Soluble Fibrin Monomer Complex and Prediction of Cardiovascular Events in Atrial Fibrillation: The Observational Murcia Atrial Fibrillation Project

  • José Miguel Rivera-Caravaca
  • Vanessa Roldán
  • Marta Romera
  • María Asunción Esteve-Pastor
  • Mariano Valdés
  • Gregory Y. H. Lip
  • Vicente Vicente
  • Francisco Marín
Original Research

Abstract

Background

Soluble fibrin monomer complex (SFMC) is a biomarker of fibrin formation abnormally elevated in clinical situations of hypercoagulability.

Objective

We investigated the association and predictive performance of SFMC for stroke, adverse cardiovascular events, cardiovascular mortality and all-cause mortality in a cohort of patients with atrial fibrillation (AF) receiving vitamin K antagonist (VKA) anticoagulant therapy.

Design

During the second semester of 2007, we included 1226 AF outpatients stable on VKAs (INR 2.0–3.0) over a period of 6 months. SFMC levels were assessed at baseline. During 6.5 (IQR 4.4–8.0) years of follow-up, we recorded all ischemic strokes, adverse cardiovascular events (composite of stroke, acute heart failure, acute coronary syndrome and cardiovascular death), cardiovascular deaths and all-cause deaths.

Participants

All patients were recruited consecutively. We excluded patients with rheumatic mitral valves, prosthetic heart valves, acute coronary syndrome, stroke, hemodynamic instability, hospital admissions or surgical interventions within the preceding 6 months.

Main Measures

SFMC levels were measured in plasma by immunoturbidimetry in an automated coagulometer (STALiatestFM, Diagnostica Stago, Asnieres, France).

Key Results

We recorded 121 (1.52%/year) ischemic strokes, 257 (3.23%/year) cardiovascular events, 67 (0.84%/year) cardiovascular deaths and 486 (6.10%/year) all-cause deaths. SFMC >12 μg/mL was not associated with stroke but was associated with higher risk of cardiovascular events (HR 1.72, 95% CI 1.31–2.26), cardiovascular mortality (HR 2.16, 95% CI 1.30–3.57) and all-cause mortality (HR 1.26, 95% CI 1.03–1.55). When SFMC >12 μg/mL was added to the CHA2DS2-VASc, there were significant improvements in predictive performance, sensitivity and reclassification for adverse cardiovascular events (c-index: 0.645 vs. 0.660, p = 0.010; IDI = 0.013, p < 0.001; NRI = 0.121, p < 0.001) and cardiovascular mortality (c-index: 0.661 vs. 0.691, p = 0.006; IDI = 0.009, p = 0.049; NRI = 0.217, p < 0.001), but decision curves demonstrated a similar net benefit and clinical usefulness.

Conclusions

In AF patients taking VKAs, high SFMC levels were associated with the risk of adverse cardiovascular events, cardiovascular mortality and all-cause mortality. The addition of SFMC to the CHA2DS2-VASc score improved its predictive performance for these outcomes, but failed to show an improvement in clinical usefulness.

KEY WORDS

atrial fibrillation anticoagulants soluble fibrin monomer complex biomarkers thrombosis mortality 

Notes

Compliance with Ethical Standards

Conflict of Interest

GYHL is a consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Microlife and Daiichi-Sankyo; and a speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche and Daiichi-Sankyo. No fees are received personally.

All remaining authors declare that they do not have a conflict of interest.

References

  1. 1.
    Lopez-Cuenca A, Marin F, Roldan V, Gonzalez-Conejero R, Hernandez-Romero D, Valdes M, et al. Genetic polymorphisms and atrial fibrillation: Insights into the prothrombotic state and thromboembolic risk. Ann Med. 2010;42:562–75.CrossRefPubMedGoogle Scholar
  2. 2.
    Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet. 2009;373:155–66.CrossRefPubMedGoogle Scholar
  3. 3.
    Spronk HM, De Jong AM, Verheule S, De Boer HC, Maass AH, Lau DH, et al. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J. 2017;38:38–50.CrossRefPubMedGoogle Scholar
  4. 4.
    Mitusch R, Siemens HJ, Garbe M, Wagner T, Sheikhzadeh A, Diederich KW. Detection of a hypercoagulable state in nonvalvular atrial fibrillation and the effect of anticoagulant therapy. Thromb Haemost. 1996;75:219–23.PubMedGoogle Scholar
  5. 5.
    Kahn SR, Solymoss S, Flegel KM. Nonvalvular atrial fibrillation: evidence for a prothrombotic state. CMAJ. 1997;157:673–81.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996;27:1760–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37:2893–962.CrossRefPubMedGoogle Scholar
  8. 8.
    Violi F, Soliman EZ, Pignatelli P, Pastori D. Atrial Fibrillation and Myocardial Infarction: A Systematic Review and Appraisal of Pathophysiologic Mechanisms. J Am Heart Assoc. 2016;5.Google Scholar
  9. 9.
    Polimeni L, Perri L, Saliola M, Basili S, Violi F. The risk of myocardial infarction in patients with atrial fibrillation: an unresolved issue. Intern Emerg Med. 2010;5:91–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Goto S, Bhatt DL, Rother J, Alberts M, Hill MD, Ikeda Y, et al. Prevalence, clinical profile, and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis. Am Heart J. 2008;156:855–63, 863.e852.CrossRefPubMedGoogle Scholar
  11. 11.
    Fauchier L, Villejoubert O, Clementy N, Bernard A, Pierre B, Angoulvant D, et al. Causes of deaths and influencing factors in patients with atrial fibrillation. Am J Med. 2016;129:1278–87.CrossRefPubMedGoogle Scholar
  12. 12.
    Singh N, Pati HP, Tyagi S, Upadhyay AD, Saxena R. Evaluation of the Diagnostic Performance of Fibrin Monomer in Comparison to d-Dimer in Patients With Overt and Nonovert Disseminated Intravascular Coagulation. Clin Appl Thromb Hemost. 2017;23:460–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Hou H, Ge Z, Ying P, Dai J, Shi D, Xu Z, et al. Biomarkers of deep venous thrombosis. J Thromb Thrombolysis. 2012;34:335–46.CrossRefPubMedGoogle Scholar
  14. 14.
    Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest. 2010;137:263–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093–1100.CrossRefPubMedGoogle Scholar
  16. 16.
    DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837–45.CrossRefPubMedGoogle Scholar
  17. 17.
    Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008;27:157–72; discussion 207–12.Google Scholar
  18. 18.
    Vickers AJ, Cronin AM, Elkin EB, Gonen M. Extensions to decision curve analysis, a novel method for evaluating diagnostic tests, prediction models and molecular markers. BMC Med Inform Decis Mak. 2008;8:53.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Vickers AJ, Elkin EB. Decision curve analysis: a novel method for evaluating prediction models. Med Decis Mak. 2006;26:565–74.CrossRefGoogle Scholar
  20. 20.
    Thomas MR, Lip GY. Novel Risk Markers and Risk Assessments for Cardiovascular Disease. Circ Res. 2017;120:133–49.CrossRefPubMedGoogle Scholar
  21. 21.
    Hijazi Z, Wallentin L, Siegbahn A, Andersson U, Christersson C, Ezekowitz J, et al. N-terminal pro-B-type natriuretic peptide for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation). J Am Coll Cardiol. 2013;61:2274–84.CrossRefPubMedGoogle Scholar
  22. 22.
    Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Ezekowitz MD, Hohnloser SH, et al. Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy. Circulation. 2012;125:1605–16.CrossRefPubMedGoogle Scholar
  23. 23.
    Ruff CT, Giugliano RP, Braunwald E, Murphy SA, Brown K, Jarolim P, et al. Cardiovascular Biomarker Score and Clinical Outcomes in Patients With Atrial Fibrillation: A Subanalysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial. JAMA Cardiol. 2016;1:999–1006.CrossRefPubMedGoogle Scholar
  24. 24.
    Danese E, Montagnana M, Cervellin G, Lippi G. Hypercoagulability, D-dimer and atrial fibrillation: an overview of biological and clinical evidence. Ann Med. 2014;46:364–71.CrossRefPubMedGoogle Scholar
  25. 25.
    Freedman B, Lip GY. “Unreal world” or “real world” data in oral anticoagulant treatment of atrial fibrillation. Thromb Haemost. 2016;116:587–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Rivera-Caravaca JM, Roldán V, Esteve-Pastor MA, Valdés M, Vicente V, Lip GYH, et al. Long-Term Stroke Risk Prediction in Patients With Atrial Fibrillation: Comparison of the ABC-Stroke and CHA2DS2-VASc Scores. J Am Heart Assoc. 2017;6:e006490.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Esteve-Pastor MA, Rivera-Caravaca JM, Roldan V, Vicente V, Valdes M, Marin F, et al. Long-term bleeding risk prediction in ‘real world’ patients with atrial fibrillation: Comparison of the HAS-BLED and ABC-Bleeding risk scores. The Murcia Atrial Fibrillation Project. Thromb Haemost. 2017;117:1848–58.CrossRefPubMedGoogle Scholar
  28. 28.
    Lee LV, Ewald GA, McKenzie CR, Eisenberg PR. The relationship of soluble fibrin and cross-linked fibrin degradation products to the clinical course of myocardial infarction. Arterioscler Thromb Vasc Biol. 1997;17:628–33.CrossRefPubMedGoogle Scholar
  29. 29.
    Saigo M, Waters DD, Abe S, Biro S, Minagoe S, Maruyama I, et al. Soluble fibrin, C-reactive protein, fibrinogen, factor VII, antithrombin, proteins C and S, tissue factor, D-dimer, and prothrombin fragment 1 + 2 in men with acute myocardial infarction </=45 years of age. Am J Cardiol. 2004;94:1410–3.CrossRefPubMedGoogle Scholar
  30. 30.
    Dopsaj V, Bogavac-Stanojevic N, Vasic D, Vukosavljevic D, Martinovic J, Kotur-Stevuljevic J, et al. Excluding deep venous thrombosis in symptomatic outpatients: is fibrin monomer aid to D-dimer analysis? Blood Coagul Fibrinolysis. 2009;20:546–51.CrossRefPubMedGoogle Scholar
  31. 31.
    Toth NK, Csanadi Z, Hajas O, Kiss A, Nagy-Balo E, Kovacs KB, et al. Intracardiac Hemostasis and Fibrinolysis Parameters in Patients with Atrial Fibrillation. Biomed Res Int. 2017;2017:3678017.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sadanaga T, Mitamura H. Soluble fibrin monomer complex levels during oral anticoagulant therapy do not predict subsequent thromboembolic events in patients with permanent atrial fibrillation. Int J Cardiol. 2013;168:578–80.CrossRefPubMedGoogle Scholar
  33. 33.
    García-Fernández A, Roldán V, Rivera-Caravaca JM, Hernández-Romero D, Valdés M, Vicente V, et al. Does von Willebrand factor improve the predictive ability of current risk stratification scores in patients with atrial fibrillation? Sci Rep. 2017;7:41565.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Pastori D, Farcomeni A, Poli D, Antonucci E, Angelico F, Del Ben M, et al. Cardiovascular risk stratification in patients with non-valvular atrial fibrillation: the 2MACE score. Intern Emerg Med. 2016;11:199–204.CrossRefPubMedGoogle Scholar
  35. 35.
    Soliman EZ, Safford MM, Muntner P, Khodneva Y, Dawood FZ, Zakai NA, et al. Atrial fibrillation and the risk of myocardial infarction. JAMA Intern Med. 2014;174:107–14.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society of General Internal Medicine 2018

Authors and Affiliations

  • José Miguel Rivera-Caravaca
    • 1
  • Vanessa Roldán
    • 1
  • Marta Romera
    • 2
  • María Asunción Esteve-Pastor
    • 3
  • Mariano Valdés
    • 3
  • Gregory Y. H. Lip
    • 4
    • 5
  • Vicente Vicente
    • 1
  • Francisco Marín
    • 3
  1. 1.Department of Hematology and Clinical Oncology Hospital General Universitario Morales Meseguer, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca)MurciaSpain
  2. 2.Department of HematologyHospital General Universitario Santa LucíaCartagenaSpain
  3. 3.Department of CardiologyHospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), CIBER-CVMurciaSpain
  4. 4.Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK
  5. 5.Aalborg Thrombosis Research Unit, Department of Clinical MedicineAalborg UniversityAalborgDenmark

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