Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists

Summary

The study aim was to identify predictive factors for major bleeding in patients receiving the novel oral factor Xa inhibitor rivaroxaban or enoxaparin-vitamin K antagonists (VKAs) for the treatment of acute symptomatic venous thromboembolism. We analysed data from patients included in the phase III EINSTEIN DVT and EINSTEIN PE studies. Factors associated with major bleeding events were assessed with best subset variable selection using Cox proportional hazards regression model. Three time windows were considered, i. e. the initial three weeks, after the third week onwards, and the entire duration of the anticoagulant treatment. Model discrimination was estimated using the C-statistic and validated internally by bootstrap techniques. Major bleeding occurred in 40 (1.0 %) of 4130 patients receiving rivaroxaban and in 72 (1.7 %) of 4116 receiving enoxaparin/VKAs, with 44 % of the major bleeding events occurring in the first three weeks of treatment. Significant risk factors for major bleeding were older age, black race, low haemoglobin concentrations, active cancer, and antiplatelet or non-steroidal anti-inflammatory drug therapy. The discrimination of the model for major bleeding was high for the first three weeks (C-statistic 0.73), from the fourth week onwards (C-statistic 0.68), and the entire period of anticoagulant treatment (C-statistic 0.74). This analysis identified risk factors for major bleeding in patients receiving the novel oral anticoagulant rivaroxaban or enoxaparin/VKAs for the treatment of acute venous thromboembolism. The prognostic model based on the combination of identified risk factors may be informative to estimate the risk of major bleeding both during the initial and later phases of anticoagulation.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Haemorrhage - anticoagulants - thrombosis - risk factors - randomised controlled trial

• References

• 1 Ageno W, Gallus AS, Wittkowsky A. et al. Oral anticoagulant therapy : antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141: e44S-e88S.
• 2 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med. 2003; 139: 893-900.
• 3 Ruíz-Giménez N, Suárez C, González R. et al. Predictive variables for major bleeding events in patients presenting with documented acute venous throm-boembolism. Findings from the RIETE Registry. Thromb Haemost. 2008; 100: 26-31.
• 4 Nieto JA, Solano R, Ruiz-Ribó MD. et al. Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry. J Thromb Haemost. 2010; 08: 1216-1222.
• 5 Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med. 1989; 87: 144-152.
• 6 Landefeld CS, Cook EF, Flatley M. et al. Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy. Am J Med. 1987; 82: 703-713.
• 7 Beyth BJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998; 105: 91-99.
• 8 Nieuwenhuis HK, Albada J, Banga JD. et al. Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin. Blood. 1991; 78: 2337-2343.
• 9 Kuijer PMM, Hutten BA, Prins MH. et al. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med. 1999; 159: 457-460.
• 10 Kearon C, Ginsberg JS, Kovacs MJ et al. for the Extended Low-Intensity Antico-agulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term preventionof recurrent venousthromboembolism. N Engl J Med. 2003; 349: 631-639.
• 11 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010; 138: 1093-100.
• 12 Gage BF, Yan Y, Milligan PE. et al. Clinical classification schemes for predicting haemorrhage: Results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006; 151: 713-719.
• 13 Poli D, Antonucci E, Testa S. et al for the Italian Federation of Anticoagulation Clinics (FCSA). Bleeding risk in very old patients on vitamin K antagonist treatment: results of a prospective collaborative study on elderly patients followed by Italian Centres for Anticoagulation. Circulation. 2011; 124: 824-829.
• 14 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 (02) (Suppl) e419S-494S.
• 15 Donzé J, Rodondi N, Waeber G. et al. Scores to predict major bleeding risk during oral anticoagulation therapy: a prospective validation study. Am J Med. 2012; 125: 1095-1102.
• 16 Riva N, Bellesini M, Di Minno MND. et al. Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism A multicentre retrospective cohort study. Thromb Haemost 2014; 112: 511-521.
• 17 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous throm-boembolism. N Engl J Med. 2010; 363: 2499-2510.
• 18 The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012; 366: 1287-1297.
• 19 Prins MH, Lensing AWA, Bauersachs R. et al, for the EINSTEIN Investigators. 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. Doi: 10.1186/1477-9560-11-21.
• 20 Hosmer (Jr) DW, Lemeshow S, Sturdivant RX. Applied Logistic Regression. 3rd Edition.. Wiley Series in Probability & Statistics;; 2003
• 21 Harrell Jr FE, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996; 15: 361-87.
• 22 Miao Y, Stijacic Cenzer I, Boscardin J. Estimating Harrell’s Optimism on Predictive Indices Using Bootstrap Samples. Paper 504-2013. SAS Global Forum 2013.
• 23 Prins MH, Lensing AWA, Brighton TA. et al. Oral rivaroxaban versus enoxapa-rin 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. The Lancet Hae-matology 2014; 01: e37-e46.
• 24 Royston PW, Sauerbrei W. Multivariable Model-building: A Pragmatic Approach to Regression Analysis Based on Fractional Polynomials for Modelling Continuous Variables. Chichester, UK: Wiley; 2008
• 25 Bauerschs RM, Lensing AWA, Prins MH. et al. Rivaroxaban versus enoxaparin/vit-amin K antagonist therapy in patients with venous thromboembolism and renal impairment. Thrombosis Journal 2014; 12: 25. Doi: 10.1186/1477-9560-12-25.
• 26 Schafer JL. Analysis of Incomplete Multivariate Data. London, United Kingdom:: Chapman & Hall;; 1997
• 27 Davidson BL, Verheijen S, Lensing AWA. et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014; 174: 947-953.
• 28 Wells PS, Forgie MA, Simms M. et al. The outpatient bleeding risk index validation of a tool for predicting bleeding rates in patients treated for deep venous thrombosis and pulmonary embolism. Arch Intern Med. 2003; 163: 917-920.
• 29 Fang MC, Go AS, Chang Y. et al. A new risk scheme to predict warfarin-associated haemorrhage. The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011; 58: 395-401.
• 30 Burgess S, Crown N, Louzada ML. et al. Clinical performance of bleeding risk scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin. J Thromb Haemost. 2013; 11: 1647-1654.
• 31 Scherz N, Méan M, Limacher A. et al. Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboem-bolism. J Thromb Haemost. 2013; 11: 435-443.
• 32 Schulman S, Beyth RJ, Kearon C. et al. Haemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008; 133: 257-298.
• 33 Olesen JB, Lip GYH, Hansen PR. et al. Bleeding risk in �real world” patients with atrial ibrillation: comparison of two established bleeding prediction schemes in a nationwide cohort. J Thromb Haemost. 2011; 09: 1460-1467.