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VTE-CAT: Reducing the burden of injections

VTE in patients with cancer – treatment guidance – evidence from RCTs

 

Learn about the use of NOACs in the treatment of CAT

 

Understanding the risk of VTE in patients with cancer

Venous thromboembolism (VTE) is a leading cause of mortality and morbidity in patients with cancer.1 The risk of VTE is ~4–7-times higher in patients with cancer compared with those without, and the risk varies by cancer type.1 Approximately 20% of all VTE cases are attributable to cancer;2 such cases are otherwise known as cancer-associated thrombosis (CAT).

TA VTE CAT diagrams

Risk of VTE in patients with cancer compared with those without1

Anticoagulant therapy is the mainstay of VTE treatment,3 but can be challenging in patients with cancer because they have a higher risk of VTE recurrence and bleeding than patients without cancer.4,5 In addition, some side effects of cancer treatments, such as thrombocytopenia and gastric disturbances, and the need for frequent interventions, further complicate the use of anticoagulants in these patients.6,7

 

How is VTE managed currently in patients with cancer?

For the treatment of acute VTE in patients with cancer, guidelines recommend the use of low molecular weight heparins (LMWHs) over vitamin K antagonists (VKAs) based on the better efficacy of LMWHs over VKAs, as demonstrated in several randomized controlled trials (RCTs) in patients with CAT.3,8-11

 

Despite the evolution from VKAs to LMWHs as the standard of care, anticoagulation treatment for CAT still has limitations. The residual risk of recurrent VTE remains high for patients receiving LMWHs, with a reported incidence of approximately 7–9%.8,12 In addition, treatment with LMWHs has been associated with various challenges, including the burden of daily injections and high treatment costs,3,13 which are especially important in patients who require long-term treatment. These factors are likely to contribute to the low persistence with long-term LMWH therapy observed in real-world evidence studies.14,15

 

Non-vitamin K antagonist oral anticoagulants (NOACs), such as rivaroxaban, edoxaban, dabigatran and apixaban, may be able to overcome some of the challenges associated with VKAs and LMWHs.7

TA VTE CAT diagrams

Key challenges associated with VKAs and LMWHs and advantages associated with NOACs7,13

Evidence from RCTs for NOACs in the treatment of CAT

The phase III Hokusai-VTE-Cancer study and the select-d pilot study provide the first randomized comparisons of NOACs versus LMWH in patients with CAT.16,17

 

In the Hokusai-VTE-Cancer study, treatment with edoxaban (60 mg once daily [od]) for up to 12 months was found to be non-inferior to dalteparin for the composite primary outcome of recurrent VTE or major bleeding in patients with CAT.16 Although the rate of recurrent VTE was reduced, the rate of major bleeding was significantly increased with edoxaban versus dalteparin.16 The results of the select-d study demonstrated that rivaroxaban (15 mg twice daily [bid] for 3 weeks followed by 20 mg od) was associated with a lower cumulative rate of VTE recurrence at 6 months than dalteparin in patients with CAT.17 However, the cumulative rate of major and clinically relevant non-major bleeding at 6 months was increased with rivaroxaban versus dalteparin.17 The majority of bleeding events in these studies occurred in the upper gastrointestinal tract of patients with gastrointestinal cancer.16,17

TA VTE CAT diagrams

Key outcomes of (A) the Hokusai-VTE-Cancer study and (B) the select-d study16,17

Based on these data, NOACs may be an effective alternative to LMWH for the treatment of VTE in patients with cancer.16,17 However, the increased bleeding risk, particularly in certain subsets of patients with cancer, suggests that patients who might benefit from this regimen need to be selected carefully.16,17

 

Summary

Patients with cancer are at an increased risk of experiencing VTE compared with those without cancer. Current guidelines recommend the use of LMWH over VKAs for the treatment of CAT. However, daily injections and the costs of LMWH therapy hinder long-term use, which is needed for the prevention of recurrent thrombotic events. NOACs circumvent some of the challenges associated with VKAs and LMWHs. Evidence from recent RCTs suggest that NOACs, such as edoxaban and rivaroxaban, are an effective alternative to LMWHs in the prevention of recurrent VTE in patients with CAT.

 

Real-world evidence for NOACs in the treatment of CAT

Real-world evidence has shown that NOACs are being widely used in patients with cancer in clinical practice, starting from before this was supported by evidence from RCTs.5 There are several studies reporting the use of rivaroxaban for the treatment of CAT in clinical practice,18-20 but real-world data for apixaban, dabigatran and edoxaban are lacking. Studies, such as the US prospective cohort study conducted by the Memorial Sloan Kettering Cancer Center or the subgroup analysis of the non-interventional XALIA study, provide some reassurance for the use of rivaroxaban in the treatment of CAT in a clinical setting.18,19

TA VTE CAT diagrams

Overview of key real-world evidence studies on rivaroxaban for the treatment of CAT18-20

Advances in clinical guidance for the treatment of CAT

New guidance that has been published since the release of the data from the Hokusai-VTE-Cancer and select-d studies now include recommendations on the use of NOACs for the treatment of acute VTE.21,22

TA VTE CAT diagrams

Overview of recommendations on the management of anticoagulation for the acute treatment of CAT published after the publication of results from Hokusai-VTE Cancer and select-d21,22

References
  • Fuentes HE, Tafur AJ, Caprini JA. Cancer-associated thrombosis. Dis Mon 2016;62:121-158. Return to content
  • Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011;117:1334–1349. Return to content
  • Kearon C, Akl EA, Ornelas J et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315–352. Return to content
  • Prandoni P, et al. Blood. 2002;100:3484–3488. Prandoni P, et al. Blood. 2002;100:3484–3488. Return to content
  • Ay C, Beyer-Westendorf J, Pabinger I. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Annals of Oncology. 2019. Return to content
  • Prandoni P. The treatment of venous thromboembolism in patients with cancer. Advances in experimental medicine and biology. 2017;906:123–135. Return to content
  • Riess H, Prandoni P, Harder S, Kreher S, Bauersachs R. Direct oral anticoagulants for the treatment of venous thromboembolism in cancer patients: potential for drug-drug interactions. Critical reviews in oncology/hematology. 2018;132:169–179. Return to content
  • Lee A.Y., Levine M.N., Baker R.I. et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-153. Return to content
  • Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost. 2006;12(4):389–396. Return to content
  • Hull RD, Pineo GF, Brant RF, et al. Self-managed long-term low-molecular-weight heparin therapy: the balance of benefits and harms. Am J Med. 2007;120(1):72–82. Return to content
  • Farge D, Bounameaux H, Brenner B et al. International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2016;17:e452-e466. Return to content
  • Lee AY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015;314(7):677–686. Return to content
  • Wharin C, Tagalakis V. Management of venous thromboembolism in cancer patients and the role of the new oral anticoagulants. Blood Rev. 2014 Jan;28(1):1-8. Return to content
  • 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;145:51–53. Return to content
  • Khorana A, McCrae K, Milentijevic D, et al. Anticoagulant treatment patterns for cancer-associated thrombosis in a commercial insurance population. Circulation. 2017;136(Suppl 1). Return to content
  • Raskob G.E., van Es N., Verhamme P. et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615–24. Return to content
  • Young AM, et al. J Clin Oncol. 2018;36:2017–2023. Young AM, et al. J Clin Oncol. 2018;36:2017–2023. Return to content
  • Soff GA, Sarasohn DMM, Haegler-Laube ES, et al. Safe and effective use of rivaroxaban for treatment of cancer associated venous thromboembolic disease. 2018. Return to content
  • Ageno W, et al. TH Open. 2017;1:e33–e42. Ageno W, et al. TH Open. 2017;1:e33–e42. Return to content
  • Kohn CG, Lyman GH, Beyer-Westendorf J, et al. Effectiveness and safety of rivaroxaban in patients with cancer-associated venous thrombosis. J Natl Compr Canc Netw. 2018;16(5):491–497. Return to content
  • Khorana AA, et al. J Thromb Haemost. 2018;16:1891–1894. Khorana AA, et al. J Thromb Haemost. 2018;16:1891–1894. Return to content
  • National Comprehensive Cancer Network. Cancer-associated venous thromboembolic disease, version 1.2019. 2019. https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. National Comprehensive Cancer Network. Cancer-associated venous thromboembolic disease, version 1.2019. 2019. https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Return to content

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