Impact of Patient Characteristics on Treatment Outcomes in Symptomatic Venous Thromboembolism: Results of HOKUSAI-VTE Randomized Trial Analysis

Abstract

Introduction In patients with venous thromboembolism (VTE), direct oral anticoagulants (DOACs) such as edoxaban, apixaban, dabigatran, and rivaroxaban are more convenient, safer, and just as effective as vitamin K antagonists (VKAs). Limited information is known about the effects of patient characteristics on VTE efficacy and safety of DOACs compared with VKAs, without appropriate effect modifier adjustment comparisons of DOACs may be biased. This study considers the effect of variables that can modify the efficacy and safety of edoxaban and warfarin, using patient-level data.

Materials and Methods The primary efficacy and safety outcomes in the HOKUSAI-VTE study were VTE recurrence and clinically relevant bleeding, respectively. Potential effect modifiers were age, creatinine clearance, and weight. The relationship between the percentage of time in international normalized ratio (INR) control and outcomes were considered for the warfarin arm. Univariate and multivariate regression were performed for each patient characteristic.

Results The relationship between treatment and VTE recurrence differed by age (interaction p = 0.007) and by creatinine clearance (p = 0.05). VTE recurrence differed by age for patients in the warfarin arm but not for those in the edoxaban arm and differed by INR control in the warfarin arm (p < 0.005). A stronger relationship between creatinine clearance and clinically relevant bleeding was found in the warfarin arm than in the edoxaban arm (p = 0.04). Clinically relevant bleeding differed by the percentage of time in INR control in the warfarin arm (p < 0.005). Age appeared to be a more important effect modifier than creatinine clearance in patients with VTE.

Discussion The finding that efficacy in older patients was greater for those taking edoxaban than for those taking warfarin in the HOKUSAI-VTE study needs further investigation. Modification of the treatment effect by age for those taking warfarin might bias estimates of comparative effectiveness among DOACs if VKAs are the reference treatment.

Keywords

venous thrombosis - edoxaban - warfarin - creatinine - effect modification - age

Authors' Contributions

B.v.H. substantially contributed to concept and design, analysis, and/or interpretation of data; critical writing and revising the intellectual content; and has given final approval of the version to be published. A.T.C. provided a substantial contribution to concept and design, analysis, and/or interpretation of data; provided critical writing and revising of the intellectual content; and has given final approval of the version to be published. E.H. provided a substantial contribution to concept and design, analysis, and/or interpretation of data; provided critical writing and revising of the intellectual content; and has given final approval of the version to be published.

Publication History

Received: 17 July 2020

Accepted: 31 July 2020

Article published online:
23 September 2020

• References

• 1 Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 2014; 112 (02) 255-263
• 2 Cohen AT, Agnelli G, Anderson FA. VTE Impact Assessment Group in Europe (VITAE). et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98 (04) 756-764
• 3 Geldhof V, Vandenbriele C, Verhamme P, Vanassche T. Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants. Thromb J 2014; 12: 21-31
• 4 Agnelli G, Buller HR, Cohen A. AMPLIFY Investigators. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
• 5 Bauersachs R, Berkowitz SD, Brenner B. EINSTEIN Investigators. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
• 6 Buller HR. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism: a pooled analysis of the Einstein DVT and Einstein PE studies. Blood 2012; 120 (21) 20
• 7 Schulman S, Kearon C, Kakkar AK. RE-COVER Study Group. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
• 8 Büller HR, Décousus H, Grosso MA. Hokusai-VTE Investigators. et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
• 9 Signorovitch JE, Sikirica V, Erder MH. et al. Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research. Value Health 2012; 15 (06) 940-947
• 10 Phillippo D, Ades T, Dias S, Palmer S, Abrams K, Welton N. NICE DSU Technical Support Document 18: Methods for population-adjusted indirect comparisons in submissions to NICE. 2016 . Accessed January 27, 2020 at: http://www.nicedsu.org.uk/wp-content/uploads/2017/05/Population-adjustment-TSD-FINAL.pdf
• 11 Schulman S, Kakkar AK, Goldhaber SZ. RE-COVER II Trial Investigators. et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
• 12 Mitchell AP, Conway SE. Rivaroxaban for treatment of venous thromboembolism in older adults. Consult Pharm 2014; 29 (09) 627-630
• 13 Fimognari FL, Repetto L, Moro L, Gianni W, Incalzi RA. Age, cancer and the risk of venous thromboembolism. Crit Rev Oncol Hematol 2005; 55 (03) 207-212