment-related factors (time-varying effects of chemotherapy and surgery) independently affected VTE risk. We also determined the effect of a VTE diagnosis on the survival of people with lung cancer.

Results:

People with lung cancer had an overall VTE incidence of 39.2 per 1000 person-years (95% confidence interval (CI), 35.4–43.5), though rates varied depending on the patient group and treatment course. Independent factors associated with increased VTE risk were metastatic disease (hazard ratio (HR)=1.9, CI 1.2–3.0 vs local disease); adenocarcinoma subtype (HR=2.0, CI 1.5–2.7, vs squamous cell; chemotherapy administration (HR=2.1, CI 1.4–3.0 vs outside chemotherapy courses); and diagnosis via emergency hospital admission (HR=1.7, CI 1.2–2.3 vs other routes to diagnosis). Patients with VTE had an approximately 50% higher risk of mortality than those without VTE.

Conclusions:

People with lung cancer have especially high risk of VTE if they have advanced disease, adenocarcinoma or are undergoing chemotherapy. The presence of VTE is an independent risk factor for death.     

Cancer et récidive thromboembolique veineuse : non-respect des recommandations de traitement

Low-molecular-weight heparins (LMWH) are the reference curative treatment of venous thromboembolism (VTE) in patients with cancer. All international guidelines recommend the long-term use of LMWH given their demonstrated superiority compared to vitamin-K antagonists (VKA) in reducing VTE recurrence in this patient population without increased risk of bleeding. However, several studies consistently show a lack of adherence to treatment recommendations, which are applied at the very best in 50% of cases. This results in a loss of chance for patients with fragile prognosis and in whom VTE represents the second cause of death. Given the expected benefit and the increased VTE prevalence in patients with cancer, full awareness is necessary to implement programs aiming at improving the therapeutic management of cancer-associated VTE. This requires multidisciplinary consideration by qualified physicians involved in the management of patients with cancer-associated VTE such as oncologists, internists and those specialized in vascular disease and hemostasis.     

Idiopathic and recurrent thromboembolic phenomena in cancer patients

Background  Venous thromboembolism (VTE) is one of the most common complications in cancer patients. It is not only associated with both reduced survival and a high number of recurrences, but an idiopathic VTE also increases the likelihood of a cancer diagnosis. Methods  Between January 2000 and October 2005 we reviewed the medical history of 88 patients who were admitted to a tertiary hospital and presented both a diagnosis of VTE and any type of tumour. The information collected included the type of tumour, the temporal association between tumour diagnosis and VTE, anticoagulation treatment applied and percentage of recurrences. Results  Ten patients (11.4%) presented the VTE prior to the cancer diagnosis; only half of them underwent a posterior tumour screening routine. Fifteen patients (17%) were diagnosed simultaneously and 71% presented the VTE after the tumour was detected. In 47 patients (53.4%) no risk factors for VTEs were detected. Twenty-nine patients (31.7%) presented a recurrent VTE, mainly during chemotherapy treatment (66%). Less than half of the patients (47.57%) were receiving treatment with low-molecular-weight heparins (LMWH). Conclusions  Idiopathic VTEs may be the first manifestation of an occult neoplasia, but tumour screening is scheduled in only a few patients. Regarding the high incidence of recurrent VTE in cancer populations, a high percentage is attributed to the underuse of LMWH, whose efficacy in preventing recurrent phenomena is superior to oral dicumarinics.