Assessment of the quality of anticoagulation management in patients with pulmonary arterial hypertension

Published:November 02, 2017DOI:


      • Patients with PAH had inconsistent control of anticoagulation.
      • Poor control could impact potential benefits of anticoagulation.



      Studies assessing the quality of anticoagulation therapy in patients with pulmonary arterial hypertension (PAH) have not been conducted.


      To assess the quality of anticoagulation management, the rate of anticoagulation-related complications in patients with PAH, and to identify risk factors for poor anticoagulation.


      This observational, retrospective cohort study included patients with confirmed PAH taking a regimen of oral anticoagulants from two centers: Brigham and Women's Hospital in Boston, and Hospital Universitario La Paz in Madrid from January 2009 to August 2015. Efficacy of anticoagulation management and time spent within therapeutic range of study participants were assessed.


      There were a total of 121 patients with PAH taking oral anticoagulants. Time spent within range (TTR) of those taking vitamin K antagonists (VKAs) was 57.0%. Forty-seven patients (38.8%) had a total of 105 anticoagulation-related events. The odds ratio of having an event in patients with a TTR < 60% was 2.43 (CI 95%, 1.01–5.83; p = 0.046). Possible factors that affected the quality of the anticoagulation were the age, sex, functional capacity, atrial fibrillation and certain pulmonary arterial hypertension specific medications.


      The quality of targeted anticoagulation in patients with PAH was low. Patients with low TTR were at a higher risk of experiencing anticoagulation-related complications. Specialized anticoagulation centers showed better management of oral anticoagulants.


      AF (atrial fibrillation), BWH (Brigham and Women's Hospital), DOACs (direct oral anticoagulants), HULP (Hospital Universitario La Paz), INR (international normalized ratio), IPAH (idiopathic pulmonary arterial hypertension), IQR (interquartilic range), mPAP (mean pulmonary artery pressure), mPAWP (mean pulmonary artery wedge pressure), NSAIDs (non-steroidal anti-inflammatory drugs), PAH (pulmonary arterial hypertension), TTR (time spent within therapeutic range), VKAs (vitamin K antagonists), VTE (venous thromboembolism), WHO (world health organization), 6MWD (six-minute walking distance)


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        • Fuster F.
        • Steele P.M.
        • Edwards W.D.
        • Gersh B.J.
        • McGoon M.D.
        • Frye R.L.
        Primary pulmonary hypertension: natural history and the importance of thrombosis.
        Circulation. 1984; 70: 580-587
        • Storstein O.
        • Efskind L.
        • Müller C.
        • Rokseth R.
        • Sander S.
        Primary pulmonary hypertension with emphasis on its etiology and treatment.
        Acta Med. Scand. 1966; 179: 197-212
        • Galiè N.
        • Corris P.A.
        • Frost A.
        • Girgis R.E.
        • Granton J.
        • Jing Z.C.
        • Klepetko W.
        • McGoon M.D.
        • McLaughlin V.V.
        • Preston I.R.
        • Rubin L.J.
        • Sandoval J.
        • Seeger W.
        • Keogh A.
        Updated treatment algorithm of pulmonary arterial hypertension.
        J. Am. Coll. Cardiol. 2013; 62: D60-D72
        • McLaughlin V.V.
        • Archer S.L.
        • Badesch D.B.
        • Barst R.J.
        • Farber H.W.
        • Lindner J.R.
        • Mathier M.A.
        • McGoon M.D.
        • Park M.H.
        • Rosenson R.S.
        • Rubin L.J.
        • Tapson V.F.
        • Varga J.
        • Harrington R.A.
        • Anderson J.L.
        • Bates E.R.
        • Bridges C.R.
        • Eisenberg M.J.
        • Ferrari V.A.
        • Grines C.L.
        • et al.
        ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association.
        Circulation. 2009; 119: 2250-2294
        • Galiè N.
        • Humbert M.
        • Vachiery J.L.
        • Gibbs S.
        • Lang I.
        • Torbicki A.
        • Simonneau G.
        • Peacock A.
        • Vonk Noordegraaf A.
        • Beghetti M.
        • Ghofrani A.
        • Gomez Sanchez M.A.
        • Hansmann G.
        • Klepetko W.
        • Lancellotti P.
        • Matucci M.
        • McDonagh T.
        • Pierard L.A.
        • Trindade P.T.
        • Zompatori M.
        • et al.
        2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
        Eur. Heart J. 2015; 46: 903-975
        • Galiè N.
        • Hoeper M.M.
        • Humbert M.
        • Torbicki A.
        • Vachiery J.L.
        • Barbera J.A.
        • Beghetti M.
        • Corris P.
        • Gaine S.
        • Gibbs J.S.
        • Gomez-Sanchez M.A.
        • Jondeau G.
        • Klepetko W.
        • Opitz C.
        • Peacock A.
        • Rubin L.
        • Zellweger M.
        • Simonneau G.
        • ESC Committee for Practice Guidelines (CPG)
        Guidelines for the diagnosis and treatment of pulmonary hypertension. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT).
        Eur. Heart J. 2009; 30: 2493-2537
        • Jansa P.
        • Hrachovinova I.
        • Ambroz D.
        • Maresova J.
        • Polacek P.
        • Simkova I.
        • Linhart A.
        • Aschermann M.
        Effect of warfarin anticoagulation on thrombin generation in patients with idiopathic pulmonary arterial hypertension.
        Bratisl. Lek. Listy. 2010; 111: 595-598
        • Henkes I.R.
        • Hazenoot T.
        • Boonstra A.
        • Huisman M.V.
        • Vonk-Noordegraaf A.
        Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension.
        Eur. Respir. J. 2013; 4: 872-878
        • Oake N.
        • Fergusson D.A.
        • Forster A.J.
        • van Walraven C.
        Frequency of adverse events in patients with poor anticoagulation: a meta-analysis.
        CMAJ. 2007; 176: 1589-1594
        • Merli G.J.
        • Tzanis G.
        Warfarin: what are the clinical implications of an out-of-range-therapeutic international normalized ratio?.
        J. Thromb. Thrombolysis. 2009; 27: 293-299
        • Jones M.
        • McEwan P.
        • Morgan C.L.
        • Peters J.R.
        • Goodfellow J.
        • Currie C.J.
        Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record likage study in a large British population.
        Heart. 2005; 91: 472-477
        • White H.D.
        • Gruber M.
        • Feyzi J.
        • Kaatz S.
        • Tse H.F.
        • Husted S.
        • Albers G.W.
        Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V.
        Arch. Intern. Med. 2007; 167: 239-245
        • Morgan C.L.
        • McEwan P.
        • Tukiendorf A.
        • Robinson P.A.
        • Clemens A.
        • Plumb J.M.
        Warfarin treatment in patients with atrial fibrillation: observing outcomes associated with varying levels of INR control.
        Thromb. Res. 2009; 124: 37-41
        • Optiz C.F.
        • Kirch W.
        • Mueller E.A.
        • Pittrow D.
        Bleeding events in pulmonary arterial hypertension.
        Eur. J. Clin. Investig. 2009; 39: 68-73
        • Robin L.J.
        • Badesch D.B.
        • Barst R.J.
        • Galie N.
        • Black C.M.
        • Keogh A.
        • Pulido T.
        • Frost A.
        • Roux S.
        • Leconte I.
        • Landzberg M.
        • Simonneau G.
        Bosentan therapy for pulmonary arterial hypertension.
        N. Engl. J. Med. 2002; 346: 896-903
        • Schulman S.
        • Kearon C.
        • on behalf of the subcommittee on control of anticoagulation of the Scientific and Standardization committee of the International Society on Thrombosis and Haemostasis
        Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Scientific and Standardization Committee Communication.
        J. Thromb. Haemost. 2005; 3: 692-694
        • Pisters R.
        • Lane D.A.
        • Niewlaat R.
        • de Vos C.B.
        • Crijns H.J.
        • Lip G.Y.
        A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
        Chest. 2010; 138: 1093-1100
        • Kaatz S.
        Determinants and measures of quality in oral anticoagulation therapy.
        J. Thromb. Thrombolysis. 2008; 25: 61-66
        • Preston I.E.
        • Roberts K.E.
        • Miller D.P.
        • Sen G.P.
        • Selej M.
        • Benton W.W.
        • Hill N.S.
        • Farber H.W.
        Effect of warfarin treatment on survival of patients with pulmonary arterial hypertension (PAH) in the registry to evaluate early and long-term PAH disease management (REVEAL).
        Circulation. 2015; 132: 2403-2411
        • Messerli M.
        • Blozik E.
        • Vriends N.
        • Hersberger K.E.
        Impact of a community pharmacist-led medication review on medicines use in patients on polypharmacy — a prospective randomised controlled trial.
        BMC Health Serv. Res. 2016; 16: 145
        • Gabriel L.
        • Delavenne X.
        • Bedouch P.
        • Khouatra C.
        • Bouvaist H.
        • Cordier J.F.
        • Mornex J.F.
        • Pison C.
        • Cottin V.
        • Bertoletti L.
        Risk of direct oral anticoagulant bioaccumulation in patients with pulmonary hypertension.
        Respiration. 2016; 91: 307-315
        • O'Brien E.C.
        • Simon D.N.
        • Allen L.A.
        • Singer D.E.
        • Fonarow G.C.
        • Kowey P.R.
        • Thomas L.E.
        • Ezekowitz M.D.
        • Mahaffey K.W.
        • Chang P.
        • Piccini J.P.
        • Peterson E.D.
        Reasons for warfarin discontinuation in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).
        Am. Heart J. 2014; 168: 487-494
        • Spivey C.A.
        • Qiao Y.
        • Liu X.
        • Mardekian J.
        • Parker R.B.
        • Phatak H.
        • Claflin A.B.
        • Kachroo S.
        • Abdulsattar Y.
        • Chakrabarti A.
        • Wang J.
        Discontinuation/interruption of warfarin therapy in patients with nonvalvular atrial fibrillation.
        J. Manag. Care Spec. Pharm. 2015; 21: 596-606
        • Dlott J.S.
        • George R.A.
        • Huang X.
        • Odeh M.
        • Kaufman H.W.
        • Ansell J.
        • Hylek E.M.
        National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation.
        Circulation. 2014; 129: 1407-1414
        • Singer D.E.
        • Hellkamp A.S.
        • Piccini J.P.
        • Mahaffey K.W.
        • Lokhnygina Y.
        • Pan G.
        • Halperin J.L.
        • Becker R.C.
        • Breithardt G.
        • Kankey G.J.
        • Hacke W.
        • Nessel C.C.
        • Patel M.R.
        • Califf R.M.
        • Fox K.A.
        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. 2013; 2e000067
        • van Walraven C.
        • Jennings A.
        • Oake N.
        • Fergusson D.
        • Forster A.J.
        Effect of study setting on anticoagulation control: a systematic review and metaregression.
        Chest. 2006; 129: 1155-1166
        • Pokorney S.D.
        • Simon D.J.
        • Thomas L.
        • Fonarow G.C.
        • Kowey P.R.
        • Chang P.
        • Singer D.E.
        • Ansell J.
        • Blanco R.G.
        • Gersh B.
        • Mahaffey K.W.
        • Hylek E.M.
        • Go A.S.
        • Piccini J.P.
        • Peterson E.D.
        • Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators
        Patients' time in therapeutic range on warfarin among US patients with atrial fibrillation: results from ORBIT-AF registry.
        Am. Heart J. 2015; 170: 141-148
        • Anguita M.
        • Bertomeu V.
        Calidad de la anticoagulación con antagonistas de la vitamina K en España: prevalencia de mal control y factores asociados.
        Rev. Esp. Cardiol. 2015; 68: 761-768
      1. Heneghan CJ, Garcia-Alamino JM, Spencer EA, Ward AM, Perera R, Bankhead C, Alonso-Coello P, Fitzmaurice D, Mahtani DR, Onakpoya IJ. Self-monitoring and self-management of oral anticoagulation. Cochrane Database Syst. Rev. 2016;(7): Art. No.: CD003839.

        • Olsson K.M.
        • Delcroix M.
        • Ghofrani H.A.
        • Tiede H.
        • Huscher D.
        • Speich R.
        • Grünig E.
        • Staehler G.
        • Rosenkranz S.
        • Halank M.
        • Held M.
        • Lange T.J.
        • Behr J.
        • Klose H.
        • Claussen M.
        • Ewert R.
        • Opitz C.F.
        • Vizza C.D.
        • Scelsi L.
        • Vonk-Noordegraaf A.
        • et al.
        Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA).
        Circulation. 2014; 129: 57-65
        • Ruff C.T.
        • Giugliano R.P.
        • Braunwald E.
        • Hoffman E.B.
        • Deenadayalu N.
        • Ezekowitz M.D.
        • Camm A.J.
        • Weitz J.I.
        • Lewis B.S.
        • Parkhomenko A.
        • Yamashita T.
        • Antman E.M.
        Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials.
        Lancet. 2014; 383: 955-962
        • Wieloch M.
        • Själander A.
        • Frykman V.
        • Rosenqvist M.
        • Eriksson N.
        • Svensson P.J.
        Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry Auricula.
        Eur. Heart J. 2011; 32: 2282-2289
        • Ageno W.
        • Gallus A.S.
        • Wittkowsky A.
        • Crowther M.
        • Hylek E.M.
        • Palareti G.
        Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
        Chest. 2012; 141: e44S-e88S
        • Pengo V.
        • Ruiz-Irastorza G.
        • Denas G.
        • Andreoli L.
        • Khamashta M.
        • Tincani A.
        High intensity anticoagulation in the prevention of the recurrence of arterial thrombosis in antiphospholipid syndrome: ‘PROS’ and ‘CONS’.
        Autoimmun. Rev. 2012; 11: 577-580
        • Witt D.M.
        • Delate T.
        • Clark N.P.
        • Martell C.
        • Tran T.
        • Crowther M.A.
        • Garcia D.A.
        • Ageno W.
        • Hylek E.M.
        • Warfarin Associated Research Projects and other EnDeavors (WARPED) Consortium
        Outcomes and predictors of very stable INR control during chronic anticoagulation therapy.
        Blood. 2009; 114: 952-956
        • Jaffer A.
        • Bragg L.
        Practical tips for warfarin soding and monitoring.
        Cleve. Clin. J. Med. 2003; 70: 361-371