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Influence of baseline anemia on long-term clinical outcomes in patients with venous thromboembolism: from the COMMAND VTE registry

  • Yugo Yamashita
  • Takeshi Morimoto
  • Hidewo Amano
  • Toru Takase
  • Seiichi Hiramori
  • Kitae Kim
  • Maki Oi
  • Masaharu Akao
  • Yohei Kobayashi
  • Mamoru Toyofuku
  • Toshiaki Izumi
  • Tomohisa Tada
  • Po-Min Chen
  • Koichiro Murata
  • Yoshiaki Tsuyuki
  • Syunsuke Saga
  • Tomoki Sasa
  • Jiro Sakamoto
  • Minako Kinoshita
  • Kiyonori Togi
  • Hiroshi Mabuchi
  • Kensuke Takabayashi
  • Hiroki Shiomi
  • Takao Kato
  • Takeru Makiyama
  • Koh Ono
  • Takeshi KimuraEmail author
  • the COMMAND VTE Registry Investigators
Article
  • 27 Downloads

Abstract

The influence of anemia on the long-term clinical outcomes has not been fully evaluated in patients with venous thromboembolism (VTE). We evaluated the influence of anemia among 3012 patients in the COMMAND VTE Registry with a median follow-up period of 1219 days. The outcomes measures were ISTH major bleeding, recurrent VTE and all-cause death. There were 1012 patients (34%) with moderate/severe anemia (Hb ≤ 10.9 g/dl), 615 patients (20%) with mild anemia (Hb 11.0–12.9 g/dl for men, and 11.0–11.9 g/dl for women), and 1385 patients (46%) without anemia. The cumulative 5-year incidence of major bleeding was significantly higher in patients with anemia (moderate/severe anemia: 17.6%, mild anemia: 12.1%, and no anemia: 8.7%, P < 0.001). After adjusting the confounders, the excess risk of mild and moderate/severe anemia, respectively, relative to no anemia for major bleeding remained significant (mild: adjusted HR 1.41: [95% CI 1.00–1.98], P = 0.048; moderate/severe: adjusted HR 1.91: [95% CI 1.42–2.58], P < 0.001, respectively). The excess risk of moderate/severe anemia relative to no anemia was also significant for mortality (adjusted HR 2.89: 95% CI 2.45–3.42, P < 0.001), but the risk was neutral for recurrent VTE (adjusted HR 1.05: 95% CI 0.76–1.45, P = 0.77). In conclusions, VTE patients with mild and moderate/severe anemia had higher risk for major bleeding events without significant excess risk for recurrent VTE events, and the risk for major bleeding events increased according to the severity of anemia. We should pay more attention to the optimal intensity and duration of anticoagulation in VTE patients with anemia.

Keywords

Venous thromboembolism Anemia Bleeding Recurrence Mortality 

Notes

Acknowledgements

We appreciate the support and collaboration of the co-investigators participating in the COMMAND VTE Registry. We are indebted to the independent clinical research organization (Research Institute for Production Development, Kyoto, Japan) for technical support.

Funding

The COMMAND VTE Registry is supported by the independent clinical research organization (Research Institute for Production Development, Kyoto, Japan) and research funding from Mitsubishi Tanabe Pharma Corporation. The research funding had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Compliance with ethical standards

Conflict of interest

Dr. Yamashita received lecture fees from Daiichi-Sankyo, Bristol-Myers Squibb, and Bayer Healthcare. Dr. Morimoto received lecture fees from Mitsubishi Tanabe Pharma and Pfizer Japan and consultant fees from Asahi Kasei, Bristol-Myers Squibb, and Boston Scientific. Dr. Akao received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare and Daiichi-Sankyo. Dr. Kimura serves as an advisory board member for Abbott Vascular and Terumo Company. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of retrospective study formal consent is not required.

Supplementary material

11239_2018_1791_MOESM1_ESM.pdf (511 kb)
Supplementary material 1 (PDF 511 KB)

References

  1. 1.
    Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, Greer IA, Heit JA, Hutchinson JL, Kakkar AK, Mottier D, Oger E, Samama MM, Spannagl M (2007) Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 98:756–764CrossRefGoogle Scholar
  2. 2.
    Kyrle PA, Rosendaal FR, Eichinger S (2010) Risk assessment for recurrent venous thrombosis. Lancet 376:2032–2039CrossRefGoogle Scholar
  3. 3.
    Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M (2014) 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 35:3033–3069CrossRefGoogle Scholar
  4. 4.
    Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK (2011) Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 123:1788–1830CrossRefGoogle Scholar
  5. 5.
    Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L (2016) Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 149:315–352CrossRefGoogle Scholar
  6. 6.
    Ando M, Fukuda I, Ito M, Kobayashi T, Masuda M, Miyahara Y, Nakanishi N, Niwa A, Ohgi S, Tajima H, Ishibashi H, Kanaoka Y, Nakamura M, Sakuma M, Satoh T, Tanabe N, Yamada N, Yamashita M, Kuriyama T, Matsubara J, Nakano T, Ozaki Y, Sakata R (2011) Guidelines for the diagnosis, treatment and prevention of pulmonary thromboembolism and deep vein thrombosis (JCS 2009). Circ J 75:1258–1281CrossRefGoogle Scholar
  7. 7.
    Stauder R, Valent P, Theurl I (2018) Anemia at older age: etiologies, clinical implications, and management. Blood 131:505–514CrossRefGoogle Scholar
  8. 8.
    Ruiz-Gimenez N, Suarez C, Gonzalez R, Nieto JA, Todoli JA, Samperiz AL, Monreal M (2008) Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 100:26–31CrossRefGoogle Scholar
  9. 9.
    Nieto JA, Solano R, Ruiz-Ribo MD, Ruiz-Gimenez N, Prandoni P, Kearon C, Monreal M (2010) Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry. J Thromb Haemost 8:1216–1222CrossRefGoogle Scholar
  10. 10.
    Yamashita Y, Morimoto T, Amano H, Takase T, Hiramori S, Kim K, Konishi T, Akao M, Kobayashi Y, Inoue T, Oi M, Izumi T, Takahashi K, Tada T, Chen PM, Murata K, Tsuyuki Y, Sakai H, Saga S, Sasa T, Sakamoto J, Yamada C, Kinoshita M, Togi K, Ikeda T, Ishii K, Kaneda K, Mabuchi H, Otani H, Takabayashi K, Takahashi M, Shiomi H, Makiyama T, Ono K, Kimura T (2018) Anticoagulation therapy for venous thromboembolism in the real world-from the COMMAND VTE Registry. Circ J 82:1262–1270CrossRefGoogle Scholar
  11. 11.
    Goldhaber SZ, Visani L, De Rosa M (1999) Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 353:1386–1389CrossRefGoogle Scholar
  12. 12.
    World Health Organization (1968) Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser 405:5–37Google Scholar
  13. 13.
    Schulman S, Kearon C (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 3:692–694CrossRefGoogle Scholar
  14. 14.
    Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369:1406–1415CrossRefGoogle Scholar
  15. 15.
    Faller N, Limacher A, Mean M, Righini M, Aschwanden M, Beer JH, Frauchiger B, Osterwalder J, Kucher N, Lammle B, Cornuz J, Angelillo-Scherrer A, Matter CM, Husmann M, Banyai M, Staub D, Mazzolai L, Hugli O, Rodondi N, Aujesky D (2017) Predictors and causes of long-term mortality in elderly patients with acute venous thromboembolism: a prospective cohort study. Am J Med 130:198–206CrossRefGoogle Scholar
  16. 16.
    Kimura T, Morimoto T, Nakagawa Y, Tamura T, Kadota K, Yasumoto H, Nishikawa H, Hiasa Y, Muramatsu T, Meguro T, Inoue N, Honda H, Hayashi Y, Miyazaki S, Oshima S, Honda T, Shiode N, Namura M, Sone T, Nobuyoshi M, Kita T, Mitsudo K (2009) Antiplatelet therapy and stent thrombosis after sirolimus-eluting stent implantation. Circulation 119:987–995CrossRefGoogle Scholar
  17. 17.
    Kuperman A, Lopez-Reyes R, Bosco LJ, Lorenzo A, Jose B, Farge Bancel D, Alfonso M, Lumbierres M, Stemer G, Monreal Bosch M, Braester A (2018) Anemia and bleeding in patients receiving anticoagulant therapy for venous thromboembolism. J Thromb Thrombolysis 45:360–368CrossRefGoogle Scholar
  18. 18.
    Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ (2013) Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 368:709–718CrossRefGoogle Scholar
  19. 19.
    Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363:2499–2510CrossRefGoogle Scholar
  20. 20.
    Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI (2013) Apixaban for extended treatment of venous thromboembolism. N Engl J Med 368:699–708CrossRefGoogle Scholar
  21. 21.
    Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361:2342–2352CrossRefGoogle Scholar
  22. 22.
    Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366:1287–1297CrossRefGoogle Scholar
  23. 23.
    Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369:799–808CrossRefGoogle Scholar
  24. 24.
    Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P (2017) Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 376:1211–1222CrossRefGoogle Scholar
  25. 25.
    Westenbrink BD, Alings M, Connolly SJ, Eikelboom J, Ezekowitz MD, Oldgren J, Yang S, Pongue J, Yusuf S, Wallentin L, van Gilst WH (2015) Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial. J Thromb Haemost 13:699–707CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yugo Yamashita
    • 1
  • Takeshi Morimoto
    • 2
  • Hidewo Amano
    • 3
  • Toru Takase
    • 4
  • Seiichi Hiramori
    • 5
  • Kitae Kim
    • 6
  • Maki Oi
    • 7
  • Masaharu Akao
    • 8
  • Yohei Kobayashi
    • 9
  • Mamoru Toyofuku
    • 10
  • Toshiaki Izumi
    • 11
  • Tomohisa Tada
    • 12
  • Po-Min Chen
    • 13
  • Koichiro Murata
    • 14
  • Yoshiaki Tsuyuki
    • 15
  • Syunsuke Saga
    • 16
  • Tomoki Sasa
    • 17
  • Jiro Sakamoto
    • 18
  • Minako Kinoshita
    • 19
  • Kiyonori Togi
    • 20
  • Hiroshi Mabuchi
    • 21
  • Kensuke Takabayashi
    • 22
  • Hiroki Shiomi
    • 1
  • Takao Kato
    • 1
  • Takeru Makiyama
    • 1
  • Koh Ono
    • 1
  • Takeshi Kimura
    • 1
    Email author
  • the COMMAND VTE Registry Investigators
  1. 1.Department of Cardiovascular Medicine, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.Department of Clinical EpidemiologyHyogo College of MedicineNishinomiyaJapan
  3. 3.Department of Cardiovascular MedicineKurashiki Central HospitalKurashikiJapan
  4. 4.Department of CardiologyKinki University HospitalOsakaJapan
  5. 5.Department of CardiologyKokura Memorial HospitalKokuraJapan
  6. 6.Department of Cardiovascular MedicineKobe City Medical Center General HospitalKobeJapan
  7. 7.Department of CardiologyJapanese Red Cross Otsu HospitalOtsuJapan
  8. 8.Department of CardiologyNational Hospital Organization Kyoto Medical CenterKyotoJapan
  9. 9.Department of Cardiovascular CenterOsaka Red Cross HospitalOsakaJapan
  10. 10.Department of CardiologyJapanese Red Cross Wakayama Medical CenterWakayamaJapan
  11. 11.Cardiovascular Center, The Tazuke Kofukai Medical Research InstituteKitano HospitalOsakaJapan
  12. 12.Department of CardiologyShizuoka General HospitalShizuokaJapan
  13. 13.Department of CardiologyOsaka Saiseikai Noe HospitalOsakaJapan
  14. 14.Department of CardiologyShizuoka City Shizuoka HospitalShizuokaJapan
  15. 15.Division of CardiologyShimada Municipal HospitalShimadaJapan
  16. 16.Department of CardiologyHyogo Prefectural Amagasaki General Medical CenterAmagasakiJapan
  17. 17.Department of CardiologyKishiwada City HospitalKishiwadaJapan
  18. 18.Department of CardiologyTenri HospitalTenriJapan
  19. 19.Department of CardiologyNishikobe Medical CenterKobeJapan
  20. 20.Division of Cardiology, Nara HospitalKinki University Faculty of MedicineIkomaJapan
  21. 21.Department of CardiologyKoto Memorial HospitalHigashiomiJapan
  22. 22.Department of CardiologyHirakata Kohsai HospitalHirakataJapan

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