Temporal trends of time in therapeutic range and incidence of cardiovascular events in patients with non-valvular atrial fibrillation

Published:April 11, 2018DOI:


      • Optimal time in therapeutic range (TTR) is essential for an effective stroke prevention.
      • To prospectively analyse temporal trends of TTR in atrial fibrillation (AF) patients
      • A decrease of TTR <70% over time is observed in almost 20% of AF patients.
      • Temporally worsening TTR (from > to <70%) is associated with higher cardiovascular risk.



      Optimal time in therapeutic range (TTR) of vitamin K antagonists (VKAs) is crucial for cardiovascular events (CVEs) prevention in non-valvular atrial fibrillation (NVAF). The relationship between temporal changes of TTR and the incidence of CVEs has been poorly investigated. We investigated 1) temporal trends of TTR in a long-term follow-up of NVAF patients; 2) the incidence of CVEs according to changes of TTR.


      Prospective observational study including 1341 NVAF outpatients (mean age 73.5 years, 42.5% male) starting VKAs. Patients were divided into 4 groups: Group 0: Optimal TTR, consistently ≥70% (n = 241); Group 1: Temporally worsening TTR, from above to below 70% (n = 263); Group 2: Temporally improving TTR, from below to above 70% (n = 270); Group 3: Suboptimal TTR, consistently <70% (n = 567).


      In a mean follow-up of 37.7 months (4214.2 patient-years), 108 CVEs occurred (2.6%/year). Survival analysis showed a graded increased risk of CVEs in relation to temporal changes in TTR, with the worst outcomes in Groups 1 and 3 (log-rank test p = 0.013). Multivariable Cox proportional hazards regression analysis showed that Group 1 vs. 0 (HR: 2.096; 95%CI 1.061–4.139, p = 0.033), Group 3 vs. 0 (HR: 2.292; 95%CI 1.205–4.361, p = 0.011), CHA2DS2VASc score (HR:1.316; 95%CI 1.153–1.501, p < 0.001) and PPIs (HR:0.453; 95%CI 0.285–0.721, p = 0.001) were independently associated with CVEs.


      A decrease of TTR <70% over time is observed in almost 20% of NVAF patients. Patients with worsening TTR temporally (ie. from initially above 70% to below 70%) have similar risk of CVEs of patients with consistently suboptimal anticoagulation.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Violi F.
        • Soliman E.Z.
        • Pignatelli P.
        • Pastori D.
        Atrial fibrillation and myocardial infarction: a systematic review and appraisal of pathophysiologic mechanisms.
        J Am Heart Assoc. 2016; 5
        • Sjogren V.
        • Grzymala-Lubanski B.
        • Renlund H.
        • Friberg L.
        • Lip G.Y.
        • Svensson P.J.
        • et al.
        Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula.
        Thromb Haemost. 2015; 113: 1370-1377
        • Connolly S.J.
        • Pogue J.
        • Eikelboom J.
        • Flaker G.
        • Commerford P.
        • Franzosi M.G.
        • et al.
        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. 2008; 118: 2029-2037
        • Wan Y.
        • Heneghan C.
        • Perera R.
        • Roberts N.
        • Hollowell J.
        • Glasziou P.
        • et al.
        Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review.
        Circ Cardiovasc Qual Outcomes. 2008; 1: 84-91
        • Xian Y.
        • O'Brien E.C.
        • Liang L.
        • Xu H.
        • Schwamm L.H.
        • Fonarow G.C.
        • et al.
        Association of Preceding Antithrombotic Treatment with Acute Ischemic Stroke Severity and in-Hospital Outcomes among Patients with Atrial Fibrillation.
        JAMA. 2017; 317: 1057-1067
        • Gallego P.
        • Roldan V.
        • Marin F.
        • Romera M.
        • Valdes M.
        • Vicente V.
        • et al.
        Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation.
        Thromb Haemost. 2013; 110: 1189-1198
        • Bertomeu-Gonzalez V.
        • Anguita M.
        • Moreno-Arribas J.
        • Cequier A.
        • Muniz J.
        • Castillo-Castillo J.
        • et al.
        Quality of anticoagulation with vitamin K antagonists.
        Clin Cardiol. 2015; 38: 357-364
        • Chan P.H.
        • Li W.H.
        • Hai J.J.
        • Chan E.W.
        • Wong I.C.
        • Tse H.F.
        • et al.
        Time in Therapeutic Range and Percentage of International Normalized Ratio in the Therapeutic Range as a Measure of Quality of Anticoagulation Control in Patients With Atrial Fibrillation.
        Can J Cardiol. 2016; 32: e23-e28
        • Pastori D.
        • Pignatelli P.
        • Saliola M.
        • Carnevale R.
        • Vicario T.
        • Del Ben M.
        • et al.
        Inadequate anticoagulation by vitamin K antagonists is associated with major adverse cardiovascular events in patients with atrial fibrillation.
        Int J Cardiol. 2015; 201: 513-516
        • Kirchhof P.
        • Benussi S.
        • Kotecha D.
        • Ahlsson A.
        • Atar D.
        • Casadei B.
        • et al.
        ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESCEndorsed by the European Stroke Organisation (ESO).
        Eur Heart J. 2016; : 2016
        • Haas S.
        • Ten Cate H.
        • Accetta G.
        • Angchaisuksiri P.
        • Bassand J.P.
        • Camm A.J.
        • et al.
        Quality of vitamin K antagonist control and 1-year outcomes in patients with atrial fibrillation: a global perspective from the GARFIELD-AF registry.
        PLoS One. 2016; 11e0164076
        • Apostolakis S.
        • Sullivan R.M.
        • Olshansky B.
        • Lip G.Y.
        Factors affecting quality of anticoagulation control amongst atrial fibrillation patients on warfarin: the SAMe-TT2R2 (Sex female, Age less than 60, Medical history, Treatment strategy [rhythm control], Tobacco use [doubled], Race [doubled] score).
        Chest. Nov 2013; 144: 1555-1563
        • Martinez C.
        • Katholing A.
        • Wallenhorst C.
        • Freedman S.B.
        Therapy persistence in newly diagnosed non-valvular atrial fibrillation treated with warfarin or NOAC. A cohort study.
        Thromb Haemost. 2016; 115: 31-39
        • Gallagher A.M.
        • Rietbrock S.
        • Plumb J.
        • van Staa T.P.
        Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis?.
        J Thromb Haemost. 2008; 6: 1500-1506
        • Rivera-Caravaca J.M.
        • Roldan V.
        • Esteve-Pastor M.A.
        • Valdes M.
        • Vicente V.
        • Lip G.Y.H.
        • et al.
        Cessation of oral anticoagulation is an important risk factor for stroke and mortality in atrial fibrillation patients.
        Thromb Haemost. 2017; 117: 1448-1454
        • Raparelli V.
        • Proietti M.
        • Cangemi R.
        • Lip G.Y.
        • Lane D.A.
        • Basili S.
        Adherence to oral anticoagulant therapy in patients with atrial fibrillation. Focus on non-vitamin K antagonist oral anticoagulants.
        Thromb Haemost. 2017; 117: 209-218
        • Pastori D.
        • Pignatelli P.
        • Angelico F.
        • Farcomeni A.
        • Del Ben M.
        • Vicario T.
        • et al.
        Incidence of myocardial infarction and vascular death in elderly patients with atrial fibrillation taking anticoagulants: relation to atherosclerotic risk factors.
        Chest. 2015; 147: 1644-1650
        • Rosendaal F.R.
        • Cannegieter S.C.
        • van der Meer F.J.
        • Briet E.
        A method to determine the optimal intensity of oral anticoagulant therapy.
        Thromb Haemost. 1993; 69: 236-239
        • Rose A.J.
        • Hylek E.M.
        • Ozonoff A.
        • Ash A.S.
        • Reisman J.I.
        • Berlowitz D.R.
        Patient characteristics associated with oral anticoagulation control: results of the veterans AffaiRs study to improve anticoagulation (VARIA).
        J Thromb Haemost. 2010; 8: 2182-2191
        • Proietti M.
        • Lane D.A.
        • Lip G.Y.
        Chronic kidney disease, time in therapeutic range and adverse clinical outcomes in anticoagulated patients with non-valvular atrial fibrillation: observations from the SPORTIF trials.
        EBioMedicine. 2016; 8: 309-316
        • Anguita Sanchez M.
        • Bertomeu Martinez V.
        • Cequier Fillat A.
        • Cs researchers
        Quality of vitamin K antagonist anticoagulation in Spain: prevalence of poor control and associated factors.
        Rev Esp Cardiol (Engl Ed). 2015; 68: 761-768
        • Odashiro K.
        • Yokoyama T.
        • Fukata M.
        • Arita T.
        • Maruyama T.
        • Akashi K.
        Anticoagulation stability depends on CHADS2 score and Hepatorenal function in warfarin-treated patients, including those with atrial fibrillation.
        J Atheroscler Thromb. 2017; 24: 68-76
        • Okumura K.
        • Komatsu T.
        • Yamashita T.
        • Okuyama Y.
        • Harada M.
        • Konta Y.
        • et al.
        Time in the therapeutic range during warfarin therapy in Japanese patients with non-valvular atrial fibrillation. - a multicenter study of its status and infuential factors.
        Circ J. 2011; 75: 2087-2094
        • Park Y.K.
        • Lee M.J.
        • Kim J.H.
        • Lee J.S.
        • Park R.W.
        • Kim G.M.
        • et al.
        Genetic and non-genetic factors affecting the quality of anticoagulation control and vascular events in atrial fibrillation.
        J Stroke Cerebrovasc Dis. 2017; 26: 1383-1390
        • Pastori D.
        • Pignatelli P.
        • Perticone F.
        • Sciacqua A.
        • Carnevale R.
        • Farcomeni A.
        • et al.
        Aspirin and renal insufficiency progression in patients with atrial fibrillation and chronic kidney disease.
        Int J Cardiol. 2016; 223: 619-624
        • Chen P.C.
        • Lip G.Y.
        • Yeh G.
        • Lin H.J.
        • Chien K.L.
        Risk of bleeding and stroke with oral anticoagulation and antiplatelet therapy in patients with atrial fibrillation in Taiwan: a nationwide cohort study.
        PLoS One. 2015; 10e0125257
        • Hashikata T.
        • Yamaoka-Tojo M.
        • Kakizaki R.
        • Nemoto T.
        • Fujiyoshi K.
        • Namba S.
        • et al.
        Ezetimibe enhances and stabilizes anticoagulant effect of warfarin.
        Heart Vessels. 2017; 32: 47-54
        • Marie I.
        • Leprince P.
        • Menard J.F.
        • Tharasse C.
        • Levesque H.
        Risk factors of vitamin K antagonist overcoagulation.
        QJM. 2012; 105: 53-62
      1. Pastori D, Polimeni L, Baratta F, Pani A, Del Ben M, Angelico F. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 2015; 47:4–11.1

        • Henriksen D.P.
        • Stage T.B.
        • Hansen M.R.
        • Rasmussen L.
        • Damkier P.
        • Pottegard A.
        The potential drug-drug interaction between proton pump inhibitors and warfarin.
        Pharmacoepidemiol Drug Saf. 2015; 24: 1337-1340
        • Dahal K.
        • Sharma S.P.
        • Kaur J.
        • Anderson B.J.
        • Singh G.
        Efficacy and safety of proton pump inhibitors in the long-term aspirin users: a meta-analysis of randomized controlled trials.
        Am J Ther. 2017; 24e559-e69
        • Velagapudi P.
        • Turagam M.K.
        • Leal M.A.
        • Kocheril A.G.
        Atrial fibrillation and acid reflux disease.
        Clin Cardiol. 2012; 35: 180-186