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CC BY-NC-ND 4.0 · Thromb Haemost 2021; 121(03): 287-296
DOI: 10.1055/s-0040-1718410
Coagulation and Fibrinolysis

Long-Term Antithrombotic Treatments Prescribed for Cardiovascular Diseases in Patients with Hemophilia: Results from the French Registry

Benoît Guillet‡   *
1   Centre Régional de Traitement des Maladies Hémorragiques, CHU de Rennes, et Université de Rennes 1, France
2   CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail), Univ Rennes, UMR_S 1085, Rennes, France
,
Guillaume Cayla‡   *
3   Service de Cardiologie CHU de Nîmes, Université de Montpellier, Nimes, France
,
Aurélien Lebreton 
4   Centre Régional de Traitement des Hémophiles, CHU de Clermont-Ferrand, France
,
Nathalie Trillot
5   Centre Régional de Traitement des Hémophiles, CHU de Lille, France
,
Bénédicte Wibaut
5   Centre Régional de Traitement des Hémophiles, CHU de Lille, France
,
Céline Falaise
6   Centre Régional de Traitement des Hémophiles, CHU La Timone, Marseille, France
,
Sabine Castet
7   Centre Régional de Traitement des Hémophiles, CHU de Bordeaux, France
,
Philippe Gautier
8   Centre Régional de Traitement des Hémophiles, CHU de Caen, France
,
Ségolène Claeyssens
9   Centre Régional de Traitement des Hémophiles, CHU de Toulouse, France
,
Jean-François Schved
10   Centre Régional de Traitement des Hémophiles, Hôpital Saint-Eloi, CHRU de Montpellier, Montpellier, France
› Author Affiliations Funding The publication was sponsored by CSL Behring, France.
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Abstract

Cardiovascular diseases (CVDs) are a major issue in aging patients with hemophilia (PWHs). Antithrombotic agents are widely used in the general population for CVD treatment, but this recommendation is not fully applicable to PWHs. To improve treatment strategies, a prospective case–control study (COCHE) that analyzed CVD management and follow-up (2 years/patient) in PWHs was performed in France from 2011 to 2018. In total, 68 PWHs (median age: 65 years [39–89]; 48 mild, 10 moderate, and 10 severe hemophilia) were included (n = 50 with acute coronary syndrome, n = 17 with atrial fibrillation, n = 1 with both). They were matched with 68 control PWHs without antithrombotic treatment. In our series, bleeding was significantly influenced by (1) hemophilia severity, with a mean annualized bleeding ratio significantly higher in COCHE patients than in controls with basal clotting factor level up to 20%, (2) antihemorrhagic regimen (on-demand vs. prophylaxis) in severe (hazard ratio [HR] = 16.69 [95% confidence interval, CI: 8.2–47.26]; p < 0.0001) and moderate hemophilia (HR = 42.43 [95% CI: 1.86–966.1]; p = 0.0028), (3) type of antithrombotic treatment in mild hemophilia, with a significantly higher risk of bleeding in COCHE patients than in controls for dual-pathway therapy (HR = 15.64 [95% CI: 1.57–115.8]; p = 0.019), anticoagulant drugs alone (HR = 9.91 [95% CI: 1.34–73.47]; p = 0.0248), dual antiplatelet therapy (HR = 5.31 [95% CI: 1.23–22.92]; p = 0.0252), and single antiplatelet therapy (HR = 3.76 [95% CI: 1.13–12.55]; p = 0.0313); and (4) HAS-BLED score ≥3 (odds ratio [OR] = 33 [95% CI: 1.43–761.2]; p = 0.0065). Gastrointestinal bleeding was also significantly higher in COCHE patients than in controls (OR = 15 [95% CI: 1.84–268]; p = 0.0141). The COCHE study confirmed that antithrombotic treatments in PWHs are associated with increased bleeding rates in function of hemophilia-specific factors and also of known factors in the general population.

Keywords

antithrombotic treatment - atrial fibrillation - cardiovascular disease - hemophilia - bleeding risk

Authors' Contributions

All authors contributed to the study concept and design. B.G., G.C., and J-F.S. recruited patients, analyzed and interpreted results, and wrote the manuscript. A.L., B.W., C.F., S.C., P.G., and S.C. recruited patients.


* Benoît Guillet and Guillaume Cayla contributed equally to the present work.


Supplementary Material



Publication History

Received: 10 June 2019

Accepted: 28 August 2020

Article published online:
24 October 2020

© 2020. 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/).

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  • References

  • 1 Mannucci PM. Back to the future: a recent history of haemophilia treatment. Haemophilia 2008; 14 (Suppl. 03) 10-18
    CrossrefPubMedGoogle Scholar
  • 2 Walker IR, Julian JA. Association of Hemophilia Clinic Directors of Canada. Causes of death in Canadians with haemophilia 1980-1995. Haemophilia 1998; 4 (05) 714-720
    CrossrefPubMedGoogle Scholar
  • 3 Larsson SA. Life expectancy of Swedish haemophiliacs, 1831-1980. Br J Haematol 1985; 59 (04) 593-602
    CrossrefPubMedGoogle Scholar
  • 4 Darby SC, Kan SW, Spooner RJ. et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007; 110 (03) 815-825
    CrossrefPubMedGoogle Scholar
  • 5 Posthouwer D, Yee TT, Makris M. et al. Antiviral therapy for chronic hepatitis C in patients with inherited bleeding disorders: an international, multicenter cohort study. J Thromb Haemost 2007; 5 (08) 1624-1629
    CrossrefPubMedGoogle Scholar
  • 6 Ljung R, Petrini P, Lindgren AC, Tengborn L, Nilsson IM. Factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339 (8808): 1550
    CrossrefPubMedGoogle Scholar
  • 7 Hay CR. The epidemiology of factor VIII inhibitors. Haemophilia 2006; 12 (Suppl. 06) 23-28
    CrossrefPubMedGoogle Scholar
  • 8 Franchini M, Salvagno GL, Lippi G. Inhibitors in mild/moderate haemophilia A: an update. Thromb Haemost 2006; 96 (02) 113-118
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Windecker S, Kolh P, Alfonso F. et al. Authors/Task Force members. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35 (37) 2541-2619
    CrossrefPubMedGoogle Scholar
  • 10 Kirchhof P, Benussi S, Kotecha D. et al. ESC Scientific Document Group. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37 (38) 2893-2962
    CrossrefPubMedGoogle Scholar
  • 11 Andrade JG, Deyell MW, Wong GC, Macle L. Antithrombotic therapy for atrial fibrillation and coronary disease demystified. Can J Cardiol 2018; 34 (11) 1426-1436
    CrossrefPubMedGoogle Scholar
  • 12 Cayla G, Morange PE, Chambost H, Schved JF. Management of cardiovascular disease in haemophilia. Thromb Res 2013; 132 (01) 8-14
    CrossrefPubMedGoogle Scholar
  • 13 Ferraris VA, Boral LI, Cohen AJ, Smyth SS, White II GC. Consensus review of the treatment of cardiovascular disease in people with hemophilia A and B. Cardiol Rev 2015; 23 (02) 53-68
    CrossrefPubMedGoogle Scholar
  • 14 Schutgens REG, van der Heijden JF, Mauser-Bunschoten EP, Mannucci PM. New concepts for anticoagulant therapy in persons with hemophilia. Blood 2016; 128 (20) 2471-2474
    CrossrefPubMedGoogle Scholar
  • 15 Jabbar AY, Baydoun H, Janbain M, Ferdinand KC. Current concepts in the management of stable ischemic heart disease and acute coronary syndrome in patients with hemophilia. Ann Transl Med 2018; 6 (15) 299
    CrossrefPubMedGoogle Scholar
  • 16 Tosetto A, Castaman G, Rodeghiero F. Bleeders, bleeding rates, and bleeding score. J Thromb Haemost 2013; 11 (Suppl. 01) 142-150
    CrossrefPubMedGoogle Scholar
  • 17 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
    CrossrefPubMedGoogle Scholar
  • 18 Mannucci PM, Schutgens RE, Santagostino E, Mauser-Bunschoten EP. How I treat age-related morbidities in elderly persons with hemophilia. Blood 2009; 114 (26) 5256-5263
    CrossrefPubMedGoogle Scholar
  • 19 Staritz P, de Moerloose P, Schutgens R, Dolan G. ADVANCE Working Group. Applicability of the European Society of Cardiology guidelines on management of acute coronary syndromes to people with haemophilia - an assessment by the ADVANCE Working Group. Haemophilia 2013; 19 (06) 833-840
    CrossrefPubMedGoogle Scholar
  • 20 Martin K, Key NS. How I treat patients with inherited bleeding disorders who need anticoagulant therapy. Blood 2016; 128 (02) 178-184
    CrossrefPubMedGoogle Scholar
  • 21 Triemstra M, Rosendaal FR, Smit C, Van der Ploeg HM, Briët E. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Intern Med 1995; 123 (11) 823-827
    CrossrefPubMedGoogle Scholar
  • 22 Plug I, Van Der Bom JG, Peters M. et al. Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study. J Thromb Haemost 2006; 4 (03) 510-516
    CrossrefPubMedGoogle Scholar
  • 23 Tuinenburg A, Mauser-Bunschoten EP, Verhaar MC, Biesma DH, Schutgens RE. Cardiovascular disease in patients with hemophilia. J Thromb Haemost 2009; 7 (02) 247-254
    CrossrefPubMedGoogle Scholar
  • 24 Sharathkumar AA, Soucie JM, Trawinski B, Greist A, Shapiro AD. Prevalence and risk factors of cardiovascular disease (CVD) events among patients with haemophilia: experience of a single haemophilia treatment centre in the United States (US). Haemophilia 2011; 17 (04) 597-604
    CrossrefPubMedGoogle Scholar
  • 25 January CT, Wann LS, Calkins H. et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74 (01) 104-132
    CrossrefPubMedGoogle Scholar
  • 26 Proietti M, Lane DA, Boriani G, Lip GYH. Stroke prevention, evaluation of bleeding risk, and anticoagulant treatment management in atrial fibrillation contemporary international guidelines. Can J Cardiol 2019; 35 (05) 619-633
    CrossrefPubMedGoogle Scholar
  • 27 Knuuti J, Wijns W, Saraste A. et al. ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2019; 00: 1-71
    PubMedGoogle Scholar
  • 28 Neumann FJ, Sousa-Uva M, Ahlsson A. et al. ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019; 40 (02) 87-165
    CrossrefPubMedGoogle Scholar
  • 29 Den Uijl IE, Mauser Bunschoten EP, Roosendaal G. et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand?. Haemophilia 2011; 17 (06) 849-853
    CrossrefPubMedGoogle Scholar
  • 30 Gómez-Outes A, Lagunar-Ruíz J, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol 2016; 68 (23) 2508-2521
    CrossrefPubMedGoogle Scholar
  • 31 Yu JK, Iorio A, Edginton AN. WAPPS co-investigators. Using pharmacokinetics for tailoring prophylaxis in people with hemophilia switching between clotting factor products: a scoping review. Res Pract Thromb Haemost 2019; 3 (03) 528-541
    CrossrefPubMedGoogle Scholar
  • 32 Mahlangu J. rFVIIIFC for hemophilia A prophylaxis. Expert Rev Hematol 2018; 11 (12) 937-943
    CrossrefPubMedGoogle Scholar
  • 33 Morfini M, Gherardini S. Pharmacokinetic-based prediction of real-life dosing of extended half-life clotting factor concentrates on hemophilia. Ther Adv Hematol 2018; 9 (06) 149-162
    CrossrefPubMedGoogle Scholar
  • 34 Fukushi K, Tominaga K, Nagashima K. et al. Gastroduodenal ulcer bleeding in elderly patients on low dose aspirin therapy. World J Gastroenterol 2018; 24 (34) 3908-3918
    CrossrefPubMedGoogle Scholar
  • 35 Szabó IL, Mátics R, Hegyi P. et al. PPIs prevent aspirin-induced gastrointestinal bleeding better than H2RAs. A systematic review and meta-analysis. J Gastrointestin Liver Dis 2017; 26 (04) 395-402
    CrossrefPubMedGoogle Scholar
  • 36 Moayyedi P, Eikelboom JW, Bosch J. et al. COMPASS Investigators. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology 2019; 157 (03) 682.e2-691.e2
    CrossrefPubMedGoogle Scholar