Postthrombotic syndrome and quality of life after deep vein thrombosis in patients treated with edoxaban versus warfarin

Ingrid M Bistervels, Roisin Bavalia, Jan Beyer-Westendorf, Arina J Ten Cate-Hoek, Sebastian M Schellong, Michael J Kovacs, Nicolas Falvo, Karina Meijer, Dominique Stephan, Wim G Boersma, Marije Ten Wolde, Francis Couturaud, Peter Verhamme, Dominique Brisot, Susan R Kahn, Waleed Ghanima, Karine Montaclair, Amanda Hugman, Patrick Carroll, Gilles Pernod, Olivier Sanchez, Emile Ferrari, Pierre-Marie Roy, Marie-Antoinette Sevestre-Pietri, Simone Birocchi, Hilde S Wik, Barbara A Hutten, Michiel Coppens, Christiane Naue, Michael A Grosso, Minggao Shi, Yong Lin, Isabelle Quéré, Saskia Middeldorp, Hokusai PTS Investigators, Ingrid M Bistervels, Roisin Bavalia, Jan Beyer-Westendorf, Arina J Ten Cate-Hoek, Sebastian M Schellong, Michael J Kovacs, Nicolas Falvo, Karina Meijer, Dominique Stephan, Wim G Boersma, Marije Ten Wolde, Francis Couturaud, Peter Verhamme, Dominique Brisot, Susan R Kahn, Waleed Ghanima, Karine Montaclair, Amanda Hugman, Patrick Carroll, Gilles Pernod, Olivier Sanchez, Emile Ferrari, Pierre-Marie Roy, Marie-Antoinette Sevestre-Pietri, Simone Birocchi, Hilde S Wik, Barbara A Hutten, Michiel Coppens, Christiane Naue, Michael A Grosso, Minggao Shi, Yong Lin, Isabelle Quéré, Saskia Middeldorp, Hokusai PTS Investigators

Abstract

Background: Postthrombotic syndrome (PTS) is a long-term complication after deep vein thrombosis (DVT) and can affect quality of life (QoL). Pathogenesis is not fully understood but inadequate anticoagulant therapy with vitamin K antagonists is a known risk factor for the development of PTS.

Objectives: To compare the prevalence of PTS after acute DVT and the long-term QoL following DVT between patients treated with edoxaban or warfarin.

Methods: We performed a long-term follow-up study in a subset of patients with DVT who participated in the Hokusai-VTE trial between 2010 and 2012 (NCT00986154). Primary outcome was the prevalence of PTS, defined by the Villalta score. The secondary outcome was QoL, assessed by validated disease-specific (VEINES-QOL) and generic health-related (SF-36) questionnaires.

Results: Between 2017 and 2020, 316 patients were enrolled in 26 centers in eight countries, of which 168 (53%) patients had been assigned to edoxaban and 148 (47%) to warfarin during the Hokusai-VTE trial. Clinical, demographic, and thrombus-specific characteristics were comparable for both groups. Mean (SD) time since randomization in the Hokusai-VTE trial was 7.0 (1.0) years. PTS was diagnosed in 85 (51%) patients treated with edoxaban and 62 (42%) patients treated with warfarin (adjusted odds ratio 1.6, 95% CI 1.0-2.6). Mean differences in QoL scores between treatment groups were not clinically relevant.

Conclusion: Contrary to our hypothesis, the prevalence of PTS tended to be higher in patients treated with edoxaban compared with warfarin. No differences in QoL were observed. Further research is warranted to unravel the role of anticoagulant therapy on development of PTS.

Keywords: edoxaban; postthrombotic syndrome; quality of life; venous thrombosis; warfarin.

Conflict of interest statement

J.B.W. reports personal fees and other from Bayer HealthCare, personal fees and other from Boehringer. Ingelheim, personal fees and other from BMS/Pfizer, personal fees and other from CSL Behring, personal fees and other personal fees and other from Daiichi Sankyo, personal fees and other from LEO Pharma, outside the submitted work. F.C. reports grants from BMS/Pfizer, personal fees and other from Bayer HealthCare, personal fees and other from AstraZeneka, personal fees and other from MSD, personal fees and other from GSK, other from Janssen, personal fees and other from Novartis, outside the submitted work. M.C. reports personal fees from Bayer HealthCare, personal fees from Boehringer Ingelheim, personal fees from Bristol‐Myers Squib, personal fees from CSL Behring, personal fees from Daiichi Sankyo, personal fees from Pfizer, personal fees from Portola, personal fees from Sanquin Blood Supply, outside the submitted work. W.G. reports grants and other from Bayer HealthCare, grants and other from Pfizer, other from Novartis, other from Amgen, other from Principia, from Sanofi, other from MSD, other from Sobi, outside the submitted work. K. Meijer receives other from Bayer HealthCare, other from Uniqure, other from Alexion, other from Octapharma, outside the submitted work. S.M. reports grants from GSK, grants from BMS/Pfizer, grants from Aspen, grants from Daiichi Sankyo, grants from Bayer HealthCare, grants from Boehringer Ingelheim, grants from Sanofi, grants from Portola, outside the submitted work. M.A.S.P. reports honoraria from Bayer, Pfizer, and Leo Pharma. O.S. reports grants from Daiichi‐Sankyo, during the conduct of the study; grants, personal fees, and nonfinancial support from Bayer HealthCare, grants, personal fees and nonfinancial support from BMS, personal fees and non‐financial support from Pfizer, grants, personal fees and non‐financial support from Boehringer Ingelheim, grants and personal fees from MSD, personal fees from Chiesi, grants and personal fees from Boston Scientifics, outside the submitted work. S.M.S. reports receiving consulting fees from Bayer and Boehringer Ingelheim, and lecture fees from Bayer, Boehringer Ingelheim, and Bristol‐Myers Squibb–Pfizer. P.V. reports grants and personal fees from Bayer HealthCare, grants and personal fees from Boehringer Ingelheim, grants and personal fees from BMS/Pfizer, personal fees from Daiichi Sankyo, personal fees from LEO Pharma, personal fees from Anthos therapeutics, personal fees from Portola Pharmaceuticals/Alexion, outside the submitted work. M.G., M.S., and Y.L. report being an employee of Daiichi‐Sankyo. No other potential conflict of interest with relation to this study were reported.

© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).

Figures

FIGURE 1
FIGURE 1
Flow chart patient selection Hokusai PTS study
FIGURE 2
FIGURE 2
(A) Generic health‐related quality of life according to treatment of acute DVT. Mean SF‐36 scores of patients with a history of acute deep vein thrombosis in patients treated with edoxaban (n = 168) and warfarin (n = 148). This graph is not corrected for any baseline characteristics. Abbreviations for SF‐36 domains: GH, general health; ME, mental health; P, pain; PF, physical functioning; RE, role emotional complaints; RP, role physical complaints; SF, social functioning; VI, vitality. Missing values: missing physical functioning: 9, missing social functioning: 8, missing role physical complaints: 12, missing role emotional: 10, missing mental: 4, missing vitality: 8, missing pain: 8, missing general health: 9. (B) Mean difference in generic health‐related quality of life according to treatment of acute DVT. Mean difference and 95% confidence interval of SF‐36 scores of patients with a history of deep vein thrombosis in patients on edoxaban (n = 168) and warfarin (n = 148), stratified per dimension. This graph is not corrected for any baseline characteristics. MCID is the minimal clinically important difference, as described in the methods section. Abbreviations for SF‐36 domains: BP, bodily pain; GH, general health; ME, mental health; PF, physical functioning; RE, role emotional complaints; RP, role physical complaints; SF, social functioning; VI, vitality

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