Download PDF
CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(08): 1384-1396
DOI: 10.1055/a-1731-3922
Stroke, Systemic or Venous Thromboembolism

Effectiveness and Safety of Oral Anticoagulants in the Treatment of Acute Venous Thromboembolism: A Nationwide Comparative Cohort Study in France

Laurent Bertoletti 
1   Service de Médecine Vasculaire et Thérapeutique, CHU de St-Etienne, Saint-Etienne, France
2   INSERM, UMR1059, Université Jean-Monnet, Paris, France
3   INSERM, CIC-1408, CHU de Saint-Etienne; all in F-42055, Saint-Etienne, France
,
Gaelle Gusto
4   Certara France, Evidence and Access, Paris, France
,
Artak Khachatryan
5   Certara UK, Evidence and Access, London, United Kingdom
,
Nadia Quignot 
4   Certara France, Evidence and Access, Paris, France
,
Jose Chaves
6   Pfizer SLU, Internal Medicine, Global Medical Affairs, Madrid, Spain
,
Audrey Moniot
7   Pfizer SAS, Internal Medicine, Medical Affairs, Paris, France
,
Ruth Mokgokong 
8   Pfizer Ltd, Health Economics and Outcomes Research, Tadworth, United Kingdom
› Author Affiliations Funding This study was sponsored by Pfizer and Bristol Myers Squibb.
› Further Information
   Permissions and Reprints

Abstract

Introduction Data from clinical trials indicate that direct oral anticoagulants (DOACs) are noninferior and safer than conventional therapy (low-molecular-weight heparin followed by a vitamin K antagonist [VKA]) for treating venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism (PE). This study compared the effectiveness and safety of DOACs and conventional therapy in a real-world setting.

Methods This observational study used French national claims data of adult, treatment-naïve patients diagnosed with VTE (majority PE) who were hospitalized and treated for VTE with a DOAC (apixaban or rivaroxaban) or VKAs during 2013 to 2018. Patients with active cancer were excluded. After propensity score matching for each DOAC-VKA comparison, risks of bleeding, recurrent VTE, and all-cause mortality were compared at 6 months. Cox proportional hazards regression was used to estimate adjusted hazard ratios of the endpoints.

Results A total of 58,137 patients were included (10,775 VKAs, 10,440 apixaban, 36,922 rivaroxaban). Propensity score-matched cohort sizes were 7,503 for apixaban and 9,179 for rivaroxaban. The hazard ratio (95% confidence interval) was significantly lower for apixaban than VKAs for bleeding requiring hospitalization (0.43 [0.32–0.59]), all-cause death (0.61 [0.51–0.74]), and first recurrent VTE (0.67 [0.52–0.85]). The hazard ratio was also significantly lower for rivaroxaban than VKAs for all-cause death (0.63 [0.53–0.74]) but not for bleeding requiring hospitalization (0.86 [0.69–1.07]) or first recurrent VTE (0.91 [0.74–1.13]).

Conclusion Apixaban was associated with superior safety and effectiveness than VKAs. All-cause mortality was lower in both DOACs than VKAs. Our results support recommendations to use DOACs over VKAs for the treatment of VTE.

Keywords

venous thromboembolism - anticoagulants - apixaban - rivaroxaban - bleeding

Supplementary Material



Publication History

Received: 09 September 2021

Accepted: 26 November 2021

Accepted Manuscript online:
04 January 2022

Article published online:
10 March 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet 2021; 398 (10294): 64-77
    Google Scholar
  • 2 Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet 2016; 388 (10063): 3060-3073
    CrossrefPubMedGoogle Scholar
  • 3 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
    Google Scholar
  • 4 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
    Google Scholar
  • 5 Keller K, Hobohm L, Ebner M. et al. Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany. Eur Heart J 2020; 41 (04) 522-529
    CrossrefPubMedGoogle Scholar
  • 6 Delluc A, Tromeur C, Le Ven F. et al; EPIGETBO study group. Current incidence of venous thromboembolism and comparison with 1998: a community-based study in Western France. Thromb Haemost 2016; 116 (05) 967-974
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 CDC. Data and statistics on venous thromboembolism. Published 2020. Accessed June 1, 2021: https://www.cdc.gov/ncbddd/dvt/data.html
    Google Scholar
  • 8 Khan F, Rahman A, Carrier M. et al; MARVELOUS Collaborators. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ 2019; 366: l4363-l4363
    Google Scholar
  • 9 McRae SJ, Ginsberg JS. Initial treatment of venous thromboembolism. Circulation 2004; 110 (09, Suppl 1 : I3-I9
    CrossrefPubMedGoogle Scholar
  • 10 Wigle P, Hein B, Bloomfield HE, Tubb M, Doherty M. Updated guidelines on outpatient anticoagulation. Am Fam Physician 2013; 87 (08) 556-566
    PubMedGoogle Scholar
  • 11 Kakkos SK, Kirkilesis GI, Tsolakis IA. Editor's Choice - efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg 2014; 48 (05) 565-575
    CrossrefPubMedGoogle Scholar
  • 12 Sardar P, Chatterjee S, Mukherjee D. Efficacy and safety of new oral anticoagulants for extended treatment of venous thromboembolism: systematic review and meta-analyses of randomized controlled trials. Drugs 2013; 73 (11) 1171-1182
    CrossrefPubMedGoogle Scholar
  • 13 Yeh CH, Gross PL, Weitz JI. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood 2014; 124 (07) 1020-1028
    CrossrefPubMedGoogle Scholar
  • 14 van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124 (12) 1968-1975
    CrossrefPubMedGoogle Scholar
  • 15 Bertoletti L, Ollier E, Duvillard C. et al. Direct oral anticoagulants: current indications and unmet needs in the treatment of venous thromboembolism. Pharmacol Res 2017; 118: 33-42
    CrossrefPubMedGoogle Scholar
  • 16 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
    Google Scholar
  • 17 Ortel TL, Neumann I, Ageno W. et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19) 4693-4738
    CrossrefPubMedGoogle Scholar
  • 18 Moustafa F, Giorgi Pierfranceschi M, Di Micco P. et al; RIETE Investigators. Clinical outcomes during anticoagulant therapy in fragile patients with venous thromboembolism. Res Pract Thromb Haemost 2017; 1 (02) 172-179
    CrossrefPubMedGoogle Scholar
  • 19 Safieddine M, Chapelle C, Ollier E. et al. Compared to randomized studies, observational studies may overestimate the effectiveness of DOACs: a metaepidemiological approach. J Clin Epidemiol 2021; 130: 49-58
    CrossrefPubMedGoogle Scholar
  • 20 Weycker D, Li X, Wygant GD. et al. Effectiveness and safety of apixaban versus warfarin as outpatient treatment of venous thromboembolism in U.S. clinical practice. Thromb Haemost 2018; 118 (11) 1951-1961
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Dawwas GK, Smith SM, Dietrich E, Lo-Ciganic WH, Park H. Comparative effectiveness and safety of apixaban versus warfarin in patients with venous thromboembolism. Am J Health Syst Pharm 2020; 77 (03) 188-195
    CrossrefPubMedGoogle Scholar
  • 22 Coleman CI, Bunz TJ, Turpie AGG. Effectiveness and safety of rivaroxaban versus warfarin for treatment and prevention of recurrence of venous thromboembolism. Thromb Haemost 2017; 117 (10) 1841-1847
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Bezin J, Duong M, Lassalle R. et al. The national healthcare system claims databases in France, SNIIRAM and EGB: powerful tools for pharmacoepidemiology. Pharmacoepidemiol Drug Saf 2017; 26 (08) 954-962
    CrossrefPubMedGoogle Scholar
  • 24 Haute Autorité de Santé. ELIQUIS (apixaban), oral anticoagulant. Published 2015. Accessed June 28, 2021: https://www.has-sante.fr/jcms/c_2038860/fr/eliquis-apixaban-anticoagulant-par-voie-orale
    Google Scholar
  • 25 Haute Autorité de Santé. XARELTO (rivaroxaban), oral anticoagulant. Published 2013. Accessed June 28, 2021: https://www.has-sante.fr/jcms/c_1615053/fr/xarelto-rivaroxaban-anticoagulant-par-voie-orale
    Google Scholar
  • 26 European Medicines Agency. Eliquis. Published 2021. Accessed January 9, 2022: https://www.ema.europa.eu/en/medicines/human/EPAR/eliquis#:~:text=The%20recommended%20dose%20is%20one,mg%20taken%20twice%20a%20day
    Google Scholar
  • 27 European Medicines Agency. Xarelto. Accessed January 9, 2022 https://www.ema.europa.eu/en/medicines/human/EPAR/xarelto 2021
    Google Scholar
  • 28 Rothman KJ, Greenland S. Modern Epidemiology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2008
    Google Scholar
  • 29 Rothman KJ. Disengaging from statistical significance. Eur J Epidemiol 2016; 31 (05) 443-444
    CrossrefPubMedGoogle Scholar
  • 30 Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med 2015; 34 (28) 3661-3679
    CrossrefPubMedGoogle Scholar
  • 31 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
    Google Scholar
  • 32 Bauersachs R, Berkowitz SD, Brenner B. et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedGoogle Scholar
  • 33 Büller HR, Prins MH, Lensin AW. et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
    Google Scholar
  • 34 Gaertner S, Cordeanu E-M, Nouri S. et al. Rivaroxaban versus standard anticoagulation for symptomatic venous thromboembolism (REMOTEV observational study): analysis of 6-month outcomes. Int J Cardiol 2017; 226: 103-109
    CrossrefPubMedGoogle Scholar
  • 35 Cohen A, Keshishian A, Lee T. et al. Effectiveness and safety of apixaban, low-molecular-weight heparin, and warfarin among venous thromboembolism patients with active cancer: a U.S. claims data analysis. Thromb Haemost 2021; 121 (03) 383-395
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 2015; 11: 967-977
    CrossrefPubMedGoogle Scholar
  • 37 Allan V, Ramagopalan SV, Mardekian J. et al. Propensity score matching and inverse probability of treatment weighting to address confounding by indication in comparative effectiveness research of oral anticoagulants. J Comp Eff Res 2020; 9 (09) 603-614
    CrossrefPubMedGoogle Scholar
  • 38 Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health 2010; 13 (02) 273-277
    CrossrefPubMedGoogle Scholar
  • 39 Cambus JP, Magnin D, Ambid-Lacombe C. et al. Anticoagulant clinics are they effective in France? Performance evaluation of six anticoagulant clinics concerning the management of vitamin K antagonists [in French]. Rev Med Interne 2013; 34 (09) 515-521
    PubMedGoogle Scholar
  • 40 Mahé I, Bal dit Sollier C, Duru G, Lamarque H, Bergmann JF, Drouet L. Use and monitoring of vitamin K antagonists in everyday medical practice. French results of the international ISAM study of patients with nonvalvular atrial fibrillation [in French]. Presse Med 2006; 35 (12, Pt 1): 1797-1803
    PubMedGoogle Scholar
  • 41 Cotté FE, Benhaddi H, Duprat-Lomon I. et al. Vitamin K antagonist treatment in patients with atrial fibrillation and time in therapeutic range in four European countries. Clin Ther 2014; 36 (09) 1160-1168
    CrossrefPubMedGoogle Scholar
  • 42 Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011; 46 (03) 399-424
    CrossrefPubMedGoogle Scholar