Oral anticoagulants (NOAC and VKA) in chronic thromboembolic pulmonary hypertension

Abstract

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. 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 <30 mL/min)Missing46 (6.7)50 (7.3)18 (2.6)6 (0.9)13 (6.6)12 (6.1)2 (1.0)3 (1.5)PH treatment at baselineRiociguat monotherapyRiociguat + ERA and/or prostanoid530 (77.6)153 (22.4)168 (84.9)30 (15.2)0.027Antiplatelet agents28 (4.1)12 (6.1)0.243Abbreviations: 6MWD, 6-min walking distance; BMI, body mass index; BPA, balloon pulmonary angioplasty; CrCl, creatinine clearance (by Cockroft−Gault formula); CTEPH, chronic thromboembolic pulmonary hypertension; ERA, endothelin receptor antagonist; mPAP, mean pulmonary artery pressure; NOAC, non-vitamin K antagonist oral anticoagulant; PAWP, pulmonary artery wedge pressure; PEA, pulmonary endarterectomy; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SD, standard deviation; SvO2, saturated venous oxygen; VKA, vitamin K antagonist; WHO FC, World Health Organization functional class.Data for continuous variables are mean ± SD, number (%), and [median; 25th percentile, 75th percentile]. Data for other variables are n (%). Values are for all patients unless otherwise stated.a Includes surgically accessible operability under investigation or PEA or surgical assessment declined by the patient.b A 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. Open table in a new tab Abbreviations: 6MWD, 6-min walking distance; BMI, body mass index; BPA, balloon pulmonary angioplasty; CrCl, creatinine clearance (by Cockroft−Gault formula); CTEPH, chronic thromboembolic pulmonary hypertension; ERA, endothelin receptor antagonist; mPAP, mean pulmonary artery pressure; NOAC, non-vitamin K antagonist oral anticoagulant; PAWP, pulmonary artery wedge pressure; PEA, pulmonary endarterectomy; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SD, standard deviation; SvO2, saturated venous oxygen; VKA, vitamin K antagonist; WHO FC, World Health Organization functional class. Data for continuous variables are mean ± SD, number (%), and [median; 25th percentile, 75th percentile]. Data for other variables are n (%). Values are for all patients unless otherwise stated. Median (range) duration of observation was 532 (0–1,367) days in the VKA group and 465 (0–1,344) days in the NOAC group. Discontinuation of anticoagulation was recorded in 48 (7.0%) patients in the VKA group and 30 patients (15.2%) in the NOAC group. In the VKA group, approximately 50%−55% of patients with data available were in the therapeutic range for international normalized ratio (INR) (2–3) (Table S2). “General” AEs were reported in 438 patients (64.1%) in the VKA group and in 135 patients (68.2%) in the NOAC group, and SAEs in 257 patients (37.6%) and 74 patients (37.4%), respectively. The most common AEs are listed in Table S3. Absolute rates of hemorrhagic and embolic/thrombotic events, numbers of events, and exposure-adjusted rates are shown in Table 2.Table 2Absolute and Exposure-adjusted Rates of Hemorrhagic and Embolic/Thrombotic Events in the VKA and NOAC Groups.Hemorrhagic eventsEmbolic/thrombotic eventsRates, n (%)VKA group (n = 683)NOAC group (n = 198)VKA group (n = 683)NOAC group (n = 198)Any eventDrug discontinuation due to eventAny serious eventDiscontinuation due to serious eventEvent-related death78 (11.4)2 (0.3)40 (5.9)2 (0.3)8 (1.2)24 (12.1)0 (0)11 (5.6)0 (0)1 (0.5)15 (2.2)1 (0.1)14 (2.0)1 (0.1)2 (0.3)6 (3.0)0 (0)5 (2.5)0 (0)0 (0)Number of events [exposure-adjusted rates]aNumber of events (rate per 100 patient-years, calculated by the number of events observed divided by [total drug exposure in years/100]).Any eventDrug discontinuation due to eventAny serious eventDiscontinuation due to serious event99 [9.5]3 [0.3]52 [5.0]3 [0.3]34 [12.1]0 [0]12 [4.3]0 [0]18 [1.7]1 [0.1]17 [1.6]1 [0.1]13 [4.6]0 [0]8 [2.9]0 [0]Abbreviations: NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist.a Number of events (rate per 100 patient-years, calculated by the number of events observed divided by [total drug exposure in years/100]). Open table in a new tab Abbreviations: NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. Absolute rates of both type of event were comparable in the two groups. Exposure-adjusted bleeding rates were similar in the two groups, while exposure-adjusted rate of embolic and/or thrombotic events was higher with NOACs than with VKAs. Demographics and disease characteristics of patients who experienced hemorrhagic or embolic/thrombotic events (Table S5) showed no clear differences from the overall populations. When AEs reported after discontinuation of VKAs or NOACs were excluded (Table S4), the absolute event rates were similar to the main analysis. Safety results for patients receiving no anticoagulation at baseline are presented in Table S6. In both groups, the most common hemorrhagic events were epistaxis and hemoptysis, and the most common embolic and/or thrombotic event was pulmonary embolism (Table 3). Serious hemoptysis was more common in the VKA group than the NOAC group. No hemorrhagic or embolic/thrombotic events were reported in patients with antiphospholipid syndrome in either group.Table 3Most Common Hemorrhagic and Embolic/Thrombotic Events in the VKA and NOAC Groups.Patients with event, n (%)VKA group (n = 683)NOAC group (n = 198)Hemorrhagic events Epistaxis19 (2.8)7 (3.5) Hemoptysis19 (2.8)5 (2.5) ContusionaSAEs 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.4 (0.6)0 Gastrointestinal hemorrhage4 (0.6)1 (0.5) International normalized ratio increasedaSAEs 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.3 (0.4)0 Lower gastrointestinal hemorrhage3 (0.4)0 Subcutaneous hematoma3 (0.4)0 Abdominal wall hematoma2 (0.3)0 Hematuria2 (0.3)0 Post-procedural hemorrhage2 (0.3)0 Hematemesis2 (0.3)2 (1.0) Hemoglobin decreased1 (0.1)2 (1.0) Menorrhagia03 (1.5) Hematoma02 (1.0)Serious hemorrhagic events Hemoptysis12 (1.8)1 (0.5) Gastrointestinal hemorrhage4 (0.6)1 (0.5) Lower gastrointestinal hemorrhage3 (0.4)0 Abdominal wall hematoma2 (0.3)0 Epistaxis2 (0.3)1 (0.5) Hematuria2 (0.3)0 Hematemesis2 (0.3)0 Hemoglobin decreasedaSAEs 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.02 (1.0)Embolic/thrombotic events Pulmonary embolism7 (1.0)4 (2.0) Acute myocardial infarction2 (0.3)0 Coronary angioplasty2 (0.3)0 Deep vein thrombosis2 (0.3)0Serious embolic/thrombotic events Pulmonary embolism7 (1.0)3 (1.5) Coronary angioplasty2 (0.3)0 Deep vein thrombosis2 (0.3)0Abbreviations: NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist.Table shows events reported in >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 et Pulmonary survival in pulmonary hypertension Heart Lung PubMed Scopus Google Scholar The in survival may reflect in CTEPH or differences in patient characteristics between common to such as and of that the two were not in or disease patients in the NOAC group received our results are therefore to and other of anticoagulants and were not and were not available for all patients. In hemorrhagic event rates similar in patients with CTEPH receiving VKAs or NOACs, but may be a for embolic and/or thrombotic events with NOACs. These results are and further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH. Humbert and from from and and from and from and the The EXPERT registry was by and a of and from and the from and the has received and from and and from and from and and/or from and and from and and from from and and from and the J. from and A. of for or from and and from and has no of to the EXPERT is an of Hoeper from during the of the from and the review of final for review of final for review of final for review of final for review of final for review of final for review of final for review of final for J. review of final for A. review of final for data review of final for review of final for review of final for of the data be according to to the European of and and and of for clinical data to and of data to from and clinical clinical and from clinical in patients for and in the and European as for This to data on new and that have been by the European and on or after 1, use to to data and from clinical studies to further that or patient on the for studies and other is in the study of the Data be to and clinical study after by an independent review is not in the by the independent review all to that patient is Medical by of were by in accordance with The by and by and at with with with

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