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Sustained atrial fibrillation increases the risk of anticoagulation-related bleeding in heart failure

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Abstract

Background

Oral anticoagulation therapy in individuals with atrial fibrillation (AF) reduces the risk of thromboembolic events at cost of an increased bleeding risk. Whether anticoagulation-related outcomes differ between patients with paroxysmal and sustained AF receiving anticoagulation is controversially discussed.

Methods

In the present analysis of the prospective multi-center cohort study thrombEVAL, the incidence of anticoagulation-related adverse events was analyzed according to the AF phenotype. Information on outcome was centrally recorded over 3 years, validated via medical records and adjudicated by an independent review panel. Study monitoring was provided by an independent institution.

Results

Overall, the sample comprised 1089 AF individuals, of whom n = 398 had paroxysmal AF and n = 691 experienced sustained AF. In Cox regression analysis with adjustment for potential confounders, sustained AF indicated an independently elevated risk of clinically relevant bleeding compared to paroxysmal AF [hazard ratio (HR) 1.40 (1.02; 1.93); P = 0.038]. For clinically relevant bleeding, a significant interaction of the pattern of AF type with concomitant heart failure (HF) was detected: HRHF 2.45 (1.51, 3.98) vs. HRno HF 0.85 (0.55, 1.34); Pinteraction = 0.003. In HF patients, sustained AF indicated also an elevated risk of major bleeding [HR 2.25 (1.26, 4.20); P = 0.006]. A simplified HAS-BLED score incorporating only information on age (> 65 years), bleeding history, and HF with sustained AF demonstrated better discriminative performance for clinically relevant bleeding than the original version: AUCHAS-BLED: 0.583 vs. AUCsimplifiedHAS-BLED: 0.642 (P = 0.004).

Conclusions

In HF patients receiving oral anticoagulation, sustained AF indicates a substantially elevated risk of bleeding.

Clinical Trial Registration

https://clinicaltrials.gov, identifier: NCT01809015.

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Abbreviations

AF:

Atrial fibrillation

AUC:

Area under the curve

CI:

Confidence interval

CVRF:

Cardiovascular risk factor

HR:

Hazard ratio

IQR:

Interquartile range

TTR:

Time in therapeutic range

References

  1. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr et al (2014) 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 Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 64(21):e1–e76

    Article  Google Scholar 

  2. de Vos CB, Pisters R, Nieuwlaat R, Prins MH, Tieleman RG, Coelen RJ et al (2010) Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol 55(8):725–731

    Article  Google Scholar 

  3. Chiang CE, Naditch-Brule L, Murin J, Goethals M, Inoue H, O’Neill J et al (2012) Distribution and risk profile of paroxysmal, persistent, and permanent atrial fibrillation in routine clinical practice: insight from the real-life global survey evaluating patients with atrial fibrillation international registry. Circ Arrhythm Electrophysiol 5(4):632–639

    Article  Google Scholar 

  4. Hohnloser SH, Pajitnev D, Pogue J, Healey JS, Pfeffer MA, Yusuf S et al (2007) Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: an ACTIVE W Substudy. J Am Coll Cardiol 50(22):2156–2161

    Article  CAS  Google Scholar 

  5. Steinberg BA, Hellkamp AS, Lokhnygina Y, Patel MR, Breithardt G, Hankey GJ et al (2015) Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J 36(5):288–296

    Article  Google Scholar 

  6. Burgess S, Crown N, Louzada ML, Dresser G, Kim RB, Lazo-Langner A (2013) Clinical performance of bleeding risk scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin. J Thromb Haemost 11(9):1647–1654

    Article  CAS  Google Scholar 

  7. Ganesan AN, Chew DP, Hartshorne T, Selvanayagam JB, Aylward PE, Sanders P et al (2016) The impact of atrial fibrillation type on the risk of thromboembolism, mortality, and bleeding: a systematic review and meta-analysis. Eur Heart J 37(20):1591–1602

    Article  Google Scholar 

  8. van Walraven C, Oake N, Wells PS, Forster AJ (2007) Burden of potentially avoidable anticoagulant-associated hemorrhagic and thromboembolic events in the elderly. Chest 131(5):1508–1515

    Article  Google Scholar 

  9. Prochaska JH, Coldewey M, Gobel S, Keller K, Hendelmeier M, Konstantinides S et al (2015) Evaluation of oral anticoagulation therapy: rationale and design of the thrombEVAL study programme. Eur J Prev Cardiol 22(5):622–628

    Article  Google Scholar 

  10. Prochaska JH, Gobel S, Keller K, Coldewey M, Ullmann A, Lamparter H et al (2015) Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service—results from the prospective, multi-center, observational cohort study thrombEVAL. BMC Med 13:14

    Article  Google Scholar 

  11. Prochaska JH, Gobel S, Keller K, Coldewey M, Ullmann A, Lamparter H et al (2017) e-Health based management of patients receiving oral anticoagulation therapy: results from the observational thrombEVAL study. J Thromb Haemost 15(7):1375–1385

    Article  CAS  Google Scholar 

  12. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E (1993) A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 69(3):236–239

    Article  CAS  Google Scholar 

  13. De Vos CB, Breithardt G, Camm AJ, Dorian P, Kowey PR, Le Heuzey JY et al (2012) Progression of atrial fibrillation in the REgistry on Cardiac rhythm disORDers assessing the control of Atrial Fibrillation cohort: clinical correlates and the effect of rhythm-control therapy. Am Heart J 163(5):887–893

    Article  Google Scholar 

  14. Banerjee A, Taillandier S, Olesen JB, Lane DA, Lallemand B, Lip GY et al (2013) Pattern of atrial fibrillation and risk of outcomes: the Loire Valley Atrial Fibrillation Project. Int J Cardiol 167(6):2682–2687

    Article  Google Scholar 

  15. Al-Khatib SM, Thomas L, Wallentin L, Lopes RD, Gersh B, Garcia D et al (2013) Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J 34(31):2464–2471

    Article  CAS  Google Scholar 

  16. Goldberger JJ, Arora R, Green D, Greenland P, Lee DC, Lloyd-Jones DM et al (2015) Evaluating the atrial myopathy underlying atrial fibrillation: identifying the arrhythmogenic and thrombogenic substrate. Circulation 132(4):278–291

    Article  Google Scholar 

  17. Deng H, Bai Y, Shantsila A, Fauchier L, Potpara TS, Lip GYH (2017) Clinical scores for outcomes of rhythm control or arrhythmia progression in patients with atrial fibrillation: a systematic review. Clin Res Cardiol 106(10):813–823

    Article  Google Scholar 

  18. Rose AJ, Ozonoff A, Grant RW, Henault LE, Hylek EM (2009) Epidemiology of subtherapeutic anticoagulation in the United States. Circ Cardiovasc Qual Outcomes 2(6):591–597

    Article  Google Scholar 

  19. Levy S, Maarek M, Coumel P, Guize L, Lekieffre J, Medvedowsky JL et al (1999) Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. The College of French Cardiologists. Circulation 99(23):3028–3035

    Article  CAS  Google Scholar 

  20. Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA et al (2003) Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 107(23):2920–2925

    Article  Google Scholar 

  21. Nieuwlaat R, Eurlings LW, Cleland JG, Cobbe SM, Vardas PE, Capucci A et al (2009) Atrial fibrillation and heart failure in cardiology practice: reciprocal impact and combined management from the perspective of atrial fibrillation: results of the Euro Heart Survey on atrial fibrillation. J Am Coll Cardiol 53(18):1690–1698

    Article  Google Scholar 

  22. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ (2001) Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 285(22):2864–2870

    Article  CAS  Google Scholar 

  23. Scott ME, Patterson GC (1969) Cardiac output after direct current conversion of atrial fibrillation. Br Heart J 31(1):87–90

    Article  CAS  Google Scholar 

  24. Packer DL, Bardy GH, Worley SJ, Smith MS, Cobb FR, Coleman RE et al (1986) Tachycardia-induced cardiomyopathy: a reversible form of left ventricular dysfunction. Am J Cardiol 57(8):563–570

    Article  CAS  Google Scholar 

  25. Corley SD, Epstein AE, DiMarco JP, Domanski MJ, Geller N, Greene HL et al (2004) Relationships between sinus rhythm, treatment, and survival in the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) Study. Circulation 109(12):1509–1513

    Article  Google Scholar 

  26. Goodman SG, Wojdyla DM, Piccini JP, White HD, Paolini JF, Nessel CC et al (2014) Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol 63(9):891–900

    Article  Google Scholar 

  27. Nielsen PB, Lane DA, Rasmussen LH, Lip GY, Larsen TB (2015) Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol 104(5):418–429

    Article  CAS  Google Scholar 

  28. Chung I, Lip GY (2006) Platelets and heart failure. Eur Heart J 27(22):2623–2631

    Article  CAS  Google Scholar 

  29. Zannad F, Greenberg B, Cleland JG, Gheorghiade M, van Veldhuisen DJ, Mehra MR et al (2015) Rationale and design of a randomized, double-blind, event-driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial. Eur J Heart Fail 17(7):735–742

    Article  CAS  Google Scholar 

  30. Spronk HM, De Jong AM, Verheule S, De Boer HC, Maass AH, Lau DH et al (2017) Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J 38(1):38–50

    Article  CAS  Google Scholar 

  31. Oldgren J, Hijazi Z, Lindback J, Alexander JH, Connolly SJ, Eikelboom JW et al (2016) Performance and validation of a novel biomarker-based stroke risk score for atrial fibrillation. Circulation 134(22):1697–1707

    Article  CAS  Google Scholar 

  32. Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY (2012) Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS (evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial fibrillation) study. J Am Coll Cardiol 60(9):861–867

    Article  Google Scholar 

  33. Hijazi Z, Oldgren J, Lindback J, Alexander JH, Connolly SJ, Eikelboom JW et al (2016) The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 387(10035):2302–2311

    Article  CAS  Google Scholar 

  34. Visser LE, van Schaik RH, van Vliet M, Trienekens PH, De Smet PA, Vulto AG et al (2004) The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Thromb Haemost 92(1):61–66

    Article  CAS  Google Scholar 

  35. Hohnloser SH, Basic E, Nabauer M (2017) Comparative risk of major bleeding with new oral anticoagulants (NOACs) and phenprocoumon in patients with atrial fibrillation: a post-marketing surveillance study. Clin Res Cardiol 106(8):618–628

    Article  CAS  Google Scholar 

  36. Santhanakrishnan R, Wang N, Larson MG, Magnani JW, McManus DD, Lubitz SA et al (2016) Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved versus reduced ejection fraction. Circulation 133(5):484–492

    Article  Google Scholar 

  37. Cheng M, Lu X, Huang J, Zhang J, Zhang S, Gu D (2014) The prognostic significance of atrial fibrillation in heart failure with a preserved and reduced left ventricular function: insights from a meta-analysis. Eur J Heart Fail 16(12):1317–1322

    Article  Google Scholar 

  38. Lubitz SA, Benjamin EJ, Ruskin JN, Fuster V, Ellinor PT (2010) Challenges in the classification of atrial fibrillation. Nat Rev Cardiol 7(8):451–460

    Article  Google Scholar 

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Acknowledgements

We are indebted to all study participants of the thrombEVAL study and all co-workers of the Center for Thrombosis and Hemostasis of the University Medical Mainz. This work contains results that are a part of the doctoral thesis of Torben Knöpfler.

Funding

The thrombEVAL study was supported by the state initiative “health economy” of the Ministries of Health and Economics, Rhineland-Palatinate, Germany (Grant identifier: AZ.623-1), the Federal Ministry of Education and Research, Germany (Grant identifier: BMBF 10E01003), the Centre for Translational Vascular Biology (CTVB) of the University Medical Center Mainz, Boehringer Ingelheim Pharma GmbH & Co. KG, Bayer Vital GmbH, Daiichi Sankyo Europe GmbH, Sanofi-Aventis Germany GmbH, IMO Institute GmbH, Portavita BV and the German Heart Foundation. The sponsoring bodies played no role in the planning, conduct or analysis of this study.

Author information

Authors and Affiliations

  1. Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Jürgen H. Prochaska, Markus Nagler, Torben Knöpfler, Lisa Eggebrecht, Heidrun Lamparter & Philipp S. Wild

  2. Center for Thrombosis and Hemostasis, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany

    Jürgen H. Prochaska, Markus Nagler, Heidrun Lamparter, Marina Panova-Noeva, Karsten Keller, Meike Coldewey, Hugo ten Cate, Thomas Münzel & Philipp S. Wild

  3. German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany

    Jürgen H. Prochaska, Sebastian Göbel, Marina Panova-Noeva, Thomas Münzel & Philipp S. Wild

  4. Center for Translational Vascular Biology (CTVB), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany

    Jürgen H. Prochaska, Torben Knöpfler, Lisa Eggebrecht, Marina Panova-Noeva, Christine Espinola-Klein, Thomas Münzel & Philipp S. Wild

  5. Center for Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg University-Mainz, Mainz, Germany

    Sebastian Göbel, Karsten Keller, Christine Espinola-Klein & Thomas Münzel

  6. Department of Medicine I, Federal Armed Forces Central Hospital, Koblenz, Germany

    Christoph Bickel

  7. Department of Medicine 3, Barmherzige Brüder Hospital, Trier, Germany

    Michael Lauterbach

  8. Center for General Medicine and Geriatric Medicine, University Medical Center Mainz, Johannes Gutenberg University-Mainz, Mainz, Germany

    Roland Hardt

  9. Thrombosis Expertise Center Maastricht, Cardiovascular Research Institute Maastricht and Maastricht University Medical Center, 6200, Maastricht, The Netherlands

    Hugo ten Cate

  10. Center for Cardiology, Cardiology II, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany

    Thomas Rostock

Authors
  1. Jürgen H. Prochaska
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  2. Sebastian Göbel
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  3. Markus Nagler
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  4. Torben Knöpfler
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  11. Michael Lauterbach
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Correspondence to Jürgen H. Prochaska or Philipp S. Wild.

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Prochaska, J.H., Göbel, S., Nagler, M. et al. Sustained atrial fibrillation increases the risk of anticoagulation-related bleeding in heart failure. Clin Res Cardiol 107, 1170–1179 (2018). https://doi.org/10.1007/s00392-018-1293-4

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