Spotlight on advances in VTE management: CALLISTO and EINSTEIN CHOICE

Miriam Bach; Rupert Bauersachs

doi:10.1160/TH16-06-0486

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(S 02): S24-S32
DOI: 10.1160/TH16-06-0486

Thrombosis and Haemostasis Supplement

Schattauer GmbH

Spotlight on advances in VTE management: CALLISTO and EINSTEIN CHOICE

Authors

Miriam Bach

¹Bayer Pharma AG, Berlin, Germany
Rupert Bauersachs

²Klinikum Darmstadt GmbH, Department of Vascular Medicine, Darmstadt, Germany

Abstract

Summary

Venous thromboembolism (VTE) is associated with numerous complications and high mortality rates. Patients with cancer are at high risk of developing cancer-associated thrombosis (CAT), and VTE recurrence is common. Evidence supporting use of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in patients with cancer is lacking – direct comparisons between NOACs and low-molecular-weight heparin (LMWH) are needed, along with patient-reported outcomes. Cancer Associated thrombosis – expLoring soLutions for patients through Treatment and Prevention with RivarOxaban (CALLISTO) is an international research programme exploring the potential of the direct, oral factor Xa inhibitor rivaroxaban for the prevention and treatment of CAT, supplementing existing data from EINSTEIN DVT and EINSTEIN PE. Here, we focus on four CALLISTO studies: A Study to Evaluate the Efficacy and Safety of Rivaroxaban Venous Thromboembolism Prophylaxis in Ambulatory Cancer Participants receiving Chemotherapy (CASSINI), Antico-agulation Therapy in SELECTeD Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D), Rivaroxaban in the Treatment of Venous Thromboembolism in Cancer Patients – a Randomized Phase III Study (CONKO-011) and a database analysis. Optimal anticoagulation duration for VTE treatment has always been unclear. Following favourable results for rivaroxaban 20 mg once-daily (Q. D.) for secondary VTE prevention (EINSTEIN EXT), EINSTEIN CHOICE is assessing rivaroxaban safety and (20 mg Q. D. or 10 mg Q. D.) vs acetylsalicylic acid (ASA), and will investigate whether an alternative rivaroxaban dose (10 mg Q. D.) could offer long-term VTE protection. It is anticipated that results from these studies will provide important answers and expand upon current evidence for rivaroxaban in VTE management.

Keywords

Cancer-associated thrombosis - venous thromboembolism - thromboprophylaxis - rivaroxaban

Full Text

References

References
1 Bayer AGPharma. Xarelto Summary of Product Characteristics. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/docu ment_library/EPAR_-_Product_Information/human/ 000944/WC500057108.pdf Accessed May 18, 2016.
2 Boehringer Ingelheim. Pradaxa Summary of Product Characteristics. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/docu ment_library/EPAR_-_Product_Information/human/ 000829/WC500041059.pdf Accessed May 18, 2016.
3 Bristol-Myers Squibb. Eliquis Summary of Product Characteristics. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/docu ment_library/EPAR_-_Product_Information/human/ 002148/WC500107728.pdf Accessed May 18, 2016.
4 Daiichi Sankyo. Lixiana Summary of Product Characteristics. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/docu ment_library/EPAR_-_Product_Information/human/ 002629/WC500189045.pdf Accessed May 18, 2016.
5 Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011; 117: 1334-1349.
6 Chew HK, Wun T, Harvey D. et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166: 458-464.
7 Sallah S, Wan JY, Nguyen NP. Venous thrombosis in patients with solid tumors: determination of frequency and characteristics. Thromb Haemost 2002; 87: 575-579.
8 Stein PD, Beemath A, Meyers FA. et al. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006; 119: 60-68.
9 Eichinger S. Cancer associated thrombosis: risk factors and outcomes. Thromb Res 2016; 140 (Suppl. 01) S12-S17.
10 Blom JW, Vanderschoot JP, Oostindier MJ. et al. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb Haemost 2006; 04: 529-535.
11 Lyman GH, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31: 2189-2204.
12 Mandala M, Falanga A, Roila F. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22 (Suppl. 06) vi85-vi92.
13 Watson HG, Keeling DM, Laffan M. et al. Guideline on aspects of cancer-related venous thrombosis. Br J Haematol 2015; 170: 640-648.
14 DiNisio M, Porreca E, Otten HM. et al. Primary prophylaxis for venous throm-boembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev 2014; 08: CD008500.
15 Prandoni P, Lensing AW, Piccioli A. et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484-3488.
16 Hutten BA, Prins MH, Gent M. et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000; 18: 3078-3083.
17 Palareti G, Legnani C, Lee A. et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000; 84: 805-810.
18 Lee AY, Levine MN, Baker RI. 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.
19 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. J Am Med Assoc 2015; 314: 677-686.
20 Akl EA, Kahale L, Barba M. et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer Cochrane Database Syst Rev 2014; 07: CD006650.
21 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149: 315-352.
22 Khorana AA, Carrier M, Garcia DA. et al. Guidance for the prevention and treatment of cancer-associated venous thromboembolism. J Thromb Thrombolysis 2016; 41: 81-91.
23 Napolitano M, Saccullo G, Malato A. et al. Optimal duration of low molecular weight heparin for the treatment of cancer-related deep vein thrombosis: the Cancer-DACUS Study. J Clin Oncol 2014; 32: 3607-3612.
24 Francis CW, Kessler CM, Goldhaber SZ. et al. Treatment of venous thromboem-bolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost 2015; 13: 1028-1035.
25 Seaman S, Nelson A, Noble S. Cancer-associated thrombosis, low-molecular-weight heparin, and the patient experience: a qualitative study. Patient Prefer Adherence 2014; 08: 453-461.
26 Linkins LA, Dans AL, Moores LK. et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012. 141 (2 Suppl) e495S-e530S.
27 Ansell J, Hirsh J, Hylek E. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. (8th Edition). Chest. 2008. 133 (6 Suppl) 160S-198S.
28 AWMF-Leitlinien-Register Nr. 065/002. Association of the Scientific Medical Societies in Germany. Available at: http://www.awmf.org/leitlinien/detail/ ll/065-002.html Accessed May 18. 2016
29 van der Hulle T, den Exter PL, Kooiman J. et al. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 2014; 12: 1116-1120.
30 Prins MH, Lensing AWA, Brighton TA. et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous throm-boembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014; 01: e37-46.
31 Bayer AGPharma. Bayer Extends Clinical Investigation of Xarelto^® for the Prevention and Treatment of Life-Threatening Blood Clots in Patients with Cancer (Press Release). Available at: https://www.xarelto.com/en/resources/newsfeed/ bayer-extends-clinical-investigation-of-xarelto-for-the-prevention-and-treatment-of-life-threatening-blood-clots-in-patients-with-cancer/ Accessed May 18. 2016
32 Gould MK, Garcia DA, Wren SM. et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012. 141 (2 Suppl) e227S-e277S.
33 Konstantinides SV, Torbicki A, Agnelli G. et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35: 3033-3069k.
34 A Study to Evaluate the Efficacy and Safety of Rivaroxaban Venous Throm-boembolism (VTE) Prophylaxis in Ambulatory Cancer Participants. https://ClinicalTrials.gov/show/NCT02555878
35 SELECT-D (Anticoagulation Therapy in SELECTeD Cancer Patients at Risk of Recurrence of Venous Thromboembolism) protocol. Warwick Medical School Clinical Trials Unit. Available at: http://www2.warwick.ac.uk/fac/med/research/ hscience/ctu/trials/cancer/select-d/select-d_protocol_v2.0_09-apr-2013.pdf. Accessed May 18. 2016
36 Rivaroxaban in the Treatment of Venous Thromboembolism (VTE) in Cancer Patients. https://ClinicalTrials.gov/show/NCT02583191
37 Mantha S, Laube E, Miao Y. et al. Safe and Effective Use of Rivaroxaban for Treatment of Cancer-Associated Venous Thromboembolic Disease: A Quality Improvement Initiative. Blood 2015; 126: 431.
38 Blom JW, Doggen CJ, Osanto S. et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. J Am Med Assoc 2005; 293: 715-722.
39 Heit JA, Silverstein MD, Mohr DN. et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809-815.
40 Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 03: 692-694.
41 Bamber L, Wang MY, Prins MH. et al. Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of acute symptomatic deep-vein thrombosis. Thromb Haemost 2013; 110: 732-741.
42 Prins MH, Bamber L, Cano SJ. et al. Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of pulmonary embolism; results from the EINSTEIN PE trial. Thromb Res 2015; 135: 281-288.
43 Mantha S, Laube E, Miao Y. et al. Safe and Effective Use of Rivaroxaban for Treatment of Cancer-Associated Venous Thromboembolic Disease: A Quality Improvement Initiative. Oral presentation at ASH 2015. San Diego, CA: USA; 2015
44 Prandoni P, Noventa F, Ghirarduzzi A. et al. The risk of recurrent venous throm-boembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92 (02) 199-205.
45 EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous throm-boembolism. N Engl J Med 2010; 363: 2499-2510.
46 EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
47 Palareti G. Bleeding with anticoagulant treatments. Hamostaseologie 2011; 31: 237-242.
48 Birocchi S, Scannella E, Ferrari L. et al. Aspirin in the secondary prevention of unprovoked thromboembolism: the WARFASA and ASPIRE studies. Intern Emerg Med 2013; 08: 757-760.
49 Weitz JI, Bauersachs R, Beyer-Westendorf J. et al. EINSTEIN CHOICE Investigators Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study. Thromb Haemost 2015; 114: 645-650.
50 Reduced-dosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic VTE (Venous Thromboembolism). https://ClinicalTrials.gov/show/ NCT02064439
51 Soff AP, Dong J, Dong A. et al. Reduced Emergency Room Utilization for Initiation of Anticoagulation with Rivaroxaban Versus Low Molecular Weight He-parin for Treatment of Cancer-Associated Thrombosis. Poster presentation at ASH 2015. Blood 2015; 126: 2068.
52 Khorana AA, McCrae K, Milentijevic D. et al. Current Practice Patterns and Patient Persistence on Anticoagulant Treatments for Cancer-Associated Thrombosis. Oral presentation at ASH 2015. Blood 2015; 126: 626.
53 Win KZ, Wilson N, Stenehejm DD. et al. Effectiveness and safety of rivaroxaban in treatment of venous thromboembolism in cancer patients. Poster presentation at ASH 2015. Blood 2016; 126: 2319.
54 Wells PS, Theberge IA, Bowdridge JC. et al. Rivaroxaban is effective therapy for high risk cancer patients with venous thromboembolic disease. Poster presentation at the 8th International Conference on Thrombosis and Hemostasis Issues in Cancer. April 2016. Thromb Res. 2016. 140 (Suppl 1) S191-S192.