Treatment of venous thromboembolism in patients with cancer: Subgroup analysis of the Matisse clinical trials

SummaryIn the initial treatment of venous thromboembolism (VTE) fondaparinux, a pentasaccharide, is a good alternative to heparin. Whether this is also true for cancer patients is unknown. We performed two post-hoc analyses of two randomized studies to compare efficacy, safety and overall survival of fondaparinux to standard initial (low-molecular-weight) heparin (LMWH) treatment in cancer patients with venous thromboembolism. Two hundred thirty-seven cancer patients with deep venous thrombosis (DVT) were initially treated with fondaparinux or enoxaparin. Two hundred forty cancer patients with pulmonary embolism (PE) received fondaparinux or unfractionated heparin. The initial treatment was followed by vitamin K antagonists. In DVT patients, the three-month recurrence rate was 5.4% in the enoxaparin recipients compared to 12.7% in those treated with fondaparinux [absolute difference 7.3%, 95% CI 0.1, 14.5]. A recurrence was observed in 8.9% of the PE patients treated with fondaparinux compared to 17.2% in the unfractionated heparin recipients [absolute difference –8.3, 95% CI –16.7, 0.1]. In both studies no difference in bleeding and overall survival was observed. Regarding overall survival and bleeding fondaparinux is comparable to enoxaparin and unfractionated heparin in cancer patients. No significant differences in recurrent VTE were observed when comparing fondaparinux with unfractionated or LMWH. Because of study limitations these results should be considered hypothesis-generating.

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The Current Status of Direct Oral Anticoagulants in Cancer-Related Venous Thromboembolism Treatment

Rational Pharmacotherapy in Cardiology ◽

10.20996/1819-6446-2020-04-10 ◽

2020 ◽

Vol 16 (2) ◽

pp. 286-295

Author(s):

К. V. Lobastov ◽

I. V. Schastlivtsev

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Similar Efficacy ◽

Current Status ◽

Patients With Cancer ◽

Increased Risk ◽

Discontinuation Of Treatment

This article is a review of epidemiology, pathogenesis and treatment of venous thromboembolism (VTE) in cancer patients. In accordance with actual guidelines, the duration of anticoagulant therapy of cancer-related venous thrombosis should be at least 6 months. The use of vitamin K antagonists (VKA) is associated with an increased risk of VTE recurrence and bleeding, so low molecular weight heparin (LMWH), in particular dalteparin, has been the "gold standard" until recently. Compared to VKA, prolonged use of LMWH can reduce the incidence of VTE recurrence without affecting the risk of bleeding or death. The main disadvantage of LMWH is low compliance, leading to premature discontinuation of treatment or switching to alternative anticoagulants. Direct oral anticoagulants (DOACs) have changed the situation. Compared to VKA, they demonstrated higher efficacy with a similar (or improved for individual DOACs) safety in patients with cancer-related VTE. Recently, the results of studies comparing the use of DOACs with dalteparin in cancer patients have been published: SELECT-D (rivaroxaban), HOKUSAI-VTE Cancer (edoxaban), ADAM VTE (apixaban), CARAVAGGIO (apixaban). Rivaroxaban showed higher efficacy than dalteparin with a similar risk of major bleeding, but an increased risk of clinically relevant non-major (CRNM) bleeding. Edoxaban had the same efficacy as dalteparin but increased risk of major but not CRNM bleeding. Apixaban showed similar efficacy and safety as dalteparin in the CARAVAGGIO study, but did not provide higher safety in the ADAM VTE study. It was noted that gastrointestinal and urogenital bleeding dominated in the structure of hemorrhagic complications of DOACs. The results of published trials are reflected in the current guidelines of the specialized societies. DOACs (particularly, rivaroxaban and edoxaban) are recommended for the VTE treatment in cancer patients.

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Treatment and secondary prevention of venous thromboembolism in cancer patients

Onkologische Welt ◽

10.1055/s-0038-1630173 ◽

2012 ◽

Vol 03 (03) ◽

pp. 121-125

Author(s):

I. Pabinger ◽

C. Ay

Keyword(s):

Clinical Trials ◽

Venous Thromboembolism ◽

Cancer Patients ◽

Oral Anticoagulants ◽

Factor Xa ◽

New Oral Anticoagulants ◽

Phase Iii ◽

Patients With Cancer ◽

Potential Use

SummaryCancer is a major and independent risk factor of venous thromboembolism (VTE). In clinical practice, a high number of VTE events occurs in patients with cancer, and treatment of cancerassociated VTE differs in several aspects from treatment of VTE in the general population. However, treatment in cancer patients remains a major challenge, as the risk of recurrence of VTE as well as the risk of major bleeding during anticoagulation is substantially higher in patients with cancer than in those without cancer. In several clinical trials, different anticoagulants and regimens have been investigated for treatment of acute VTE and secondary prophylaxis in cancer patients to prevent recurrence. Based on the results of these trials, anticoagulant therapy with low-molecular-weight heparins (LMWH) has become the treatment of choice in cancer patients with acute VTE in the initial period and for extended and long-term anticoagulation for 3-6 months. New oral anticoagulants directly inhibiting thrombin or factor Xa, have been developed in the past decade and studied in large phase III clinical trials. Results from currently completed trials are promising and indicate their potential use for treatment of VTE. However, the role of the new oral thrombin and factor Xa inhibitors for VTE treatment in cancer patients still has to be clarified in further studies specifically focusing on cancer-associated VTE. This brief review will summarize the current strategies of initial and long-term VTE treatment in patients with cancer and discuss the potential use of the new oral anticoagulants.

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Diagnosis and Initial Treatment of Venous Thromboembolism in Patients With Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.23.5788 ◽

2009 ◽

Vol 27 (29) ◽

pp. 4889-4894 ◽

Cited By ~ 39

Author(s):

Michael B. Streiff

Keyword(s):

Venous Thromboembolism ◽

Initial Treatment ◽

Vena Cava ◽

Initial Therapy ◽

Primary Objective ◽

Thrombotic Disease ◽

Venous Stenting ◽

Patients With Cancer ◽

Vena Cava Filters ◽

Increased Risk

Purpose Venous thromboembolism (VTE) is a common complication of cancer and its therapy. The purpose of this article is to review the diagnosis and initial treatment of VTE in the patient with cancer. Methods I conducted a survey of the English-language literature on topics relevant to the diagnosis and initial treatment of VTE in patients with cancer. Results Patients with cancer are at increased risk for VTE because of the presence of multiple risk factors for thrombotic disease. The most common signs and symptoms of VTE as well as the utility of clinical prediction rules and D-dimer testing in the diagnosis of VTE in the patient with cancer are reviewed. Duplex ultrasound and computer tomography angiography are the primary objective diagnostic modalities for VTE. Low molecular weight heparin is the preferred initial therapy for VTE. Until further data emerge, thrombolysis and vena cava filters should be reserved for patients in whom anticoagulation is insufficient or contraindicated. Outpatient management is feasible for carefully selected patients with cancer with deep vein thrombosis (DVT) and low-risk pulmonary embolism. Anticoagulation is the preferred initial therapy for cancer patients with central venous catheter–associated DVT, calf DVT, and unsuspected VTE. Conclusion Optimal initial management of VTE in patients with cancer entails maintaining a high index of suspicion for thrombotic disease, confirming diagnostic suspicions with objective testing and evidence-based use of anticoagulation, and adjunctive therapeutic modalities (thrombolysis, vena cava interruption, venous stenting). Further investigation of initial diagnostic and treatment strategies for VTE focusing on patients with cancer are warranted.

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Prevention and treatment of venous thromboembolism in patients with cancer

Hematology ◽

10.1182/asheducation-2014.1.312 ◽

2014 ◽

Vol 2014 (1) ◽

pp. 312-317 ◽

Cited By ~ 4

Author(s):

Agnes Y.Y. Lee

Keyword(s):

Venous Thromboembolism ◽

Vitamin K ◽

Vitamin K Antagonists ◽

Hospital Setting ◽

Chemotherapeutic Agents ◽

Ambulatory Setting ◽

Individual Risk ◽

Patients With Cancer ◽

Gastrointestinal Problems ◽

Prevention And Treatment

Abstract Robust evidence remains scarce in guiding best practice in the prevention and treatment of venous thromboembolism in patients living with cancer. Recommendations from major consensus guidelines are largely based on extrapolated data from trials performed mostly in noncancer patients, observational studies and registries, studies using surrogate outcomes, and underpowered randomized controlled trials. Nonetheless, a personalized approach based on individual risk assessment is uniformly recommended for inpatient and outpatient thromboprophylaxis and there is consensus that anticoagulant prophylaxis is warranted in selected patients with a high risk of thrombosis. Prediction tools for estimating the risk of thrombosis in the hospital setting have not been validated, but the use of prophylaxis in the ambulatory setting in those with a high Khorana score is under active investigation. Symptomatic and incidental thrombosis should be treated with anticoagulant therapy, but little is known about the optimal duration. Pharmacologic options for prophylaxis and treatment are still restricted to unfractionated heparin, low molecular weight heparin, and vitamin K antagonists because there is currently insufficient evidence to support the use of target-specific, non-vitamin K-antagonist oral anticoagulants. Although these agents offer practical advantages over traditional anticoagulants, potential drug interaction with chemotherapeutic agents, gastrointestinal problems, hepatic and renal impairment, and the lack of rapid reversal agents are important limitations that may reduce the efficacy and safety of these drugs in patients with active cancer. Clinicians and patients are encouraged to participate in clinical trials to advance the care of patients with cancer-associated thrombosis.

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

Oncology Reviews ◽

10.4081/oncol.2011.34 ◽

2011 ◽

pp. 191-204

Author(s):

Alpesh N. Amin ◽

Steven B. Deitelzweig

Keyword(s):

At Risk ◽

Venous Thromboembolism ◽

Cancer Patients ◽

Assessment Model ◽

Major Surgery ◽

Medical Illness ◽

Patients With Cancer ◽

Increased Risk ◽

National Quality ◽

American Society

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.

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Success of Online CME at Improving Knowledge and Confidence Around Guideline-Directed Management of Cancer-Associated Thrombosis

Blood ◽

10.1182/blood-2020-137153 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-13

Author(s):

Caroline Padbury ◽

Margaret Harris ◽

Michael LaCouture ◽

Jelena Spyropoulos

Keyword(s):

Clinical Practice ◽

Venous Thromboembolism ◽

Cancer Patients ◽

Treatment Guidelines ◽

Conflicts Of Interest ◽

Oral Anticoagulants ◽

Roundtable Discussion ◽

Patients With Cancer ◽

Cancer Associated Thrombosis ◽

Post Assessment

Title:Success of Online CME at Improving Knowledge and Confidence Around Guideline-Directed Management of Cancer-Associated Thrombosis Study Objectives:Recent guidance statements recommend the use of direct oral anticoagulants (DOACs) as primary thromboprophylaxis in ambulatory patients with cancer who are starting chemotherapy and in patients with cancer and acute venous thromboembolism at low risk of bleeding and no drug-drug interactions.[Farge 2019; Key 2020] Yet, many clinicians lack knowledge and confidence with integrating DOACs into management strategies for patients with cancer in accordance to guideline recommendations.[Cushman 2015; Khorana 2016] We sought to determine if online continuing medical education (CME) could improve the knowledge and confidence of hematologists/oncologists regarding guideline-directed use of DOACs in the management of cancer-associated thrombosis. Methods:This CME intervention comprised of a 30-minute online video-based roundtable discussion among experts in the field of cancer-associated thrombosis management. Responses to 3 multiple-choice, knowledge questions and 1 self-efficacy, 5-point Likert scale confidence question were analyzed using a repeated pairs pre-/post-assessment study design. A chi-square test (P <.05 is considered significant) assessed pre- to post-activity change . The activity launched December 23, 2019, and data were collected through February 24, 2020. Results:In total, 71 Hematologists/Oncologists were included in this study. Overall, there were knowledge and confidence improvements seen among all groups from pre- to post-assessment: 27% of hematologists/oncologists (P<.01) improved at identifying guideline-directed therapy regarding recommended thromboprophylaxis in patients with cancer per guideline recommendations.27% of hematologists/oncologists (P<.01) improved at selecting guideline-appropriate treatment options for cancer-associated thrombosis.44% of hematologists/oncologists had an increase in confidence in managing thrombosis in patients with cancer. Continued educational gaps: 25% of hematologists/oncologists failed to select guideline recommended DOAC therapy for thromboprophylaxis in cancer patients.45% of hematologists/oncologists failed to select guideline recommended DOAC therapy for treatment of thrombosis in cancer patients.66% of hematologists/oncologists still remain at only a rating of 1 to 3 on a scale of 1 to 5 in their confidence managing thrombosis in patients with cancer. Conclusion:This study demonstrates the success of online, CME-accredited, video-based roundtable discussion with experts in the field on significantly improving knowledge and confidence of hematologists/oncologists related to the guideline-recommended use of DOACs in the management of cancer-associated thrombosis. Continued gaps were also identified for future educational targets. Sources of support: Developed through an independent educational grant from Janssen in partnership with the University of Chicago. References: Cushman M, Creager MA. Improving awareness and outcomes related to venous thromboembolism. JAMA. 2015;314(18):1913-4. Farge D, Frere C, Connors JM, et al. 2019 International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. The Lancet Oncology. 2019;20(10):e566-581. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2020 Feb 10;38(5):496-520. Khorana AA, Yannicelli D, McCrae KR, et al. Evaluation of US prescription patterns: are treatment guidelines for cancer-associated venous thromboembolism being followed? Thromb Res. 2016 Sep;145:51-3. Disclosures No relevant conflicts of interest to declare.

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

Oncology Reviews ◽

10.4081/oncol.2011.191 ◽

2011 ◽

Vol 5 (3) ◽

pp. 191

Author(s):

Alpesh N. Amin ◽

Steven B. Deitelzweig

Keyword(s):

At Risk ◽

Venous Thromboembolism ◽

Cancer Patients ◽

Assessment Model ◽

Major Surgery ◽

Medical Illness ◽

Patients With Cancer ◽

Increased Risk ◽

National Quality ◽

American Society

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Preventing Venous Thromboembolism in Ambulatory Patients with Cancer: A Narrative Review

Cancers ◽

10.3390/cancers12030612 ◽

2020 ◽

Vol 12 (3) ◽

pp. 612 ◽

Cited By ~ 1

Author(s):

Anne Rossel ◽

Helia Robert-Ebadi ◽

Christophe Marti

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Absolute Risk ◽

Narrative Review ◽

Relative Reduction ◽

Number Needed To Treat ◽

Chemotherapeutic Regimen ◽

Patients With Cancer ◽

Increased Risk ◽

Risk Of Cancer

Venous thromboembolism (VTE) is frequent among patients with cancer. Ambulatory cancer patients starting chemotherapy have a 5% to 10% risk of cancer associated thrombosis (CAT) within the first year after cancer diagnosis. This risk may vary according to patient characteristics, cancer location, cancer stage, or the type of chemotherapeutic regimen. Landmark studies evaluating thrombophrophylaxis with low molecular weight heparin (LMWH) for ambulatory cancer patients have shown a relative reduction in the rate of symptomatic VTE of about one half. However, the absolute risk reduction is modest among unselected patients given a rather low risk of events resulting in a number needed to treat (NNT) of 40 to 50. Moreover, this modest benefit is mitigated by a trend towards an increased risk of bleeding, and the economic and patient burden due to daily injections of LMWH. For these reasons, routine thromboprophylaxis is not recommended by expert societies. Advances in VTE risk stratification among cancer patients, and growing evidence regarding efficacy and safety of direct oral anticoagulants (DOACs) for the treatment and prevention of CAT have led to reconsider the paradigms of this risk–benefit assessment. This narrative review aims to summarize the recent evidence provided by randomized trials comparing DOACs to placebo in ambulatory cancer patients and its impact on expert recommendations and clinical practice.

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First-Line Therapies for VTE Treatment and Secondary Prophylaxis in Patients With Cancer: A New Direction

Journal of Pharmacy Practice ◽

10.1177/0897190018775580 ◽

2018 ◽

Vol 33 (3) ◽

pp. 356-363

Author(s):

Samantha M. Vogel ◽

Leticia V. Smith ◽

Evan J. Peterson

Keyword(s):

Venous Thromboembolism ◽

English Language ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Secondary Prophylaxis ◽

Careful Consideration ◽

Patients With Cancer ◽

Study Selection ◽

Meta Analyses

Objective: To review evidence behind anticoagulants in cancer-associated venous thromboembolism (VTE) with a focus on low-molecular-weight heparins (LMWH) and the role of direct oral anticoagulants (DOACs). Data Sources: PubMed was searched using terms “venous thromboembolism,” “cancer,” and “anticoagulation.” This search was restricted to clinical trials, meta-analyses, and subgroup analyses. Additional references were identified from reviewing literature citations. Study Selection: English-language prospective and retrospective studies assessing the efficacy and safety of LMWH and DOACs in patients with cancer. Data Analysis: Several trials were analyzed that compared anticoagulation therapies for prevention of recurrent VTE in patients with cancer. Many studies comparing LMWH and vitamin K antagonists (VKAs) found nonsignificant differences between therapies. A single study demonstrated that LMWHs are superior to VKAs. This evidence supporting LMWH for long-term VTE treatment in patients with cancer is based on comparison to VKA, but results are limited by methodological issues, and the benefit of LMWH may be driven by poor control. Subanalyses of DOAC trials suggest these are equally or more effective as VKA in cancer, but this conclusion is underpowered. Conclusion: DOACs have the potential to bypass many challenges with traditional therapy. After analyzing the evidence available, we conclude that after careful consideration of risks and benefits, use of DOACs for VTE treatment are a reasonable option in patients with cancer.

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