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Journal of Thrombosis and Thrombolysis

, Volume 46, Issue 3, pp 316–324 | Cite as

Warfarin for prevention of thromboembolism in atrial fibrillation: comparison of patient characteristics and outcomes of the “Real-World” Michigan Anticoagulation Quality Improvement Initiative (MAQI2) registry to the RE-LY, ROCKET-AF, and ARISTOTLE trials

  • Andrew B. Hughey
  • Xiaokui Gu
  • Brian Haymart
  • Eva Kline-Rogers
  • Steve Almany
  • Jay Kozlowski
  • Dennis Besley
  • Gregory D. Krol
  • Syed Ahsan
  • Scott Kaatz
  • James B. Froehlich
  • Geoffrey D. Barnes
Article
  • 135 Downloads

Abstract

Randomized controlled trials (RCTs) examining warfarin use for stroke prevention in atrial fibrillation (AF) may not accurately reflect real-world populations. We aimed to determine the representativeness of the RCT populations to real-world patients and to describe differences in the characteristics of trial populations from trial eligible patients in a real-world setting. We hypothesized that a significant fraction of real-world patients would not qualify for the RE-LY, ROCKET-AF, and ARISTOTLE trials and that real-world patients qualifying for the studies may have more strokes and bleeding events. We compared the inclusion and exclusion criteria, patient characteristics, and clinical outcomes from RE-LY, ROCKET-AF, and ARISTOTLE against data from the Michigan Anticoagulation Quality Improvement Initiative (MAQI2), a regional network of six community- and academic-based anticoagulation clinics. Of the 1446 non-valvular AF patients in the MAQI2 registry taking warfarin, approximately 40–60% would meet the selection criteria used in RE-LY (788, 54.5%), ROCKET-AF (566, 39.1%), and ARISTOTLE (866, 59.9%). The most common reasons for exclusion from one or more trial were anemia (15.1%), other concurrent medications (11.2%), and chronic kidney disease (9.4%). Trial-eligible MAQI2 patients were older, more frequently female, with a higher rate of paroxysmal AF, and lower rates of congestive heart failure, previous stroke, and previous myocardial infarction than the trial populations. MAQI2 patients eligible for each trial had a lower rate of stroke and similar rate of major bleeding than was observed in the trials. A sizable proportion of real-world AF patients managed in anticoagulation clinics would not have been eligible for the RE-LY, ROCKET-AF, and ARISOTLE trials. The expected stroke risk reduction and bleeding risk among real-world AF patients on warfarin may not be congruent with published clinical trial data.

Keywords

Atrial fibrillation Anticoagulation Warfarin Real world Outcomes 

Notes

Acknowledgements

Blue Cross-Blue Shield of Michigan/Blue Care Network provided funding for data collection and analysis, but was not involved in the interpretation of the data, the decision to publish, or the preparation of the manuscript. GB is supported on the NIH grant T32-HL007853.

Compliance with Ethical Standards

Conflict of interest

Steve Almany: Grant support from Boston Scientific Watchman, Michigan Anticoagulation Quality, and Abbott Absorb trial. Consultant for Kona, Trice Orthopedics, and Micardia. Ownership/partnership/principal with Biostar Ventures and Ablative Solutions. Scott Kaatz: Grant support from Boehringer-Ingelheim, Bristol-Myers Squibb, Bayer/Jansen/Johnson and Johnson, Eisai, Iverson Genetics Diagnostics/Medicare, National Institute of Health, Canadian Institute of Health Research, Blue Cross/Blue Shield of Michigan. Speaker honorarium from Jansen/Johnson and Johnson, Boehringer-Ingelheim, and Bristol-Myers Squibb. Consultant for Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Jansen/Johnson and Johnson, and Daiichi Sankyo. Non-profit board membership with AC Forum, National Certification Board of Anticoagulation Providers, and National Blood Clot Alliance Medical and Scientific Advisory Board. James B. Froehlich: Consultant for Merck, Bristol-Meyers Squibb, Pfizer, Sanofi-Aventis, Janssen Pharamaceuticals, Aralez and Ortho-McNeil. Research grants from Sanofi-Aventis, Blue Cross/Blue Shield of Michigan, Mardigian Foundation, Fibromuscular Disease Society of America. Geoffrey D. Barnes: Research grant support from Bristol Meyers Squibb/Pfizer and Blue Cross/Blue Shield of Michigan. Consultant for Portola and Aralez. Andrew B. Hughey, Xiaokui Gu, Brian Haymart, Eva Kline-Rogers, Jay Kozlowski, Dennis Besley, Gregory D. Krol, Syed Ahsan, declares that they have no conflict of interest.

Supplementary material

11239_2018_1698_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 KB)

References

  1. 1.
    Wolf PA, Abbott RD, Kannel WB (1991) Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22(8):983–988CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B (1989) Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet 333(8631):175–179CrossRefGoogle Scholar
  3. 3.
    The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators (1990) The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. New Engl J Med 323(22):1505–1511.  https://doi.org/10.1056/NEJM199011293232201 CrossRefGoogle Scholar
  4. 4.
    Stroke Prevention in Atrial Fibrillation Study (1991) Final results. Circulation 84(2):527–539CrossRefGoogle Scholar
  5. 5.
    Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, Krause-Steinrauf H, Kurtzke JF, Nazarian SM, Radford MJ, Veterans affairs stroke prevention in nonrheumatic atrial fibrillation investigators et al (1992) Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. New Engl J Med 327(20):1406–1412.  https://doi.org/10.1056/NEJM199211123272002 CrossRefPubMedGoogle Scholar
  6. 6.
    EAFT (European Atrial Fibrillation Trial) Study Group (1993) Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 342(8882):1255–1262Google Scholar
  7. 7.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, Committee R-LS, Investigators (2009) Dabigatran versus warfarin in patients with atrial fibrillation. New Engl J Med 361(12):1139–1151.  https://doi.org/10.1056/NEJMoa0905561 CrossRefPubMedGoogle Scholar
  8. 8.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM, Investigators RA (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 365(10):883–891.  https://doi.org/10.1056/NEJMoa1009638 CrossRefPubMedGoogle Scholar
  9. 9.
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L, Committees A, Investigators (2011) Apixaban versus warfarin in patients with atrial fibrillation. New Engl J Med 365(11):981–992.  https://doi.org/10.1056/NEJMoa1107039 CrossRefPubMedGoogle Scholar
  10. 10.
    Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, Singer DE (2010) Warfarin discontinuation after starting warfarin for atrial fibrillation. Circ Cardiovasc Qual Outcomes 3(6):624–631.  https://doi.org/10.1161/CIRCOUTCOMES.110.937680 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Reynolds MR, Shah J, Essebag V, Olshansky B, Friedman PA, Hadjis T, Lemery R, Bahnson TD, Cannom DS, Josephson ME, Zimetbaum P (2006) Patterns and predictors of warfarin use in patients with new-onset atrial fibrillation from the FRACTAL Registry. Am J Cardiol 97(4):538–543.  https://doi.org/10.1016/j.amjcard.2005.09.086 CrossRefPubMedGoogle Scholar
  12. 12.
    Reynolds MW, Fahrbach K, Hauch O, Wygant G, Estok R, Cella C, Nalysnyk L (2004) Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest 126(6):1938–1945.  https://doi.org/10.1378/chest.126.6.1938 CrossRefPubMedGoogle Scholar
  13. 13.
    Baker WL, Cios DA, Sander SD, Coleman CI (2009) Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Managed Care Pharm 15(3):244–252CrossRefGoogle Scholar
  14. 14.
    Barnes GD, Kaatz S, Golgotiu V, Gu X, Leidal A, Kobeissy A, Haymart B, Kline-Rogers E, Kozlowski J, Almany S, Leyden T, Froehlich JB (2013) Use of warfarin for venous thromboembolism prophylaxis following knee and hip arthroplasty: results of the Michigan Anticoagulation Quality Improvement Initiative (MAQI2). J Thromb Thrombolysis 35(1):10–14.  https://doi.org/10.1007/s11239-012-0766-y CrossRefPubMedGoogle Scholar
  15. 15.
    Michigan Anticoagulation Quality Improvement Initiative Website (2014) http://www.maqi2.org
  16. 16.
    Connolly SJ, Wallentin L, Yusuf S (2014) Additional events in the RE-LY trial. New Engl J Med 371(15):1464–1465.  https://doi.org/10.1056/NEJMc1407908 CrossRefPubMedGoogle Scholar
  17. 17.
    Lopes RD, Alexander JH, Al-Khatib SM, Ansell J, Diaz R, Easton JD, Gersh BJ, Granger CB, Hanna M, Horowitz J, Hylek EM, McMurray JJ, Verheugt FW, Wallentin L, Investigators A (2010) Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 159(3):331–339.  https://doi.org/10.1016/j.ahj.2009.07.035 CrossRefPubMedGoogle Scholar
  18. 18.
    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):2864–2870CrossRefPubMedGoogle Scholar
  19. 19.
    Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E (1993) A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 69(3):236–239CrossRefPubMedGoogle Scholar
  20. 20.
    Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the S, Standardization Committee of the International Society on T, Haemostasis (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 3(4):692–694.  https://doi.org/10.1111/j.1538-7836.2005.01204.x CrossRefPubMedGoogle Scholar
  21. 21.
    Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, for the Subcommittee on Control of Anticoagulation (2015) Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 13(11):2119–2126CrossRefGoogle Scholar
  22. 22.
    Van Spall HG, Wallentin L, Yusuf S, Eikelboom JW, Nieuwlaat R, Yang S, Kabali C, Reilly PA, Ezekowitz MD, Connolly SJ (2012) Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: an analysis of patients receiving warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation 126(19):2309–2316.  https://doi.org/10.1161/CIRCULATIONAHA.112.101808 CrossRefPubMedGoogle Scholar
  23. 23.
    Singer DE, Hellkamp AS, Piccini JP, Mahaffey KW, Lokhnygina Y, Pan G, Halperin JL, Becker RC, Breithardt G, Hankey GJ, Hacke W, Nessel CC, Patel MR, Califf RM, Fox KA, Investigators RA (2013) Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial. J Am Heart Assoc 2(1):e000067.  https://doi.org/10.1161/JAHA.112.000067 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sahai H, Khurshid A (1996) Statistics in epidemiology: methods, techniques, and applications. CRC Press, Boca RatonGoogle Scholar
  25. 25.
    Lee S, Monz BU, Clemens A, Brueckmann M, Lip GY (2012) Representativeness of the dabigatran, apixaban and rivaroxaban clinical trial populations to real-world atrial fibrillation patients in the United Kingdom: a cross-sectional analysis using the General Practice Research Database. BMJ Open.  https://doi.org/10.1136/bmjopen-2012-001768 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Schoof N, Schnee J, Schneider G, Gawlik M, Zint K, Clemens A, Bartels DB (2014) Characteristics of patients with non-valvular atrial fibrillation using dabigatran or warfarin in the US. Curr Med Res Opin 30(5):795–804.  https://doi.org/10.1185/03007995.2013.879529 CrossRefPubMedGoogle Scholar
  27. 27.
    Desai NR, Krumme AA, Schneeweiss S, Shrank WH, Brill G, Pezalla EJ, Spettell CM, Brennan TA, Matlin OS, Avorn J, Choudhry NK (2014) Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications. Am J Med 127(11):1075–1082.  https://doi.org/10.1016/j.amjmed.2014.05.013 CrossRefPubMedGoogle Scholar
  28. 28.
    Lip GY (2007) Coronary artery disease and ischemic stroke in atrial fibrillation. Chest 132(1):8–10.  https://doi.org/10.1378/chest.07-0500 CrossRefPubMedGoogle Scholar
  29. 29.
    Conway DS, Lip GY (2004) Comparison of outcomes of patients with symptomatic peripheral artery disease with and without atrial fibrillation (the West Birmingham Atrial Fibrillation Project). Am J Cardiol 93(11):1422–1425.  https://doi.org/10.1016/j.amjcard.2004.02.047 CrossRefPubMedGoogle Scholar
  30. 30.
    Siu CW, Jim MH, Ho HH, Miu R, Lee SW, Lau CP, Tse HF (2007) Transient atrial fibrillation complicating acute inferior myocardial infarction: implications for future risk of ischemic stroke. Chest 132(1):44–49.  https://doi.org/10.1378/chest.06-2733 CrossRefPubMedGoogle Scholar
  31. 31.
    Schmitt J, Duray G, Gersh BJ, Hohnloser SH (2009) Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J 30(9):1038–1045.  https://doi.org/10.1093/eurheartj/ehn579 CrossRefPubMedGoogle Scholar
  32. 32.
    Steinberg BA, Hellkamp AS, Lokhnygina Y, Patel MR, Breithardt G, Hankey GJ, Becker RC, Singer DE, Halperin JL, Hacke W, Nessel CC, Berkowitz SD, Mahaffey KW, Fox KA, Califf RM, Piccini JP, Committee R-AS, Investigators (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.  https://doi.org/10.1093/eurheartj/ehu359 CrossRefPubMedGoogle Scholar
  33. 33.
    Vanassche T, Lauw MN, Eikelboom JW, Healey JS, Hart RG, Alings M, Avezum A, Diaz R, Hohnloser SH, Lewis BS, Shestakovska O, Wang J, Connolly SJ (2015) Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES. Eur Heart J 36(5):281–287.  https://doi.org/10.1093/eurheartj/ehu307 CrossRefPubMedGoogle Scholar
  34. 34.
    Al-Khatib SM, Thomas L, Wallentin L, Lopes RD, Gersh B, Garcia D, Ezekowitz J, Alings M, Yang H, Alexander JH, Flaker G, Hanna M, Granger CB (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.  https://doi.org/10.1093/eurheartj/eht135 CrossRefPubMedGoogle Scholar
  35. 35.
    Raji M, Lowery M, Lin YL, Kuo YF, Baillargeon J, Goodwin JS (2013) National utilization patterns of warfarin use in older patients with atrial fibrillation: a population-based study of Medicare Part D beneficiaries. Ann Pharmacother 47(1):35–42.  https://doi.org/10.1345/aph.1R515 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Andrew B. Hughey
    • 1
  • Xiaokui Gu
    • 1
  • Brian Haymart
    • 1
  • Eva Kline-Rogers
    • 1
  • Steve Almany
    • 2
  • Jay Kozlowski
    • 3
  • Dennis Besley
    • 4
  • Gregory D. Krol
    • 5
  • Syed Ahsan
    • 5
  • Scott Kaatz
    • 6
  • James B. Froehlich
    • 1
  • Geoffrey D. Barnes
    • 1
  1. 1.Frankel Cardiovascular CenterUniversity of Michigan Health SystemAnn ArborUSA
  2. 2.Michigan Heart GroupWilliam Beaumont HospitalRoyal OakUSA
  3. 3.Cardiology and Vascular AssociatesHuron Valley-Sinai HospitalCommerce TownshipUSA
  4. 4.West Michigan HeartGrand RapidsUSA
  5. 5.Henry Ford HospitalDetroitUSA
  6. 6.Hurley Medical CenterFlintUSA

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