Download PDF
Semin Thromb Hemost 2014; 40(08): 852-859
DOI: 10.1055/s-0034-1395156
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

When the Rubber Meets the Road: Adherence and Persistence with Non–Vitamin K Antagonist Oral Anticoagulants and Old Oral Anticoagulants in the Real World—A Problem or A Myth ?

Deepa Suryanarayan
1   Department of Medicine and Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Sam Schulman
1   Department of Medicine and Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
2   Department of Medicine, Karolinska Institutet, Stockholm, Sweden
› Author Affiliations
Further Information

Publication History

Publication Date:
10 November 2014 (online)

    Permissions and Reprints

Abstract

For patients taking vitamin K antagonist (VKA) anticoagulants, poor adherence to the drug regimen is associated with a lower percent time in therapeutic range and also with an increased risk of thromboembolic complications. The non–vitamin K antagonist oral anticoagulants (NOACs) do not require routine laboratory monitoring and therefore the risk of nonadherence remaining undetected and without any corrective attempts must be recognized. Persistence with the NOACs and VKA was quite comparable in the phase III trials, whereas a postmarketing study demonstrated better persistence with dabigatran than with warfarin. Preliminary studies on adherence to the dabigatran regimen have shown poor adherence in 12 to 27%, and also for this drug such behavior seems associated with an unfavorable outcome. There is uncertainty about the best methods to evaluate adherence. Studies on the adherence are needed for all the NOACs, for different clinical settings and patient populations. A combination of strategies should probably be used to achieve the best possible adherence, including patient education and some form of automatic reminders.

Keywords

anticoagulant therapy - adherence - persistence
 

  • References

  • 1 Mueller RL, Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future. Circulation 1994; 89 (1) 432-449
    CrossrefPubMedGoogle Scholar
  • 2 Fareed J, Hoppensteadt DA, Fareed D , et al. Survival of heparins, oral anticoagulants, and aspirin after the year 2010. Semin Thromb Hemost 2008; 34 (1) 58-73
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Husted S, de Caterina R, Andreotti F , et al; ESC Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease. Non-vitamin K antagonist oral anticoagulants (NOACs): No longer new or novel. Thromb Haemost 2014; 111 (5) 781-782
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Rojas-Hernandez CM, Garcia DA. The novel oral anticoagulants. Semin Thromb Hemost 2013; 39 (2) 117-126
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Hippocrates. Decorum, XVI. In: Jones WH, , ed. Hippocrates with an English Translation. London: Heinemann; 1923
    Google Scholar
  • 6 Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353 (5) 487-497
    CrossrefPubMedGoogle Scholar
  • 7 Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001; 23 (8) 1296-1310
    CrossrefPubMedGoogle Scholar
  • 8 Fischer MA, Stedman MR, Lii J , et al. Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med 2010; 25 (4) 284-290
    CrossrefPubMedGoogle Scholar
  • 9 Simpson SH, Eurich DT, Majumdar SR , et al. A meta-analysis of the association between adherence to drug therapy and mortality. BMJ 2006; 333 (7557) 15
    CrossrefPubMedGoogle Scholar
  • 10 Peidro-Garcés L, Otero-Fernandez R, Lozano-Lizarraga L. Adherence to and satisfaction with oral outpatient thromboembolism prophylaxis compared to parenteral: SALTO study [in Spanish]. Rev Esp Cir Ortop Traumatol 2013; 57 (1) 53-60
    PubMedGoogle Scholar
  • 11 World Health Organization. Adherence to long-term therapies: evidence for action. Available at: http://www.who.int/chp/knowledge/publications/adherence_report/en/ . Accessed August 2, 2014
    PubMedGoogle Scholar
  • 12 Doggrell SA. Adherence to medicines in the older-aged with chronic conditions: does intervention by an allied health professional help?. Drugs Aging 2010; 27 (3) 239-254
    CrossrefPubMedGoogle Scholar
  • 13 Holbrook A, Schulman S, Witt DM , et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2 Suppl): e152S-e84S
    CrossrefPubMedGoogle Scholar
  • 14 Levi M, de Peuter OR, Kamphuisen PW. Management strategies for optimal control of anticoagulation in patients with atrial fibrillation. Semin Thromb Hemost 2009; 35 (6) 560-567
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Waterman AD, Milligan PE, Bayer L, Banet GA, Gatchel SK, Gage BF. Effect of warfarin nonadherence on control of the International Normalized Ratio. Am J Health Syst Pharm 2004; 61 (12) 1258-1264
    PubMedGoogle Scholar
  • 16 Chen SY, Wu N, Gulseth M , et al. One-year adherence to warfarin treatment for venous thromboembolism in high-risk patients and its association with long-term risk of recurrent events. J Manag Care Pharm 2013; 19 (4) 291-301
    PubMedGoogle Scholar
  • 17 Gallagher AM, Setakis E, Plumb JM, Clemens A, van Staa TP. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011; 106 (5) 968-977
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Mant J, Hobbs FD, Fletcher K , et al; BAFTA investigators. Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007; 370 (9586) 493-503
    CrossrefPubMedGoogle Scholar
  • 19 Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007; 115 (21) 2689-2696
    CrossrefPubMedGoogle Scholar
  • 20 De Schryver EL, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A ; Dutch TIA trial and SPIRIT study groups. Non-adherence to aspirin or oral anticoagulants in secondary prevention after ischaemic stroke. J Neurol 2005; 252 (11) 1316-1321
    CrossrefPubMedGoogle Scholar
  • 21 Davis NJ, Billett HH, Cohen HW, Arnsten JH. Impact of adherence, knowledge, and quality of life on anticoagulation control. Ann Pharmacother 2005; 39 (4) 632-636
    CrossrefPubMedGoogle Scholar
  • 22 Fang MC, Go AS, Chang Y, Borowsky L, Pomernacki NK, Singer DE ; ATRIA Study Group. Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. J Am Coll Cardiol 2008; 51 (8) 810-815
    CrossrefPubMedGoogle Scholar
  • 23 Levi M, Hobbs FD, Jacobson AK , et al. Improving antithrombotic management in patients with atrial fibrillation: current status and perspectives. Semin Thromb Hemost 2009; 35 (6) 527-542
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Arnsten JH, Gelfand JM, Singer DE. Determinants of compliance with anticoagulation: A case-control study. Am J Med 1997; 103 (1) 11-17
    CrossrefPubMedGoogle Scholar
  • 25 Nikolaus T, Kruse W, Bach M, Specht-Leible N, Oster P, Schlierf G. Elderly patients' problems with medication. An in-hospital and follow-up study. Eur J Clin Pharmacol 1996; 49 (4) 255-259
    CrossrefPubMedGoogle Scholar
  • 26 Kimmel SE, Chen Z, Price M , et al. The influence of patient adherence on anticoagulation control with warfarin: results from the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study. Arch Intern Med 2007; 167 (3) 229-235
    CrossrefPubMedGoogle Scholar
  • 27 Platt AB, Localio AR, Brensinger CM , et al. Risk factors for nonadherence to warfarin: results from the IN-RANGE study. Pharmacoepidemiol Drug Saf 2008; 17 (9) 853-860
    CrossrefPubMedGoogle Scholar
  • 28 Salmela B, Joutsi-Korhonen L, Armstrong E, Lassila R. Active online assessment of patients using new oral anticoagulants: bleeding risk, compliance, and coagulation analysis. Semin Thromb Hemost 2012; 38 (1) 23-30
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Larsen TB, Rasmussen LH, Skjøth F , et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013; 61 (22) 2264-2273
    CrossrefPubMedGoogle Scholar
  • 30 Coleman CI, Limone B, Sobieraj DM , et al. Dosing frequency and medication adherence in chronic disease. J Manag Care Pharm 2012; 18 (7) 527-539
    CrossrefPubMedGoogle Scholar
  • 31 Thorne K, Jayathissa S, Dee S , et al. Adherence and outcomes of patients prescribed dabigatran (Pradaxa) in routine clinical practice. Intern Med J 2014; 44 (3) 261-265
    CrossrefPubMedGoogle Scholar
  • 32 Zalesak M, Siu K, Francis K , et al. Higher persistence in newly diagnosed nonvalvular atrial fibrillation patients treated with dabigatran versus warfarin. Circ Cardiovasc Qual Outcomes 2013; 6 (5) 567-574
    CrossrefPubMedGoogle Scholar
  • 33 Stanek EJ, Agatep BC, Herrera V , et al. Assessment of initial U.S. dabigatran utilization and short-term persistence. Circulation 2011; 124 (21, Supplement): A16675
    PubMedGoogle Scholar
  • 34 Michel J, Mundell D, Boga T, Sasse A. Dabigatran for anticoagulation in atrial fibrillation - early clinical experience in a hospital population and comparison to trial data. Heart Lung Circ 2013; 22 (1) 50-55
    CrossrefPubMedGoogle Scholar
  • 35 Lee PY, Han SY, Miyahara RK. Adherence and outcomes of patients treated with dabigatran: pharmacist-managed anticoagulation clinic versus usual care. Am J Health Syst Pharm 2013; 70 (13) 1154-1161
    CrossrefPubMedGoogle Scholar
  • 36 Schulman S, Shortt B, Robinson M, Eikelboom JW. Adherence to anticoagulant treatment with dabigatran in a real-world setting. J Thromb Haemost 2013; 11 (7) 1295-1299
    CrossrefPubMedGoogle Scholar
  • 37 Shore S, Carey EP, Turakhia MP , et al. Adherence to dabigatran therapy and longitudinal patient outcomes: insights from the veterans health administration. Am Heart J 2014; 167 (6) 810-817
    CrossrefPubMedGoogle Scholar
  • 38 Walenga JM, Hoppensteadt DA. Monitoring the new antithrombotic drugs. Semin Thromb Hemost 2004; 30 (6) 683-695
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Wong PY, Schulman S, Woodworth S, Holbrook A. Supplemental patient education for patients taking oral anticoagulants: systematic review and meta-analysis. J Thromb Haemost 2013; 11 (3) 491-502
    CrossrefPubMedGoogle Scholar
  • 40 Roumie CL, Elasy TA, Greevy R , et al. Improving blood pressure control through provider education, provider alerts, and patient education: a cluster randomized trial. Ann Intern Med 2006; 145 (3) 165-175
    CrossrefPubMedGoogle Scholar
  • 41 Balamurugan A, Ohsfeldt R, Hughes T, Phillips M. Diabetes self-management education program for Medicaid recipients: a continuous quality improvement process. Diabetes Educ 2006; 32 (6) 893-900
    CrossrefPubMedGoogle Scholar
  • 42 Heidbuchel H, Verhamme P, Alings M , et al; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013; 15 (5) 625-651
    CrossrefPubMedGoogle Scholar
  • 43 Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 2007; 120 (8) 713-719
    CrossrefPubMedGoogle Scholar
  • 44 Hussein MA, Chapman RH, Benner JS , et al. Does a single-pill antihypertensive/lipid-lowering regimen improve adherence in US managed care enrolees? A non-randomized, observational, retrospective study. Am J Cardiovasc Drugs 2010; 10 (3) 193-202
    CrossrefPubMedGoogle Scholar
  • 45 Liu Q, Abba K, Alejandria MM, Balanag VM, Berba RP, Lansang MA. Reminder systems and late patient tracers in the diagnosis and management of tuberculosis. Cochrane Database Syst Rev 2008; (4) CD006594
    PubMedGoogle Scholar
  • 46 Wei J, Hollin I, Kachnowski S. A review of the use of mobile phone text messaging in clinical and healthy behaviour interventions. J Telemed Telecare 2011; 17 (1) 41-48
    CrossrefPubMedGoogle Scholar
  • 47 Connolly S, Pogue J, Hart R , et al; ACTIVE Writing Group of the ACTIVE Investigators. 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 2006; 367 (9526) 1903-1912
    CrossrefPubMedGoogle Scholar
  • 48 The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997; 42 (6) 857-865
    CrossrefPubMedGoogle Scholar
  • 49 Olsson SB. Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362 (9397) 1691-1698
    CrossrefPubMedGoogle Scholar
  • 50 Albers GW, Diener HC, Frison L , et al; SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 2005; 293 (6) 690-698
    CrossrefPubMedGoogle Scholar
  • 51 Connolly SJ, Ezekowitz MD, Yusuf S , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
    CrossrefPubMedGoogle Scholar
  • 52 Schulman S, Kearon C, Kakkar AK , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
    CrossrefPubMedGoogle Scholar
  • 53 Schulman S, Kakkar AK, Goldhaber SZ , et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (7) 764-772
    CrossrefPubMedGoogle Scholar
  • 54 Schulman S, Kearon C, Kakkar AK , et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (8) 709-718
    CrossrefPubMedGoogle Scholar
  • 55 Patel MR, Mahaffey KW, Garg J , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
    CrossrefPubMedGoogle Scholar
  • 56 Bauersachs R, Berkowitz SD, Brenner B , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedGoogle Scholar
  • 57 Büller HR, Prins MH, Lensin AW , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
    CrossrefPubMedGoogle Scholar
  • 58 Agnelli G, Buller HR, Cohen A , et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (9) 799-808
    CrossrefPubMedGoogle Scholar
  • 59 Agnelli G, Buller HR, Cohen A , et al; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (8) 699-708
    CrossrefPubMedGoogle Scholar
  • 60 Granger CB, Alexander JH, McMurray JJ , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
    CrossrefPubMedGoogle Scholar
  • 61 Giugliano RP, Ruff CT, Braunwald E , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
    CrossrefPubMedGoogle Scholar
  • 62 Büller HR, Décousus H, Grosso MA , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
    CrossrefPubMedGoogle Scholar