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Thromb Haemost 2016; 116(S 02): S41-S49
DOI: 10.1160/TH16-06-0488
Thrombosis and Haemostasis Supplement
Schattauer GmbH

Spotlight on real-world evidence for the treatment of DVT: XALIA

Walter Ageno
1   Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
,
Alexander G. G. Turpie
2   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations Financial support: Editorial support was funded by Bayer Pharma AG.
Further Information

Publication History

Received: 29 June 2016

Accepted: 10 July 2016

Publication Date:
15 December 2017 (online)

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Summary

Venous thromboembolism (VTE), comprising both deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and common cardiovascular disease associated with the risk of chronic complications, recurrent VTE events and even death. The treatment landscape has, in recent years, seen a paradigm shift from the use of traditional anticoagulants (low-molecular-weight heparin [LMWH] overlapping with and followed by a vitamin K antagonist [VKA]) to non-VKA oral anticoagulants (NOACs). This class of agents, encompassing direct factor Xa inhibitors and direct thrombin inhibitors have shown non-inferior efficacy and better safety to standard of care in randomised controlled trials (RCTs). The direct, oral factor Xa inhibitor rivaroxaban was the first to be approved for treatment of acute DVT and PE and secondary prevention of recurrent VTE events based on data from EINSTEIN DVT and EINSTEIN PE, respectively. Real-world evidence now helps to further support data from RCTs, and also bridges the gap for physicians regarding any areas of clinical uncertainty that may not be addressed by RCTs. XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was the first large, prospective, observational, real-world study that has investigated the safety and effectiveness profile of rivaroxaban in patients with DVT and PE associated with DVT in routine clinical practice. This article will present the key clinical outcomes from this important global non-interventional study, and will discuss remaining questions to be addressed in Phase IV studies.

Keywords

Deep-vein thrombosis - pulmonary embolism - rivaroxaban - non-interventional
 

  • References

  • 1 Piazza G, Goldhaber SZ. Venous thromboembolism and atherothrombosis: an integrated approach. Circulation 2010; 121: 2146-2150.
    CrossrefPubMedGoogle Scholar
  • 2 Sogaard KK, Schmidt M, Pedersen L. et al. 30-year mortality after venous thromboembolism: a population-based cohort study. Circulation 2014; 130: 829-836.
    CrossrefPubMedGoogle Scholar
  • 3 Prandoni P, Lensing AW, Cogo A. et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
    CrossrefPubMedGoogle Scholar
  • 4 Prandoni P, Noventa F, Ghirarduzzi A. et al. The risk of recurrent venous thromboembolism 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: 199-205.
    CrossrefPubMedGoogle Scholar
  • 5 Fernandez MM, Hogue S, Preblick R. et al. Review of the cost of venous thromboembolism. Clinicoecon Outcomes Res 2015; 07: 451-462.
    PubMedGoogle Scholar
  • 6 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines; Chest. 2012. 141 (2 Suppl): e419S-e494S.
    Google Scholar
  • 7 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.
    PubMedGoogle Scholar
  • 8 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
    PubMedGoogle Scholar
  • 9 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.
    PubMedGoogle Scholar
  • 10 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149: 315-352.
    CrossrefPubMedGoogle Scholar
  • 11 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.
    PubMedGoogle Scholar
  • 12 EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
    CrossrefPubMedGoogle Scholar
  • 13 EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
    CrossrefPubMedGoogle Scholar
  • 14 Prins MH, Lensing AW, Bauersachs R. et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11: 21.
    CrossrefPubMedGoogle Scholar
  • 15 Ageno W, Mantovani LG, Haas S. et al. XALIA: rationale and design of a non-interventional study of rivaroxaban compared with standard therapy for initial and long-term anticoagulation in deep vein thrombosis. Thromb J 2014; 12: 16.
    CrossrefPubMedGoogle Scholar
  • 16 Ageno W, Mantovani LG, Haas S. et al. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol 2016; 03: e12-e21.
    PubMedGoogle Scholar
  • 17 Deb S, Austin PC, Tu JV. et al. A Review of Propensity-Score Methods and Their Use in Cardiovascular Research. Can J Cardiol 2016; 32: 259-265.
    CrossrefPubMedGoogle Scholar
  • 18 Eerenberg ES, Middeldorp S, Levi M. et al. Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists. J Thromb Haemost 2015; 13: 1590-1596.
    CrossrefPubMedGoogle Scholar
  • 19 Beyer-Westendorf J, Forster K, Pannach S. et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014; 124: 955-962.
    CrossrefPubMedGoogle Scholar
  • 20 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.
    CrossrefPubMedGoogle Scholar
  • 21 Nieto JA, Camara T, Gonzalez-Higueras E. et al. Clinical outcome of patients with major bleeding after venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100: 789-796.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Pahs L, Beavers C, Schuler P. The Real-World Treatment of Hemorrhages Associated With Dabigatran and Rivaroxaban: A Multicenter Evaluation. Crit Pathw Cardiol 2015; 14: 53-61.
    CrossrefPubMedGoogle Scholar
  • 23 Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000; 160: 769-774.
    CrossrefPubMedGoogle Scholar
  • 24 Lobo JL, Jimenez D, Teresa OM. et al. Recurrent venous thromboembolism during coumarin therapy. Data from the computerised registry of patients with venous thromboembolism. Br J Haematol 2007; 138: 400-403.
    CrossrefPubMedGoogle Scholar
  • 25 Martinez C, Cohen AT, Bamber L. et al. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 2014; 112: 255-263.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Jara-Palomares L, Sanchez-Oro-Gomez R, Elias-Hernandez T. et al. Rivaroxaban for the treatment of venous thromboembolism. A “real-life” perspective in 103 patients. Thromb Res 2014; 134: 617-621.
    CrossrefPubMedGoogle Scholar
  • 27 Schastlivtsev IV, Lobastov KV, Barinov VE. et al. Treatment of acute deep vein thrombosis with new oral anticoagulant rivaroxaban: the first experience. Khirurgiia 2014; 06: 61-66.
    PubMedGoogle Scholar
  • 28 Köhler C, Werth S, Tittl L. et al. Acute Treatment Of Pulmonary Embolism With Rivaroxaban - Real Life Data From The Prospective Dresden NOAC Registry (NCT01588119). Blood 2013; 122: 2380.
    CrossrefPubMedGoogle Scholar
  • 29 Tagalakis V, Patenaude V, Kahn SR. et al. Incidence of and mortality from venous thromboembolism in a real-world population: the Q-VTE Study Cohort. Am J Med 2013; 126: 832-821.
    PubMedGoogle Scholar
  • 30 Lecumberri R, Alfonso A, Jimenez D. et al. Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost 2013; 110: 834-843.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Michalski F, Werth S, Kohler C. et al. Centrally Adjudicated Cause of Death during NOAC Treatment - Results of the Prospective Dresden NOAC Registry (NCT01588119). Blood 2014; 124: 2876.
    PubMedGoogle Scholar
  • 32 van Bellen B, Bamber L, Correa de CF. et al. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin 2014; 30: 829-837.
    CrossrefPubMedGoogle Scholar
  • 33 Beam DM, Kahler ZP, Kline JA. Immediate Discharge and Home Treatment With Rivaroxaban of Low-risk Venous Thromboembolism Diagnosed in Two U. S. Emergency Departments: A One-year Preplanned Analysis. Acad Emerg Med 2015; 22: 788-795.
    CrossrefPubMedGoogle Scholar
  • 34 Deitelzweig S, Kline J, Margolis JM. et al. Comparison of rivaroxaban or warfarin use for venous thromboembolism on inpatient length of stay. J Am Coll Cardiol 2016; 67: 2065.
    CrossrefPubMedGoogle Scholar
  • 35 Merli GJ, Hollander JE, Lefebvre P. et al. Costs of hospital visits among patients with deep vein thrombosis treated with rivaroxaban and LMWH/warfarin. J Med Econ 2016; 19: 84-90.
    CrossrefPubMedGoogle Scholar
  • 36 Timp JF, Braekkan SK, Versteeg HH. et al. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122: 1712-1723.
    CrossrefPubMedGoogle Scholar
  • 37 Prandoni P, Trujillo-Santos J, Surico T. et al. Recurrent thromboembolism and major bleeding during oral anticoagulant therapy in patients with solid cancer: findings from the RIETE registry. Haematologica 2008; 93: 1432-1434.
    CrossrefPubMedGoogle Scholar
  • 38 Gussoni G, Frasson S, La Regina M. et al. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res 2013; 131: 24-30.
    CrossrefPubMedGoogle Scholar
  • 39 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.
    CrossrefPubMedGoogle Scholar
  • 40 Watson HG, Keeling DM, Laffan M. et al. Guideline on aspects of cancer-related venous thrombosis. Br J Haematol 2015; 170: 640-648.
    CrossrefPubMedGoogle Scholar
  • 41 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.
    CrossrefPubMedGoogle Scholar
  • 42 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.
    PubMedGoogle Scholar
  • 43 AWMF-Leitlinien-Register Nr. 065/002. Association of the Scientific Medical Societies in Germany. Available at: http://www.awmf.org/uploads/tx_szleitli nien/065–002l_S2k_VTE_2016–01.pdf Accessed May 18, 2016.
    PubMedGoogle Scholar
  • 44 Vedovati MC, Germini F, Agnelli G. et al. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest 2015; 147: 475-483.
    CrossrefPubMedGoogle Scholar
  • 45 Prins MH, Lensing AWA, Brighton TA. et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014; 01: e37-46.
    PubMedGoogle Scholar
  • 46 Kneeland PP, Fang MC. Current issues in patient adherence and persistence: focus on anticoagulants for the treatment and prevention of thromboembolism. Patient Prefer Adherence 2010; 04: 51-60.
    PubMedGoogle Scholar
  • 47 Kearon C, Ginsberg JS, Kovacs MJ. et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349: 631-639.
    CrossrefPubMedGoogle Scholar
  • 48 Agnelli G, Buller HR, Cohen A. et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368: 699-708.
    CrossrefPubMedGoogle Scholar
  • 49 Schulman S, Kearon C, Kakkar AK. et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368: 709-718.
    CrossrefPubMedGoogle Scholar
  • 50 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Yeh CH, Gross PL, Weitz JI. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood 2014; 124: 1020-1028.
    CrossrefPubMedGoogle Scholar
  • 52 Agnelli G, Buller HR, Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799-808.
    CrossrefPubMedGoogle Scholar
  • 53 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
    CrossrefPubMedGoogle Scholar
  • 54 Wan S, Quinlan DJ, Agnelli G. et al. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004; 110: 744-749.
    CrossrefPubMedGoogle Scholar
  • 55 Meyer G, Vicaut E, Danays T. et al. Fibrinolysis for patients with intermediaterisk pulmonary embolism. N Engl J Med 2014; 370: 1402-1411.
    CrossrefPubMedGoogle Scholar
  • 56 Sharifi M, Bay C, Schwartz F. et al. Safe-dose thrombolysis plus rivaroxaban for moderate and severe pulmonary embolism: drip, drug, and discharge. Clin Cardiol 2014; 37: 78-82.
    CrossrefPubMedGoogle Scholar
  • 57 Sharifi M, Vajo Z, Freeman W. et al. Transforming and simplifying the treatment of pulmonary embolism: “safe dose” thrombolysis plus new oral anticoagulants. Lung 2015; 193: 369-374.
    CrossrefPubMedGoogle Scholar
  • 58 Goldhaber SZ, Ageno W, Asella I. et al. A global prospective cohort study of dabigatran for the treatment of venous thromboembolism (RE-COVERY). J Thromb Haemost 2016; 14 (Suppl. 01) 729.
    PubMedGoogle Scholar
  • 59 Theobald K, Capan M, Herbold M. et al. Quality assurance in non-interventional studies. Ger Med Sci 2009; 07 Doc 29.
    PubMedGoogle Scholar
  • 60 Borah BJ, Moriarty JP, Crown WH. et al. Applications of propensity score methods in observational comparative effectiveness and safety research: where have we come and where should we go?. J Comp Eff Res 2014; 03: 63-78.
    CrossrefPubMedGoogle Scholar
  • 61 Camm AJ, Amarenco P, Haas S. et al. XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016; 37: 1145-1153.
    CrossrefPubMedGoogle Scholar
  • 62 Turpie AG, Haas S, Kreutz R. et al. A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. Thromb Haemost 2014; 111: 94-102.
    Article in Thieme ConnectPubMedGoogle Scholar