Oral anticoagulants (NOAC and VKA) in chronic thromboembolic pulmonary hypertension
2022; Elsevier BV; Volume: 41; Issue: 6 Linguagem: Inglês
10.1016/j.healun.2022.02.002
ISSN1557-3117
AutoresMarc Humbert, Gérald Simonneau, David Pittrow, Marion Delcroix, Joanna Pepke‐Żaba, David Langleben, Lisa Mielniczuk, Pilar Escribano Subías, Repke J. Snijder, Joan Albert Barberà, Jens Klotsche, Christian Meier, Marius M. Hoeper,
Tópico(s)Heart Failure Treatment and Management
ResumoEXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study in patients with pulmonary hypertension treated with riociguat. Patients were followed for 1–4 years, and the primary outcomes were adverse events (AEs) and serious AEs (SAEs), including embolic/thrombotic and hemorrhagic events. Here we report data on patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving a vitamin K antagonist (VKA; n = 683) or a non-vitamin K antagonist oral anticoagulant (NOAC; n = 198) at baseline. AEs and SAEs were reported in 438 patients (64.1%) and 257 patients (37.6%), respectively, in the VKA group, and in 135 patients (68.2%) and 74 patients (37.4%) in the NOAC group. Exposure-adjusted hemorrhagic event rates were similar in the two groups, while exposure-adjusted embolic and/or thrombotic event rates were higher in the NOAC group, although the numbers of events were small. Further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH. EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study in patients with pulmonary hypertension treated with riociguat. Patients were followed for 1–4 years, and the primary outcomes were adverse events (AEs) and serious AEs (SAEs), including embolic/thrombotic and hemorrhagic events. Here we report data on patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving a vitamin K antagonist (VKA; n = 683) or a non-vitamin K antagonist oral anticoagulant (NOAC; n = 198) at baseline. AEs and SAEs were reported in 438 patients (64.1%) and 257 patients (37.6%), respectively, in the VKA group, and in 135 patients (68.2%) and 74 patients (37.4%) in the NOAC group. Exposure-adjusted hemorrhagic event rates were similar in the two groups, while exposure-adjusted embolic and/or thrombotic event rates were higher in the NOAC group, although the numbers of events were small. Further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH. Lifelong anticoagulation is recommended for patients with chronic thromboembolic pulmonary hypertension (CTEPH).1Galiè N Humbert M Vachiery JL 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 Respir J. 2015; 46: 903-975Crossref PubMed Scopus (1870) Google Scholar,2Delcroix M Torbicki A Gopalan D et al.ERS statement on chronic thromboembolic pulmonary hypertension.Eur Respir J. 2021; 572002828Crossref Scopus (79) Google Scholar Vitamin K antagonists (VKAs) have traditionally been used, but are limited by food and drug interactions, need for frequent monitoring, and bleeding risk.3Hart RG Benavente O McBride R Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.Ann Intern Med. 1999; 131: 492-501Crossref PubMed Scopus (1490) Google Scholar,4Hindricks G Potpara T Dagres N et al.2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).Eur Heart J. 2021; 42: 373-498Crossref PubMed Scopus (2081) Google Scholar Non-vitamin K antagonist oral anticoagulants (NOACs) were developed to overcome some of these limitations, but few data have been published in CTEPH. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) was an international, prospective, non-interventional registry to monitor the long-term safety of riociguat in clinical practice.5Ghofrani HA Gomez Sanchez MA Humbert M et al.Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: final safety data from the EXPERT registry.Respir Med. 2020; 178106220PubMed Google Scholar,6Hoeper MM Gomez Sanchez MA Humbert M et al.Riociguat treatment in patients with pulmonary arterial hypertension: final safety data from the EXPERT registry.Respir Med. 2020; 177106241PubMed Google Scholar The objective of the current study was to compare the safety of NOACs with VKAs, particularly regarding hemorrhagic and embolic/thrombotic events, in patients with CTEPH in EXPERT. EXPERT ran from May 2014 to March 2018 as described previously.5Ghofrani HA Gomez Sanchez MA Humbert M et al.Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: final safety data from the EXPERT registry.Respir Med. 2020; 178106220PubMed Google Scholar,6Hoeper MM Gomez Sanchez MA Humbert M et al.Riociguat treatment in patients with pulmonary arterial hypertension: final safety data from the EXPERT registry.Respir Med. 2020; 177106241PubMed Google Scholar Patients were followed for 1–4 years from enrollment or until 30 days after stopping riociguat, with data collected approximately every 3–6 months. The primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs). Data were also captured on anticoagulant use and safety, including embolic and/or thrombotic and hemorrhagic events. Details of methods are shown in the Supplementary Material (online). EXPERT was conducted in accordance with good pharmacovigilance practices. Protocol approvals were obtained from independent ethics committees or institutional review boards at all participating centers. Informed written consent was obtained from all patients. Of 956 patients with CTEPH, 198 (20.7%) were receiving a NOAC at baseline (rivaroxaban, n = 164; apixaban, n = 23; dabigatran, n = 10; edoxaban, n = 1) and 683 (71.4%) were receiving a VKA (warfarin, n = 269; phenprocoumon, n = 237; acenocoumarol, n = 177). Another 27 patients (2.8%) were receiving unfractionated heparin or low-molecular-weight heparin, and 48 (5.0%) had no reported anticoagulation. The present analysis included only patients receiving VKA or NOACs at baseline. In total, 87.6% and 82.3% of patients receiving concomitant VKAs and NOACs, respectively, completed the study (Figure S1). Baseline characteristics are shown in Table 1. Mean disease duration was shorter in the NOAC group, the distribution of disease types differed significantly between the groups, and riociguat monotherapy was less common in the VKA group. Comorbidities are shown in Table S1.Table 1Baseline Demographics and Disease Characteristics in the VKA and NOAC GroupsVKA group (n = 683)NOAC group (n = 198)p valueaIncludes surgically accessible operability under investigation or PEA or surgical assessment declined by the patient.Age, years66.5±13.6 [69.0; 58, 77]66.0±14.5 [69.5; 56, 78]0.924Age group, years <65 65 to <75 ≥75260 (38.1)186 (27.2)237 (34.7)72 (36.4)58 (29.3)68 (34.3)0.836Female sex404 (59.2)123 (62.1)0.453BMI, kg/m²28.9±17.5 [27.0; 24, 30.7]28.0±6.6 [27.1; 23.9, 31.1]0.890Smoking status Never Former Current421 (61.6)237 (34.7)25 (3.7)134 (67.7)53 (26.8)11 (5.6)0.075CTEPH typeInoperablePersistent PH following PEAPersistent PH following BPAOtherbA Mann–Whitney U test was used for continuously distributed data and a χ2 test for categorical data in order to compare patients treated with VKAs and NOACs.Missing306 (44.8)164 (24.0)13 (1.9)161 (23.6)39 (5.7)87 (43.9)36 (18.2)11 (5.6)50 (25.3)14 (7.1)0.033Disease duration of initial CTEPH diagnosis, years3.9±4.2 [2.7; 0.9, 5.8] (n = 645)2.2±3.4 [1.1; 0.3, 2.7] (n = 196)<0.001WHO FC, % (I/II/III/IV/unknown)4/38/51/2/54/38/47/6/50.7066MWD, m368±128 [378; 285, 455] (n = 591)360±128 [361; 262, 450] (n = 160)0.501mPAP, mmHg43±12 [43; 34, 51] (n = 612)42±11 [41; 33, 49] (n = 175)0.080PVR, dyn·s·cm–5656±521 [561; 400, 818] (n = 554)635±457 [530; 351, 786] (n = 160)0.209PAWP, mmHg11±5 [10; 8, 14] (n = 586)11±5 [11; 8, 14] (n = 163)0.771Cardiac index, L/min/m22.7±3.0 [2.4; 2.0, 2.9] (n = 543)2.5±0.8 [2.3; 2.0, 2.8] (n = 157)0.624RAP, mmHg9±6 [8; 5, 12] (n = 509)8±5 [8; 5, 11] (n = 151)0.213SvO2 (%)64±9 [64; 59, 69] (n = 434)64±10 [66; 58, 71] (n = 139)0.411Renal impairment at baselineNoYesUnknownMissing548 (80.2)120 (17.6)5 (0.7)10 (1.5)160 (80.8)30 (15.2)1 (0.5)7 (3.5)Severity of renal impairmentMild (CrCl 50−80 mL/min)Moderate (CrCl 30−49 mL/min)Severe (CrCl 1 patient in either group.a SAEs were reported in EXPERT according to Medical Dictionary for Regulatory Activities (MedDRA) terms using Standardized MedDRA Query (SMQ). The SMQ "Hemorrhages" includes terms such as "hemoglobin decreased" that might not be considered hemorrhagic events in the clinical setting. Open table in a new tab Abbreviations: NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Table shows events reported in >1 patient in either group. Estimated Kaplan−Meier survival rates (95% confidence interval) at 1, 2, and 3 years were 95% (91–98), 90% (82–94), and 80% (65–89) in the NOAC group and 95% (92–96), 85% (81–88%), and 80% (74–85) in the VKA group (Figure S2). AEs reported during the acute post-procedural phase of pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty are described in the Supplementary Material. NOACs are not currently recommended for patients with CTEPH.2Delcroix M Torbicki A Gopalan D et al.ERS statement on chronic thromboembolic pulmonary hypertension.Eur Respir J. 2021; 572002828Crossref Scopus (79) Google Scholar It is not clear why so many patients received NOACs in our study, but increasing use of these agents has also been reported elsewhere.7Bunclark K Newnham M Chiu YD et al.A multicenter study of anticoagulation in operable chronic thromboembolic pulmonary hypertension.J Thromb Haemost. 2020; 18: 114-122Crossref PubMed Scopus (39) Google Scholar,8Porres-Aguilar M Hoeper MM Rivera-Lebron BN Heresi GA Mukherjee D Tapson VF. Direct oral anticoagulants in chronic thromboembolic pulmonary hypertension.J Thromb Thrombolysis. 2021; 52: 791-796Crossref PubMed Scopus (2) Google Scholar This may reflect the recommendation for NOACs in pulmonary embolism guidelines.9Konstantinides SV Meyer G. The 2019 ESC guidelines on the diagnosis and management of acute pulmonary embolism.Eur Heart J. 2019; 40: 3453-3455Crossref PubMed Scopus (107) Google Scholar Other studies in CTEPH have reported similar or lower bleeding rates with NOACs than with VKAs, while results for venous thromboembolism recurrence have been inconsistent.7Bunclark K Newnham M Chiu YD et al.A multicenter study of anticoagulation in operable chronic thromboembolic pulmonary hypertension.J Thromb Haemost. 2020; 18: 114-122Crossref PubMed Scopus (39) Google Scholar,10Sedhom R Megaly M Gupta E Amanullah A. Use of direct oral anticoagulants in chronic thromboembolic pulmonary hypertension: a systematic review.J Thromb Thrombolysis. 2021; https://doi.org/10.1007/s11239-021-02501-8Crossref PubMed Scopus (2) Google Scholar,11Sena S Bulent M Derya K et al.Real-life data of direct anticoagulant use, bleeding risk and venous thromboembolism recurrence in chronic thromboembolic pulmonary hypertension patients: an observational retrospective study.Pulm Circ. 2020; 102045894019873545Crossref PubMed Scopus (12) Google Scholar Our results show similar absolute and exposure-adjusted rates of hemorrhagic events with VKAs and NOACs, while exposure-adjusted rates of embolic and/or thrombotic events were higher with NOACs. However, the numbers of events were small and the excess of embolic and/or thrombotic events could be a chance observation or related to differences in baseline characteristics between the 2 groups. Questions regarding the use of NOACs in CTEPH have been reviewed elsewhere.8Porres-Aguilar M Hoeper MM Rivera-Lebron BN Heresi GA Mukherjee D Tapson VF. Direct oral anticoagulants in chronic thromboembolic pulmonary hypertension.J Thromb Thrombolysis. 2021; 52: 791-796Crossref PubMed Scopus (2) Google Scholar The higher rate of discontinuation of NOACs (15.2%) versus VKAs (7.0%) in the current study may have contributed to the excess of embolic and/or thrombotic events. Renal function (Table 1), concomitant diseases (Table S1), and use of pulmonary hypertension-approved therapies (Table 1) were similar in the 2 groups; it therefore seems unlikely that the differences in outcomes were related to preference for VKAs in patients with renal impairment, or to imbalances in concomitant diseases or use of pulmonary hypertension-approved therapies. These questions are discussed further in the Supplementary Material. Survival at 3 years—80% in both groups—was similar to patients with CTEPH in EXPERT overall (79%),5Ghofrani HA Gomez Sanchez MA Humbert M et al.Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: final safety data from the EXPERT registry.Respir Med. 2020; 178106220PubMed Google Scholar and to intermediate-risk patients in the COMPERA registry (78%),12Delcroix M Staehler G Gall H et al.Risk assessment in medically treated chronic thromboembolic pulmonary hypertension patients.Eur Respir J. 2018; 521800248Crossref Scopus (32) Google Scholar but higher than in non-operated patients in older registries.5Ghofrani HA Gomez Sanchez MA Humbert M et al.Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: final safety data from the EXPERT registry.Respir Med. 2020; 178106220PubMed Google Scholar,13Gall H Felix JF Schneck FK et al.The Giessen Pulmonary Hypertension Registry: survival in pulmonary hypertension subgroups.J Heart Lung Transplant. 2017; 36: 957-967Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar The apparent improvement in survival may reflect advances in CTEPH management, or differences in patient characteristics between studies. Study limitations include those common to registries, such as missing values and lack of randomization, meaning that the two groups were not balanced in sample size or disease characteristics. Most patients in the NOAC group received rivaroxaban; our results are therefore mainly applicable to rivaroxaban and other Factor Xa inhibitors. Dosages of anticoagulants and their indications were not routinely recorded, and INRs were not available for all patients. In conclusion, hemorrhagic event rates appear similar in patients with CTEPH receiving VKAs or NOACs, but there may be a signal for increased embolic and/or thrombotic events with NOACs. These results are hypothesis-generating, and further studies are required to determine the long-term effects of various anticoagulation strategies in CTEPH. Marc Humbert reports grants, personal fees, and non-financial support from GlaxoSmithKline, personal fees from AstraZeneca, Merck, Novartis, Roche, Sanofi, and Teva, grants and personal fees from Acceleron, grants and personal fees from Actelion and Bayer, outside the submitted work. The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Gérald Simonneau reports personal fees and non-financial support from Actelion, Bayer, and MSD, outside the submitted work. David Pittrow reports personal fees from Actelion, Aspen, Bayer, Biogen, Boehringer Ingelheim, MSD, Sanofi, and Shire, outside the submitted work. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GlaxoSmithKline. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, and United Therapeutics. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, Ferrer, and GlaxoSmithKline, outside the submitted work. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck, and research support through his institution from Actelion, Ferrer, GlaxoSmithKline, and Merck. Jens Klotsche has no conflicts of interest relevant to the EXPERT study. Christian Meier is an employee of Bayer AG. Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Acceleron, Actelion, Jansen, MSD, and Pfizer, outside the submitted work. Marc Humbert. Conceptualization; methodology; investigation; resources; writing – review & editing; supervision; approval of final draft for submission. Gérald Simonneau. Conceptualization; methodology; investigation; resources; writing – review & editing; supervision; approval of final draft for submission. David Pittrow. Conceptualization; methodology; investigation; resources; writing – review & editing; supervision; project administration; approval of final draft for submission. Marion Delcroix. Investigation; resources; writing – review & editing; supervision; approval of final draft for submission. Joanna Pepke-Zaba. Investigation; resources; writing – review & editing; supervision; approval of final draft for submission. David Langleben. Investigation; resources; writing – review & editing; supervision; approval of final draft for submission. Lisa M. Mielniczuk. Investigation; resources; writing – review & editing; supervision; approval of final draft for submission. Pilar Escribano Subias. Investigation; resources; writing – review & editing; supervision; approval of final draft for submission. Repke J. Snijder. Investigation; resources; writing – review & editing; supervision; approval of final draft for submission. Joan A. Barberà. Investigation; resources; writing – review & editing; supervision; approval of final draft for submission. Jens Klotsche. Conceptualization; methodology; software; validation; formal analysis; resources; data curation; writing – review & editing; visualization; approval of final draft for submission. Christian Meier. Conceptualization; methodology; validation; writing – review & editing; supervision; project administration; funding acquisition; approval of final draft for submission. Marius M. Hoeper. Conceptualization; methodology; investigation; resources; writing – review & editing; supervision; approval of final draft for submission. Availability of the data underlying this publication will be determined according to Bayer's commitment to the European Federation of Pharmaceutical Industries and Associations and Pharmaceutical Research and Manufacturers of America principles for responsible clinical trial data sharing, pertaining to scope, time point, and process of data access. Bayer commits to sharing upon request from qualified scientific and medical researchers' patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the USA and European Union as necessary for doing legitimate research. This commitment applies to data on new medicines and indications that have been approved by the European Union and US regulatory agencies on or after January 1, 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to do further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the study sponsors section of the portal. Data access will be granted to anonymized patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded. Medical writing services provided by Richard Murphy, PhD, of Adelphi Communications Ltd, Macclesfield, UK, were funded by Bayer AG, Berlin, Germany, in accordance with Good Publication Practice (GPP3) guidelines. The authors acknowledge database administration by Torsten Tille, Dresden, and project administration by Mrs. Romy Hoppenz and Mrs. Linda Kottke at GWT-TUD GmbH, Dresden. Download .docx (.17 MB) Help with docx files Download .docx (.03 MB) Help with docx files Download .docx (.03 MB) Help with docx files
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