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Canadian Journal of Cardiology

Excessive Prolongation of Coagulation Time During Treatment With Direct Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation

Published:February 26, 2019DOI:https://doi.org/10.1016/j.cjca.2019.02.012

      Abstract

      Background

      Conventional coagulation assays have poor sensitivity and specificity for assessing the anticoagulant effect of direct oral anticoagulants (DOACs). This study aimed to evaluate the causes and consequences of the excessive prolongation of coagulation time in patients with nonvalvular atrial fibrillation who receive DOACs.

      Methods

      We retrospectively analysed 1521 patients (age, 66 ± 12 years). The prothrombin time (PT) and activated partial thromboplastin time (APTT) were averaged if they were measured more than twice depending on the respective DOAC and dosage across individuals. Excessive coagulation time prolongation was defined as PT or APTT of >2 standard deviations over the median for each DOAC.

      Results

      In all, 1913 DOAC cases were found. Excessive prolongation (EP), which was noted in 88 patients (5.8%), was found to be significantly associated with inappropriately high DOAC dosage and body weight (≤ 60 kg). During follow-up (median, 8.9 months), thromboembolisms developed in 10 patients (0.66%) and bleeding events in 85 (5.6%). Bleeding events were significantly higher in patients with excessive prolongation (EP group) than in those without (P = 0.013). Of the 53 patients in the EP group, 15 (28%) were positive for antiphospholipid antibodies, 6 (11%) had inappropriately high prescription dosages, 4 (8%) had coagulation factor deficiencies, and 3 (6%) had severe liver dysfunction.

      Conclusions

      Bleeding event rates were remarkably higher in patients receiving DOACs that caused EP of PT or APTT. Thus, following the current guidelines and administering the recommended dose of DOACs are fundamentally important. Patients with the body weight of <60 kg should be considered for dosage reduction or DOAC withdrawal.

      Résumé

      Contexte

      La sensibilité et la spécificité des épreuves de coagulation classiques sont insuffisantes pour évaluer l'effet anticoagulant des anticoagulants oraux directs (AOD). Cette étude visait à évaluer les causes et les conséquences d'une prolongation excessive du temps de coagulation chez des patients présentant une fibrillation auriculaire non valvulaire traités par AOD.

      Méthodologie

      Nous avons effectué une analyse rétrospective de 1521 patients (âge, 66 ± 12 ans). Les moyennes du temps de prothrombine (TP) et du temps partiel de thromboplastine activée (TPTA) ont été calculées si ces valeurs étaient mesurées plus de deux fois selon l'AOD et la posologie de chaque patient. La prolongation excessive du temps de coagulation était définie par un TP ou un TPTA > 2 écarts types par rapport à la médiane pour chaque AOD.

      Résultats

      En tout, 1913 patients traités par un AOD ont été recensés. La prolongation excessive (PE), observée chez 88 patients (5,8 %), s'est avérée être associée de façon significative avec une posologie d'AOD trop élevée et avec le poids corporel (≤ 60 kg). Au cours de la période de suivi (durée médiane, 8,9 mois), on a noté l'apparition de thromboembolies chez 10 patients (0,66 %) et d'événements hémorragiques chez 85 patients (5,6 %). Le nombre d'événements hémorragiques était significativement plus élevé chez les patients présentant une prolongation excessive (groupe PE) que chez ceux ayant un temps de coagulation normal (p = 0,013). Parmi les 53 patients du groupe PE, 15 (28 %) avaient obtenu un résultat positif au dépistage des anticorps antiphospholipides, 6 (11 %) s'étaient vus prescrire une posologie trop élevée, 4 (8 %) avaient des déficits en facteurs de coagulation et 3 (6 %) présentaient une dysfonction hépatique grave.

      Conclusions

      Les taux d'événements hémorragiques étaient nettement plus élevés chez les patients recevant des AOD causant une PE du TP ou du TPTA. Par conséquent, il est d'une importance fondamentale de suivre les lignes directrices en vigueur et d'administrer la dose d'AOD recommandée. Chez les patients dont le poids corporel est < 60 kg, il est conseillé d'envisager une diminution de la dose ou la cessation de l'AOD.
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      References

        • Barnes G.D.
        • Lucas E.
        • Alexander G.C.
        • Goldberger Z.D.
        National trends in ambulatory oral anticoagulant use.
        Am J Med. 2015; 128: 1300-1305
        • Miyares M.A.
        • Davis K.
        Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient.
        Am J Health Syst Pharm. 2012; 69: 1473-1484
        • Blann A.D.
        • Lip G.Y.H.
        Laboratory monitoring of the non-vitamin K oral anticoagulants.
        J Am Coll Cardiol. 2014; 64: 1140-1142
        • Samuelson B.T.
        • Cuker A.
        • Siegal D.M.
        • Crowther M.
        • Garcia D.A.
        Laboratory assessment of the anticoagulant activity of direct oral anticoagulants (DOACs): a systematic review.
        Chest. 2016; 151: 127-138
        • Kubitza D.
        • Becka M.
        • Zuehlsdorf M.
        • Mueck W.
        Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects.
        J Clin Pharmacol. 2007; 47: 218-226
        • Stangier J.
        • Rathgen K.
        • Stähle H.
        • Gansser D.
        • Roth W.
        The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects.
        Br J Clin Pharmacol. 2007; 64: 292-303
        • Frost C.
        • Wang J.
        • Nepal S.
        • et al.
        Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects.
        Br J Clin Pharmacol. 2013; 75: 476-487
        • Krekels E.H.
        • Niebecker R.
        • Karlsson M.O.
        • et al.
        Population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation in the ENGAGE AF-TIMI 48 Study, a phase III clinical trial.
        Clin Pharmacokinet. 2016; 55: 1079-1090
        • Schulman S.
        • Kearon C.
        Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
        J Thromb Haemost. 2005; 3: 692-694
        • Kawabata M.
        • Yokoyama Y.
        • Sasano T.
        • et al.
        Bleeding events and activated partial thromboplastin time with dabigatran in clinical practice.
        J Cardiol. 2013; 62: 121-126
        • Favaloro E.J.
        • Lipppi G.
        • Koutts J.
        Laboratory testing of anticoagulants: the present and the future.
        Pathology. 2011; 43: 682-692
        • Ebner M.
        • Birschmann I.
        • Peter A.
        • et al.
        Emergency coagulation assessment during treatment with direct oral anticoagulants. Limitations and solutions.
        Stroke. 2017; 48: 2457-2463
        • Gladstone D.J.
        • Geerts W.H.
        • Douketis J.
        • et al.
        How to monitor patients receiving direct oral anticoagulants for stroke prevention in atrial fibrillation: a practice tool endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society.
        Ann Intern Med. 2015; 163: 382-385
        • Pisters R.
        • Lane D.A.
        • Nieuwlaat R.
        • et al.
        A novel user-friendly score (HAS-BLED) to assess one year risk of major bleeding in atrial fibrillation patients: the Euro Heart Survey.
        Chest. 2010; 138: 1093-1100
        • Eikelboom J.W.
        • Wallentin L.
        • Connolly S.J.
        • et al.
        Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.
        Circulation. 2011; 123: 2363-2372
        • Oldgren J.
        • Alings M.
        • Darius H.
        • et al.
        Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial.
        Ann Intern Med. 2011; 155: 660-667
        • Lopes R.D.
        • Al-Khatib S.M.
        • Wallentin L.
        • et al.
        Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial.
        Lancet. 2012; 380: 1749-1758
        • Kundu A.
        • Sardar P.
        • Chatterjee S.
        • et al.
        Minimizing the risk of bleeding with NOACs in the elderly.
        Drugs Aging. 2016; 33: 491-500
        • Majeed A.
        • Schulman S.
        Bleeding and antidotes in new oral anticoagulants.
        Best Pract Res Clin Haematol. 2013; 26: 191-202
        • Heidbuchel H.
        • Verhamme P.
        • Alings M.
        • et al.
        Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with nonvalvular atrial fibrillation.
        Europace. 2015; 17: 1467-1507
        • Ageno W.
        • Gallus A.S.
        • Wittkowsky A.
        • et al.
        Oral anticoagulation therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
        Chest. 2012; 141: e44S-e88S
        • Garcia D.
        • Erkan D.
        Diagnosis and management of the antiphospholipid syndrome.
        N Engl J Med. 2018; 378: 2010-2021
        • Andrade D.
        • Cervera R.
        • Cohen H.
        • et al.
        15th International Congress on Antiphospholipid Antibodies Task Force on Antiphospholipid Syndrome treatment trends report.
        in: Erkan D. Lockshin M.D. Antiphospholipid syndrome: current research highlights and clinical insights. Springer, New York2017: 317-338
        • Helin T.A.
        • Pakkanen A.
        • Lassila R.
        • Joutsi-Korhonen L.
        Laboratory assessment of novel oral anticoagulants: method suitability and variability between coagulation laboratories.
        Clin Chem. 2013; 59: 807-814
        • Samama M.M.
        • Martinoli J.L.
        • LeFlem L.
        • et al.
        Assessment of laboratory assays to measure rivaroxaban—an oral, direct factor Xa inhibitor.
        Thromb Haemost. 2010; 103: 815-825
        • Favaloro E.J.
        • Bonar R.
        • Butler J.
        • Marsden K.
        Laboratory testing for the new oral anticoagulants: a review of current practice.
        Pathology. 2013; 45: 435-437
        • Tripodi A.
        The laboratory and the direct oral anticoagulants.
        Blood. 2013; 121: 4032-4035
        • Crowther M.
        • Crowther M.A.
        Antidotes for novel oral anticoagulants: current status and future potential.
        Arterioscler Thromb Vasc Biol. 2015; 35: 1736-1745

      Linked Article

      • Monitoring Direct Oral Anticoagulants: Longing for the Days When We Were in Control?
        Canadian Journal of CardiologyVol. 35Issue 6
        • Preview
          For 6 decades, health care professionals and patients, felt “in control” of oral anticoagulation. Warfarin dosing was titrated to values of prothrombin time (PT) within a range of international normalized ratios (INRs). Lamentably, this control was, in part, an illusion. Dose adjustments were made according to art and experience to retrospectively correct abnormal INRs that had been out of range for an unknown period of time between the last 2 INR measurements. Too many patients found frequent INR measurements objectionable and often avoided testing.
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