Anti-coagulation therapy for pulmonary hypertension: necessity and dilemmas

doi:10.16352/j.issn.1001-6325.2024.08.1062

Abstract

Abstract: Pulmonary hypertension (PH) is a rare and life-threatening disease. Over past two decades, rapid advancements in treatment techniques have significantly improved the prognosis of two major subgroups of PH entities: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Given the underlying pathological feature of in situ thrombosis of small arteries, anti-coagulation was previously considered to be a supportive therapy for PAH to improve prognosis. However, due to a lack of robust evidence, it is not recommended by the current guidelines. In contrast, lifelong anticoagulation is recommended for CTEPH patients to prevent thrombus recurrence and in situ thrombosis, based on the thromboembolic etiology. Furthermore, with the advent of direct oral anticoagulants, there are now more options for anti-coagulation therapy in PH. Nevertheless, due to the complexity of PH etiology and the heterogeneity of treatment approaches, anti-coagulation management remains challenging. This article reviews and evaluates the current status and safety issue of anti-coagulation therapy for PH patients, providing guidance and insights for clinical practice and research in this field.

Key words: pulmonary hypertension, chronic thromboembolic pulmonary hypertension, anti-coagulation, targeted drug, drug interactions

CLC Number:

R543.2

HU Song, HUA Lu, ZHANG Jian. Anti-coagulation therapy for pulmonary hypertension: necessity and dilemmas[J]. Basic & Clinical Medicine, 2024, 44(8): 1062-1067.

References

[1] Ruopp NF, Cockrill BA. Diagnosis and treatment of pulmonary arterial hypertension: a review[J]. JAMA, 2022, 327: 1379-1391. doi:10.1001/jama.2022.4402.
[2] Teerapuncharoen K, Bag R. Chronic thromboembolic pulmonary hypertension[J]. Lung, 2022, 200: 283-299. doi:10.1007/s00408-022-00539-w.
[3] Bejjani A, Khairani CD, Assi A, et al. When direct oral anticoagulants should not be standard treatment: JACC State-of-the-Art review[J]. J Am Coll Cardiol, 2024, 83: 444-465. doi:10.1016/j.jacc.2023.10.038.
[4] Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension[J]. Eur Heart J, 2022, 43: 3618-3731. doi:10.1093/eurheartj/ehac237.
[5] Humbert M, Sitbon O, Guignabert C, et al. Treatment of pulmonary arterial hypertension: recent progress and a look to the future[J]. Lancet Respir Med, 2023, 11: 804-819. doi:10.1016/S2213-2600(23)00264-3.
[6] Rawal H, Suman A, Bhoite RR, et al. Anticoagulation in pulmonary arterial hypertension: Do we know the answer?[J]. Curr Probl Cardiol, 2021, 46: 100738. doi:10.1016/j.cpcardiol.2020.100738.
[7] Hoeper MM, Sosada M, Fabel H. Plasma coagulation profiles in patients with severe primary pulmonary hypertension[J]. Eur Respir J, 1998, 12: 1446-1449. doi:10.1183/09031936.98.12061446.
[8] Khan MS, Usman MS, Siddiqi TJ, et al. Is anticoagula-tion beneficial in pulmonary arterial hypertension?[J]. Circ Cardiovasc Qual Outcomes, 2018, 11: e004757. doi:10.1161/CIRCOUTCOMES.118.004757.
[9] Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern manage-ment era[J]. Circulation, 2010, 122: 156-163. doi:10.1161/CIRCULATIONAHA.109.911818.
[10] Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry[J]. Chest, 2010, 137: 376-387. doi:10.1378/chest.09-1140.
[11] Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)[J]. Circulation, 2014, 129: 57-65. doi:10.1161/CIRCULATIONAHA.113.004526.
[12] Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension[J]. N Engl J Med, 2013, 369: 809-818. doi:10.1056/NEJMoa1213917.
[13] Caldeira D, Loureiro MJ, Costa J, et al. Oral anticoagulation for pulmonary arterial hypertension: systematic review and meta-analysis[J]. Can J Cardiol, 2014, 30: 879-887. doi:10.1016/j.cjca.2014.04.016.
[14] Johnson SR, Mehta S, Granton JT. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review[J]. Eur Respir J, 2006, 28: 999-1004. doi:10.1183/09031936.06.00015206.
[15] Wang P, Hu L, Yin Y, et al. Can anticoagulants improve the survival rate for patients with idiopathic pulmonary arterial hypertension? A systematic review and meta-analysis[J]. Thromb Res, 2020, 196:251-256. doi:10.1016/j.thromres.2020.08.024.
[16] Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension[J]. Chest, 2006, 130: 545-552. doi:10.1378/chest.130.2.545.
[17] Lai J, Feng S, Xu S, et al. Effects of oral anticoagulant therapy in patients with pulmonary diseases[J]. Front Cardiovasc Med, 2022, 9:987652. doi:10.3389/fcvm.2022.987652.
[18] Henkens IR, Hazenoot T, Boonstra A, et al. Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension[J]. Eur Respir J, 2013, 41: 872-878. doi:10.1183/09031936.00039212.
[19] Date N, Nakajima D, Ikeda M, et al. Effect of epoprostenol-induced thrombocytopaenia on lung transplantation for pulmonary arterial hypertension[J]. Eur J Cardiothorac Surg, 2024, 65:ezae108. doi:10.1093/ejcts/ezae108.
[20] Roldan T, Rios JJ, Villamanan E, et al. Complications associated with the use of oral anticoagulation in patients with pulmonary arterial hypertension from two referral centers[J]. Pulm Circ, 2017, 7: 692-701. doi:10.1177/2045893217721903.
[21] Gabriel L, Delavenne X, Bedouch P, et al. Risk of direct oral anticoagulant bioaccumulation in patients with pulmonary hypertension[J]. Respiration, 2016, 91: 307-315. doi:10.1159/000445122.
[22] Delcroix M, Torbicki A, Gopalan D, et al. ERS statement on chronic thromboembolic pulmonary hypertension[J]. Eur Respir J, 2021, 57:2002828. doi:10.1183/13993003.02828-2020.
[23] Simonneau G, Dorfmuller P, Guignabert C, et al. Chronic thromboembolic pulmonary hypertension: the magic of pathophysiology[J]. Ann Cardiothorac Surg, 2022, 11: 106-119. doi:10.21037/acs-2021-pte-10.
[24] Benzidia I, Robitaille C, Abualsaud A, et al. Safety and efficacy of direct oral anticoagulants in patients with chronic thromboembolic pulmonary hypertension[J]. Thromb Res, 2023, 229:139-145. doi:10.1016/j.thromres.2023.07.002.
[25] Kramm T, Wilkens H, Fuge J, et al. Incidence and characteristics of chronic thromboembolic pulmonary hypertension in Germany[J]. Clin Res Cardiol, 2018, 107: 548-553. doi:10.1007/s00392-018-1215-5.
[26] Hu S, Tan JS, Liu S, et al. The long-term survival in patients with chronic thromboembolic pulmonary hyperten-sion: experience from a single center in China[J]. J Thromb Thrombolysis, 2022, 53: 926-933. doi:10.1007/s11239-021-02594-1.
[27] Sena 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[J]. Pulm Circ, 2020, 10: 2045894019873545. doi:10.1177/2045894019873545.
[28] Bunclark K, Newnham M, Chiu YD, et al. A multicenter study of anticoagulation in operable chronic thromboembolic pulmonary hypertension[J]. J Thromb Haemost, 2020, 18: 114-122. doi:10.1111/jth.14649.
[29] Barati S, Amini H, Ahmadi ZH, et al. Evaluating the efficacy and safety of rivaroxaban as a warfarin alternative in chronic thromboembolic pulmonary hypertension patients undergoing pulmonary endarterectomy: A randomized clinical trial[J]. Rev Port Cardiol, 2023, 42: 139-144. doi:10.1016/j.repc.2021.09.023.
[30] Ishisaka Y, Watanabe A, Takagi H, et al. Anticoagulation in chronic thromboembolic pulmonary hypertension: A systematic review and meta-analysis[J]. Thromb Res, 2023, 231:91-98. doi:10.1016/j.thromres.2023.10.003.
[31] Bertoletti L, Mismetti V, Giannakoulas G. Use of anticoagulants in patients with pulmonary hypertension[J]. Hamostaseologie, 2020, 40: 348-355. doi:10.1055/a-1171-3995.
[32] Taskar KS, Yang X, Neuhoff S, et al. Clinical relevance of hepatic and renal P-gp/BCRP inhibition of drugs: An international transporter consortium perspective[J]. Clin Pharmacol Ther, 2022, 112: 573-592. doi:10.1002/cpt.2670.
[33] Margelidon-Cozzolino V, Delavenne X, Catella-Chatron J, et al. Indications and potential pitfalls of anticoagulants in pulmonary hypertension: Would DOACs become a better option than VKAs?[J]. Blood Rev, 2019, 37:100579. doi:10.1016/j.blre.2019.05.003.
[34] Huppertz A, Werntz L, Meid AD, et al. Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John′s wort should be avoided[J]. Br J Clin Pharmacol, 2018, 84: 2903-2913. doi:10.1111/bcp.13757.
[35] Frost CE, Byon W, Song Y, et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor[J]. Br J Clin Pharmacol, 2015, 79: 838-846. doi:10.1111/bcp.12541.
[36] Washam JB, Hellkamp AS, Lokhnygina Y, et al. Efficacy and safety of rivaroxaban versus warfarin in patients taking nondihydropyridine calcium channel blockers for atrial fibrillation (from the ROCKET AF Trial)[J]. Am J Cardiol, 2017, 120: 588-594. doi:10.1016/j.amjcard.2017.05.026.
[37] Margelidon-Cozzolino V, Hodin S, Jacqueroux E, et al. In vitro assessment of pharmacokinetic drug-drug interactions of direct oral anticoagulants: type 5-phosphodie-sterase inhibitors are inhibitors of rivaroxaban and apixaban efflux by P-glycoprotein[J]. J Pharmacol Exp Ther, 2018, 365: 519-525. doi:10.1124/jpet.117.245993.
[38] Jacqueroux E, Mercier C, Margelidon-Cozzolino V, et al. In vitro assessment of P-gp and BCRP transporter-mediated drug-drug interactions of riociguat with direct oral anticoagulants[J]. Fundam Clin Pharmacol, 2020, 34: 109-119. doi:10.1111/fcp.12504.