Anticoagulation Post EAP CTPH PDF

Received: 4 July 2019 | Accepted: 23 September 2019 DOI: 10.1111/jth.14649 ORIGINAL ARTICLE A multicenter study of anticoagulation in operable chronic thromboembolic pulmonary hypertension Katherine Bunclark1 | Michael Newnham1,2 | Yi‐Da Chiu1,3 | Alessandro Ruggiero1 | Sofia S. Villar1,3...

Received: 4 July 2019 | Accepted: 23 September 2019 DOI: 10.1111/jth.14649 ORIGINAL ARTICLE A multicenter study of anticoagulation in operable chronic thromboembolic pulmonary hypertension Katherine Bunclark1 | Michael Newnham1,2 | Yi‐Da Chiu1,3 | Alessandro Ruggiero1 | Sofia S. Villar1,3 | John E. Cannon1 | Gerry Coghlan4 | Paul A. Corris5 | Luke Howard6 | David Jenkins1 | Martin Johnson7 | David G. Kiely8 | Choo Ng1 | Nicholas Screaton1 | Karen Sheares1 | Dolores Taboada1 | Steven Tsui1 | Stephen John Wort9 | Joanna Pepke‐Zaba1 | Mark Toshner1,2 1 Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK Abstract 2 Department of Medicine, University of Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is an un- Cambridge, Cambridge, UK common complication of acute pulmonary emboli necessitating lifelong anticoagula- 3 MRC BSU, University of Cambridge, Cambridge, UK tion. Despite this, few data exist on the safety and efficacy of vitamin K antagonists 4 Royal Free Hospital, London, UK (VKAs) in CTEPH and none for direct oral anticoagulants (DOACs). 5 Institute of Cellular Medicine, Newcastle Objectives: To evaluate outcomes and complication rates in CTEPH following pulmo- upon Tyne, UK 6 nary endarterectomy (PEA) for individuals receiving VKAs or DOACs. National Heart and Lung Institute, London, UK Methods: Consecutive CTEPH patients undergoing PEA between 2007 and 2018 7 Golden Jubilee National Hospital, Glasgow, were included in a retrospective analysis. Postoperative outcomes, recurrent venous UK thromboembolism (VTE), and bleeding events were obtained from patient medical 8 Sheffield Teaching Hospitals, Sheffield, UK 9 records. Royal Brompton Hospital, London, UK Results: Seven hundred ninety‐four individuals were treated with VKAs and 206 Correspondence with DOACs following PEA. Mean observation period was 612 (standard deviation: Mark Toshner, Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Robinson 702) days. Significant improvements in hemodynamics and functional status were Way, Cambridge CB2 0AY, UK. observed in both groups following PEA (P <.001). Major bleeding events were equiv- Email: [email protected] alent (P = 1) in those treated with VKAs (0.67%/person‐year) and DOACs (0.68%/ person‐year). The VTE recurrence was proportionately higher (P =.008) with DOACs (4.62%/person‐year) than VKAs (0.76%/person‐year), although survival did not differ. Conclusions: Post‐PEA functional and hemodynamic outcomes appear unaffected by anticoagulant choice. Bleeding events were similar, but recurrent VTE rates sig- nificantly higher in those receiving DOACs. Our study provides a strong rationale for prospective registry data and/or studies to evaluate the safety of DOACs in CTEPH. KEYWORDS anticoagulant, complications, pulmonary hypertension, venous thromboembolism, warfarin Manuscript Handled by: Sabine Eichinger Final decision: Sabine Eichinger, 23 September 2019 114 | © 2019 International Society on Thrombosis and wileyonlinelibrary.com/journal/jth J Thromb Haemost. 2020;18:114–122. Haemostasis BUNCLARK ET AL. | 115 1 | I NTRO D U C TI O N Essentials Chronic thromboembolic pulmonary hypertension (CTEPH) is an Lifelong anticoagulation is recommended in thrombo- uncommon complication of acute pulmonary embolism.1 It is char- embolic pulmonary hypertension (CTEPH). acterized by the elevation of mean pulmonary artery pressure (PAP) We provide the largest evaluation of anticoagulation in the presence of organized occlusive thromboemboli in the pulmo- outcomes and complication rates in CTEPH. nary arteries following at least 3 months of effective anticoagula- Bleeding rates were similar but recurrent thromboem- tion.1 Pulmonary endarterectomy (PEA) is the treatment of choice in bolism higher with direct oral anticoagulants. those with surgically accessible thrombi. 2,3 Lifelong anticoagulation We provide a strong rationale for further prospective is recommended in all. 2,3 study of anticoagulation in CTEPH. Conventionally, VKAs have been used in the treatment of CTEPH. 2 Although these compounds have proven to be safe and ef- fective in the management of VTE, limited data exist on CTEPH.4,5 2.2 | Study design Henkens et al.4 reported a major bleeding rate of 2.4%/person‐year and Jujo‐Sanada et al.5 major bleeding and VTE recurrence rates of Demographic, functional, and hemodynamic data at preoperative 5% and 1.2%/person‐year, respectively, in CTEPH patients treated baseline and first follow‐up within 1 year of PEA were collected with VKAs. prospectively in dedicated databases at Royal Papworth Hospital. In recent years, four DOACs have been approved for the treat- Patient‐reported outcomes were assessed by the Cambridge ment of acute VTE in the United Kingdom (Edoxaban, Rivaroxaban, Pulmonary Hypertension Outcome Review (CAMPHOR), a pulmo- Dabigatran, and Apixaban).6-9 Large‐scale studies in acute VTE in- nary hypertension‐specific health‐related outcome measure com- dicate DOACs to be as effective in preventing VTE and with fewer prising three scales evaluating symptoms, activity levels, and quality 10-12 major bleeding complications than VKAs. Given the similar ef- of life. Symptom and Quality of Life scales are both scored out of 25 ficacy, potential lower side‐effect profile, and administrative con- with Activities having a maximum score of 30. Each CAMPHOR scale venience of DOACs over VKAs, the number of patients on DOACs is negatively weighted so that a higher score reflects worse quality presenting to CTEPH centers is rising and in some regions now su- of life and greater functional limitation.16 Longitudinal data regard- 13 persedes VKA use. Given limited data regarding the safety and ing anticoagulation and complications were retrospectively assessed efficacy of VKAs in CTEPH and the evolving use of DOACs, an eval- from review of patient medical records. Thrombophilia was deemed uation of anticoagulation in CTEPH is warranted. if there was a history of factor V Leiden; prothrombin gene mutation; protein C, S, or antithrombin III deficiency; or antiphospholipid syn- drome. International Normalized Ratio (INR) management for VKAs 2 | M E TH O DS was undertaken by local anticoagulation services with the exception of inpatient admission to Royal Papworth Hospital. 2.1 | Patient selection Consecutive CTEPH patients undergoing PEA at the UK National 2.3 | Anticoagulation management PEA Centre (Royal Papworth Hospital) between 1 August 2007 and 30 June 2018 were included in a retrospective analysis. Standard surgical practice at Royal Papworth Hospital is for oral Follow‐up was included up to 1 March 2019. Pediatric cases, those anticoagulation to be discontinued at the time of PEA. Vitamin K with chronic thromboembolism without pulmonary hypertension antagonistss are stopped 5 days and DOACs 24 to 72 h prior to (mean PAP ≤ 20 mm Hg),14 and individuals with CTEPH mimick- PEA dependent on the agent’s half‐life. Subcutaneous treatment ing conditions (e.g. vasculitis and sarcoma) were excluded from dose low‐molecular‐weight heparin is commenced day 2 postop- analysis. The diagnosis of CTEPH was based on international cri- eratively and continued until oral anticoagulation is stabilized. 1 teria. Suitability for PEA was determined by a multidisciplinary Vitamin K antagonists are recommenced at maintenance dose on team composed of pulmonary hypertension physicians, specialist patient discharge from the Intensive Care Unit with a standard tar- cardiothoracic radiologists, and pulmonary endarterectomy sur- get INR range of 2 to 3. Direct oral anticoagulantss were recom- geons. Pulmonary endarterectomy was based on surgical tech- menced at an individual’s usual dose at time of hospital discharge. 15 nique as previously described. Follow‐up was for a minimum of Given the alteration to anticoagulation regimes and the additional 1 year at Royal Papworth Hospital and up to 5 years under the care contribution of the surgical procedure including cardiac bypass in of one of the eight UK specialist pulmonary hypertension cent- the perioperative period, mortality and complication rates during ers following PEA. This research was supported by funding from the period between PEA and recommencement of oral anticoagu- the National Institute for Health Research Cambridge Biomedical lation were excluded from analysis. Research Centre. This study was deemed to be research that did Lifelong anticoagulation is recommended in all following PEA. not require ethics by the Royal Papworth Hospital Research and The management of long‐term anticoagulation after PEA hospital Development department. discharge was undertaken by the patient’s general practice or local 116 | BUNCLARK ET AL. anticoagulation clinic with oversight from a specialist pulmonary hy- VKA or DOACs were 1.6%, 1.6%, and 0% respectively. Complete pertension center. Those treated with VKAs were maintained with cases data were used in analyses. Between‐group and within‐group an INR in the target range of 2 to 3, unless otherwise indicated by comparisons were made using parametric and non‐parametric tests hematology services. Should the INR fall beneath the target range, as appropriate. A P value of