Long-term effect of subcutaneous treprostinil in patients with pulmonary hypertension: rationale and design of the phase IV, multicentre, observational TREPAR-HP study

Adrián Lescano, Nicolás Atamañuk, Guillermo Bortman, Jorge Cáneva, Mirta Diez, Guillermo Giacomi, Luís Lema, Eduardo R. Perna

Abstract

Background: Pulmonary hypertension (PH) is a chronic, progressive condition with high morbidity and mortality due to right heart (RH) failure. Prognosis depends on RH adaptability and remodelling in response to increased pulmonary arterial pressure. There is little information regarding risk variables and prognostic factors in the Argentinian population, current risk scores have not been validated, and its impact on free-event survival is still unknown. Prostacyclin analogues are the first-line treatment for high-risk patients. However, there is limited evidence on its clinical benefits, long-term effects, and impact on RH remodelling in the Argentinian population.

Methods: The study was designed as a national, multicentre, prospective, observational, phase IV study including 100 patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension, treated with subcutaneous treprostinil and followed up for 48 months. The study will be conducted in parallel with the patients' standard management and treatment in each centre. The primary objective is to assess the long-term improvement or reversal of RH remodelling (RHRR) parameters obtained by echocardiography. Secondary objectives include the evaluation of the prognostic value of RHRR parameters and the rate of clinical events, the treatment effect in terms of pulmonary vascular resistance, right ventricle systolic function, morbidity and all-cause mortality, quality of life, and safety and tolerability.

Conclusions: This study will help to determine the clinical benefits, long-term effects, and impact on RH remodelling of prostacyclin analogues in Argentina.

Trial registration: The trial was registered at Registro Nacional de Investigaciones en Salud (RENIS) in Argentina (https://sisa.msal.gov.ar/sisa/#sisa; registration number IS003303).

Keywords

Observational study, Pulmonary hypertension, Protocol, Phase IV trial, Treprostinil

Full Text:

PDF

References

Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, 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. 2016;37(1):67-119.

Lopes AA, Bandeira AP, Flores PC, Santana MV. Pulmonary hypertension in Latin America: pulmonary vascular disease: the global perspective. Chest. 2010;137(6):78s-84s.

Lau EMT, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017;14(10):603-14.

Echazarreta DF, Perna ER, Coronel ML, Diez M, Lescano AJ, Atamañuk AN, et al. Collaborative registry of pulmonary hypertension in Argentina (RECOPILAR). Final analysis. Medicina (B Aires). 2021;81(2):180-90.

Talavera ML, Cáneva JO, Favaloro LE, Klein F, Boughen RP, Bozovich GE, et al. Hipertensión arterial pulmonar. Registro de un centro de referencia en Argentina. Rev Am Med Resp. 2014;14(2):144-52.

Valverde AB, Soares JM, Viana KP, Gomes B, Soares C, Souza R. Pulmonary arterial hypertension in Latin America: epidemiological data from local studies. BMC Pulm Med. 2018;18(1):106.

Humbert M, Guignabert C, Bonnet S, Dorfmüller P, Klinger JR, Nicolls MR, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J. 2019;53(1):1801887.

Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1).

Kumar P, Thudium E, Laliberte K, Zaccardelli D, Nelsen A. A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration. Clin Pharmacokinet. 2016;55(12):1495-505.

Pedersen LM, Kruger M, Grimm D, Infanger M, Wehland M. The prostacyclin analogue treprostinil in the treatment of pulmonary arterial hypertension. Basic Clin Pharmacol Toxicol; 2019.

Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165(6):800-4.

Barst RJ, Galie N, Naeije R, Simonneau G, Jeffs R, Arneson C, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006;28(6):1195-203.

Lang I, Gomez-Sanchez M, Kneussl M, Naeije R, Escribano P, Skoro-Sajer N, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest. 2006;129(6):1636-43.

Sadushi-Kolici R, Jansa P, Kopec G, Torbicki A, Skoro-Sajer N, Campean IA, et al. Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial. Lancet Respir Med. 2019;7(3):239-48.

Raina A, Humbert M. Risk assessment in pulmonary arterial hypertension. Eur Respir Rev. 2016;25(142):390.

Fine NM, Chen L, Bastiansen PM, Frantz RP, Pellikka PA, Oh JK, et al. Outcome prediction by quantitative right ventricular function assessment in 575 subjects evaluated for pulmonary hypertension. Circ Cardiovasc Imaging. 2013;6(5):711-21.

Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, et al. Right Heart Adaptation to Pulmonary Arterial Hypertension: Physiology and Pathobiology. J Am Coll Cardiol. 2013;62(25):D22-D33.

Badagliacca R, Poscia R, Pezzuto B, Papa S, Reali M, Pesce F, et al. Prognostic relevance of right heart reverse remodeling in idiopathic pulmonary arterial hypertension. J Heart Lung Transplant. 2018;37(2):195-205.

Badagliacca R, Papa S, Manzi G, Miotti C, Luongo F, Sciomer S, et al. Usefulness of Adding Echocardiography of the Right Heart to Risk-Assessment Scores in Prostanoid-Treated Pulmonary Arterial Hypertension. JACC Cardiovasc Imaging. 2020;13(9):2054-56.

D'Alto M, Badagliacca R, Argiento P, Romeo E, Farro A, Papa S, et al. Risk Reduction and Right Heart Reverse Remodeling by Upfront Triple Combination Therapy in Pulmonary Arterial Hypertension. Chest. 2020;157(2):376-83.

Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the Echocardiographic Assessment of the Right Heart in Adults: A Report from the American Society of Echocardiography: Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23(7):685-713.

Benza R, Kanwar M, Raina A, Scott JV, Zhao C, Selej M, et al. Development and Validation of an Abridged Version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for Use in Patients With Pulmonary Arterial Hypertension. Chest. 2020;159:337-46.

Garin O, Soriano N, Ribera A, Ferrer M, Pont À, Alonso J, et al. Validación de la versión española del Minnesota Living with Heart Failure Questionnaire. Rev Esp Cardiol. 2008;61(3):251-59.

Ministerio de Salud. Salud publica. Resolución 1480/2011. Guía para Investigaciones con Seres Humanos. Boletín Oficial de la República Argentina. Available at: https://www.uba.ar/ archivossecyt/image/Resolucion1480-11%20Naci %C3%B3n.pdf Accessed on 12 August 2021.

Lescano A, Damianich G, Crippa D, Besmalinovich E, Farina J, Fernández I, et al. Factores pronósticos en hipertensión pulmonar: Nuestra experiencia. Insuf Card. 2018;13(2):51-6.

Farmakis IT, Demerouti E, Karyofyllis P, Karatasakis G, Stratinaki M, Tsiapras D, et al. Echocardiography in Pulmonary Arterial Hypertension: Is It Time to Reconsider Its Prognostic Utility? J Clin Med. 2021;10(13).

Yorke J, Deaton C, Campbell M, McGowen L, Sephton P, Kiely DG, et al. Symptom severity and its effect on health-related quality of life over time in patients with pulmonary hypertension: a multisite longitudinal cohort study. BMJ Open Respir Res. 2018;5(1):e000263.

Mathai SC, Suber T, Khair RM, Kolb TM, Damico RL, Hassoun PM. Health-related Quality of Life and Survival in Pulmonary Arterial Hypertension. Ann Am Thorac Soc. 2016;13(1):31-9.

Levine DJ. Pulmonary arterial hypertension: updates in epidemiology and evaluation of patients. Am J Manag Care. 2021;27(3):S35-S41.

Mathier MA, McDevitt S, Saggar R. Subcutaneous treprostinil in pulmonary arterial hypertension: Practical considerations. J Heart Lung Transplant. 2010;29(11):1210-7.

Delcroix M, Howard L. Pulmonary arterial hypertension: the burden of disease and impact on quality of life. Eur Respir Rev. 2015;24(138):621-9.

Ferrari P, Armstrong I, Aldrighetti R, Howard L, Ryftenius H, Fischer A, et al. Impact of pulmonary arterial hypertension (PAH) on the lives of patients and carers. Eur Respir J. 2013;42(57):P2631.

Cenedese E, Speich R, Dorschner L, Ulrich S, Maggiorini M, Jenni R, et al. Measurement of quality of life in pulmonary hypertension and its significance. Eur Respir J. 2006;28(4):808.