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Estimation of the impact of warfarin’s time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials

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Abstract

Warfarin’s time-in-therapeutic range (TTR) is highly variable among patients with nonvalvular atrial fibrillation (NVAF). The objective of this study was to estimate the impact of variations in wafarin’s TTR on rates of stroke/systemic embolism (SSE) and major bleedings among NVAF patients in the ARISTOTLE, ROCKET-AF, and RE-LY trials. Additionally, differences in medical costs for clinical endpoints when novel oral anticoagulants (NOACs) were used instead of warfarin at different TTR values were estimated. Quartile ranges of TTR values and corresponding event rates (%/patient − year = %/py) of SSE and major bleedings among NVAF patients treated with warfarin were estimated from published literature and FDA documents. The associations of SSE and major bleeding rates with TTR values were evaluated by regression analysis and then the calculated regression coefficients were used in analysis of medical cost differences associated with use of each NOAC versus warfarin (2010 costs; US payer perspective) at different TTRs. Each 10 % increase in warfarin’s TTR correlated with a −0.32 %/py decrease in SSE rate (R2 = 0.61; p < 0.001). Although, the rate of major bleedings decreased as TTR increased, it was not significant (−0.035 %/py, p = 0.63). As warfarin’s TTR increased from 30 to 90 % the estimated medical cost decreased from −$902 to −$83 for apixaban, from −$506 to +$314 for rivaroxaban, and from −$596 to +$223 for dabigatran. Among NVAF patients there is a significant negative correlation between warfarin’s TTR and SSE rate, but not major bleedings. The variations in warfarin’s TTR impacted the economic comparison of use of individual NOACs versus warfarin.

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References

  1. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS (2006) Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980–2000, and implications on the projections for future prevalence. Circulation 114:119–125

    Article  PubMed  Google Scholar 

  2. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and risk factors in atrial fibrillation (ATRIA) study. JAMA 285:2370–2375

    Article  CAS  PubMed  Google Scholar 

  3. Miniño BAM, Murphy SL, Jiaquan X, Kochanek KD (2011) National vital statistics reports deaths: final data for 2008 59:1–157

  4. Naccarelli GV, Varker H, Lin J, Schulman KL (2009) Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol 104:1534–1539

    Article  PubMed  Google Scholar 

  5. Kim MH, Lin J, Hussein M, Kreilick C, Battleman D (2009) Cost of atrial fibrillation in United States managed care organizations. Adv Ther 26:847–857

    Article  PubMed  Google Scholar 

  6. Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146:857–867

    Article  PubMed  Google Scholar 

  7. Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, Lip GY, Manning WJ, American College of Chest Physicians (2008) Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 133:546S–592S

    Article  CAS  PubMed  Google Scholar 

  8. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS (2011) 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 57:e101–e198

    Article  PubMed  Google Scholar 

  9. Atrial Fibrillation Investigators (1994) Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 154:1449–1457

    Article  Google Scholar 

  10. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, American College of Chest Physicians (2008) Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 133:160S–198S

    Article  CAS  PubMed  Google Scholar 

  11. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S (2006) Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 367:1903–1912

    Article  CAS  PubMed  Google Scholar 

  12. The SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators (1998) Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III Study. JAMA 279:1273–1277

    Article  Google Scholar 

  13. Miura T, Nishinaka T, Terada T, Yonezawa K (2009) Relationship between aging and dosage of warfarin: the current status of warfarin anticoagulant therapy for Japanese outpatients in a Department of Cardiovascular Medicine. J Cardiol 53:355–360

    Article  PubMed  Google Scholar 

  14. 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 Manag Care Pharm 15:244–252

    PubMed  Google Scholar 

  15. Birman-Deych E, Radford MJ, Nilasena DS, Gage BF (2006) Use and effectiveness of warfarin in medicare beneficiaries with atrial fibrillation. Stroke 37:1070–1074

    Article  CAS  PubMed  Google Scholar 

  16. Caro JJ (2004) An economic model of stroke in atrial fibrillation: the cost of suboptimal oral anticoagulation. Am J Manag Care 10:S451–S458

    PubMed  Google Scholar 

  17. Chiquette E, Amato MG, Bussey HI (1998) Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and health care costs. Arch Intern Med 158:1641–1647

    Article  CAS  PubMed  Google Scholar 

  18. 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, RE-LY Steering Committee Investigators (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151

    Article  CAS  PubMed  Google Scholar 

  19. 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, ARISTOTLE Committees Investigators (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992

    Article  CAS  PubMed  Google Scholar 

  20. 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, ROCKETAF Investigators (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891

    Article  CAS  PubMed  Google Scholar 

  21. Deitelzweig S, Amin A, Jing Y, Makenbaeva D, Wiederkehr D, Lin J, Graham J (2012) Medical cost reductions associated with the usage of novel oral anticoagulants versus warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF and ARISTOTLE trials. J Med Econ 15:776–785

    Article  PubMed  Google Scholar 

  22. Boehringer Ingelheim Pharmaceuticals Inc. FDA draft briefing document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC). NDA 22-512: PRADAXA® (dabigatran etexilate) tablets

  23. Janssen Pharmaceuticals Inc (2011) FDA draft briefing document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC). NDA 202439: XARELTO® (rivaroxaban) tablets

  24. Bureau of Labor Statistics US Department of Labor. Consumer Price Index December 2010. USDL-11-0018 2011. http://www.bls.gov/news.release/archives/cpi_01142011.pdf. Accessed 17 May 2013

  25. Mercaldi CJ, Ciarametaro M, Hahn B, Chalissery G, Reynolds MW, Sander SD, Samsa GP, Matchar DB (2011) Cost efficiency of anticoagulation with warfarin to prevent stroke in medicare beneficiaries with nonvalvular atrial fibrillation. Stroke 42:112–118

    Article  PubMed  Google Scholar 

  26. Sorensen SV, Kansal AR, Connolly S, Peng S, Linnehan J, Bradley-Kennedy C, Plumb JM (2011) Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective. Throm Haemost 105:908–919

    Article  CAS  Google Scholar 

  27. Earnshaw SR, Scheiman J, Fendrick AM, McDade C, Pignone M (2011) Cost-utility of aspirin and proton pump inhibitors for primary prevention. Arch Intern Med 171:218–225

    Article  PubMed Central  PubMed  Google Scholar 

  28. Spyropoulos AC, Lin J (2007) Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. J Manag Care Pharm 13:475–486

    PubMed  Google Scholar 

  29. Center for Medicare and Medicaid Services. Medicare fee schedule, payment and reimbursement benefit guideline, CPT code billing: medicare fee schedule for office visit CPT codes—2011, CPT code 99213, 99214, 99203. http://www.medicarepaymentandreimbursement.com/p/medicare-fee-schedule-for-office-visit.html. Accessed 17 May 2013

  30. Wallentin L, Lopes RD, Hanna M et al (2013) Efficacy and safety of apixaban compared with warfarin at different levels of predicted INR control for stroke prevention in atrial fibrillation. Circulation 127:2166–2176

    Article  CAS  PubMed  Google Scholar 

  31. Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG, Healey JS, Yusuf S, ACTIVEW Investigators (2008) Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 118:2029–2037

    Article  CAS  PubMed  Google Scholar 

  32. Gottlieb LK, Salem-Schatz S (1994) Anticoagulation in atrial fibrillation. Does efficacy in clinical trials translate into effectiveness in practice? Arch Intern Med 154:1945–1953

    Article  CAS  PubMed  Google Scholar 

  33. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ, RE-LY investigators (2010) Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 376:975–983

    Article  CAS  PubMed  Google Scholar 

  34. Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, Singer DE (2011) A new risk scheme to predict warfarin-associated hemorrhage: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. J Am Coll Cardiol 58:395–401

    Article  PubMed Central  PubMed  Google Scholar 

  35. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S (2007) Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 115:2689–2696

    Article  CAS  PubMed  Google Scholar 

  36. Ansell JE, Hughes R (1996) Evolving models of warfarin management: anticoagulation clinics, patient self-monitoring, and patient self-management. Am Heart J 132:1095–1100

    Article  CAS  PubMed  Google Scholar 

  37. White HD, Gruber M, Feyzi J, Kaatz S, Tse HF, Husted S, Albers GW (2007) Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Arch Intern Med 167:239–245

    Article  CAS  PubMed  Google Scholar 

  38. Veeger NJ, Piersma-Wichers M, Tijssen JG, Hillege HL, van der Meer J (2005) Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Br J Haematol 128:513–519

    Article  PubMed  Google Scholar 

  39. Analy$ource Online (2013) First Databank Inc., South San Francisco

  40. Harrington AR, Armstrong EP, Nolan PE Jr, Malone DC (2013) Cost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation. Stroke 44:1676–1681

    Article  PubMed  Google Scholar 

  41. The Henry J Kaiser Family Foundation. US health care costs: issue modules, background brief. http://www.kaiseredu.org/Issue-Modules/US-Health-Care-Costs/Background-Brief.aspx. Accessed 17 May 2013

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Acknowledgments

This research was supported by Bristol-Myers Squibb and Pfizer. We would like to acknowledge M. Lingohr-Smith from Novosys Health for the editorial support and review of this manuscript. This support was funded by Bristol-Myers Squibb and Pfizer.

Conflict of interest

Y. Jing, D. Makenbaeva and J. Graham are employees of Bristol-Myers Squibb and own stock in the company. D. Wiederkehr is an employee of Pfizer and owns stock in the company. J. Lin is an employee of Novosys Health, which has received financial support from Bristol-Myers Squibb and Pfizer in connection with conducting this study and development of this manuscript. A. Amin and S. Deitelzweig are paid consultants for Novosys Health in connection with conducting this study.

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Authors and Affiliations

  1. Department of Medicine, Hospitalist Program, School of Medicine, University of California, UCIMC, 101 The City Drive South, Building 58, Room 110, ZC-4076H, Mail Code: 4076, Irvine, CA, 92868, USA

    Alpesh Amin

  2. Ochsner Clinic Foundation, New Orleans, LA, USA

    Steve Deitelzweig

  3. Bristol-Myers Squibb, Plainsboro, NJ, USA

    Yonghua Jing, Dinara Makenbaeva & John Graham

  4. Pfizer, New York City, NY, USA

    Daniel Wiederkehr

  5. Novosys Health, Flemington, NJ, USA

    Jay Lin

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  1. Alpesh Amin
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Correspondence to Alpesh Amin.

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Amin, A., Deitelzweig, S., Jing, Y. et al. Estimation of the impact of warfarin’s time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials. J Thromb Thrombolysis 38, 150–159 (2014). https://doi.org/10.1007/s11239-013-1048-z

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