Abstract
Background
Pulmonary hypertension (PH) is a rare and complex disease with poor prognosis, which requires lifelong treatment.
Objective
To describe 3-year follow-up real-life data on treatment with soluble guanylate cyclase stimulators (Riociguat) of patients with PH, measuring current risk assessment parameters.
Methods
This study retrospectively collected clinical and epidemiological data of patients with PH of group 1 (pulmonary arterial hypertension) and group 4 (chronic thromboembolic PH). Non-invasive and invasive parameters corresponding to the risk assessment were analyzed at baseline and follow-up. Statistical analyses were performed using the SPSS 18.0 software, and p-values < 0.050 were considered statistically significant.
Results
In total, 41 patients receiving riociguat were included in the study. Of them, 31 had already completed 3 years of treatment and were selected for the following analysis. At baseline, 70.7% of patients were in WHO functional class III or IV. After 3 years of treatment, the WHO functional class significantly improved in all patients. In addition, the median of the 6-minute walk test (6MWT) significantly increased from 394 ± 91 m at baseline to 458 ± 100 m after 3 years of follow-up (p= 0.014). The three-year survival rate was 96.7%.
Conclusion
In our real-life cohort, most patients with PH treated with riociguat showed stable or improved risk parameters, especially in the 6MWT, at 3 years of follow-up.
Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Pulmonary Wedge Pressure
Resumo
Fundamento
A hipertensão pulmonar (HP) é uma doença rara e complexa com prognóstico ruim, que exige tratamento pela vida toda.
Objetivo
Descrever dados de 3 anos de acompanhamento da vida real sobre o tratamento com estimuladores de guanilato ciclase solúvel (Riociguate) de pacientes com HP, medindo parâmetros atuais de avaliação de risco.
Métodos
Coletamos dados clínicos e epidemiológicos retrospectivamente de pacientes com HP do grupo 1 (hipertensão arterial pulmonar) e do grupo 4 (HP tromboembólica crônica). Parâmetros não invasivos e invasivos correspondentes à avaliação de risco foram analisados na linha de base e no acompanhamento. Foram realizadas análises estatísticas usando o software SPSS 18.0, e os p-valores <0,050 foram considerados estatisticamente significativos.
Resultados
No total, 41 pacientes tratados com riociguate foram incluídos no estudo. Entre eles, 31 já concluíram 3 anos de tratamento e foram selecionados para a seguinte análise. Na linha de base, 70,7% dos pacientes estavam nas classes funcionais III ou IV da OMS. Depois de 3 anos de tratamento, a classe funcional da OMS melhorou significativamente em todos os pacientes. Além disso, a mediana do teste de caminhada de 6 minutos (TC6M) aumentou significativamente de 394 ± 91 m na linha de base para 458 ± 100 m após 3 anos de acompanhamento (p= 0,014). O índice de sobrevida após três anos foi de 96,7%.
Conclusão
Em nossa coorte de vida real, a maioria dos pacientes com HP tratados com riociguate demonstraram parâmetros de risco estáveis ou melhores, especialmente no TC6M, aos 3 anos de acompanhamento.
Hipertensão Arterial Pulmonar; Hipertensão Pulmonar; Pressão Propulsora Pulmonar
Introduction
Pulmonary hypertension (PH) is a progressive clinical condition, characterized by the elevation of mean pulmonary arterial pressure (mPAP) to greater than 20 mmHg when at rest.11. 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):1801913. doi: 10.1183/13993003.01913-2018. Prior to the modern era of PH therapy, the average life expectancy after diagnosis had been 2.8 years for adults with PH.2 The development and availability of new therapies have significantly improved the quality of life and the survival of PH patients.33. Poch D, Mandel J. Pulmonary Hypertension. Ann Intern Med. 2021;174(4):49-64. doi: 10.7326/AITC202104200. , 44. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An Evaluation of Long-term Survival from Time of Diagnosis in Pulmonary Arterial Hypertension from the REVEAL Registry. Chest. 2012;142(2):448-56. doi: 10.1378/chest.11-1460.
PH is classified into five clinical subgroups: pulmonary arterial hypertension (PAH), PH due to left-sided heart disease, PH due to chronic lung disease, chronic thromboembolic PH (CTEPH), and PH with an unclear and/or multifactorial mechanisms.33. Poch D, Mandel J. Pulmonary Hypertension. Ann Intern Med. 2021;174(4):49-64. doi: 10.7326/AITC202104200. This categorization considers a similar clinical presentation, pathological findings, hemodynamic characteristics, and treatment strategy.55. 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. doi: 10.1093/eurheartj/ehv317. Specifically, PAH (group 1) and CTEPH (group 4) are characterized as pre-capillary PH, with pulmonary arterial wedge pressure ≤15 mmHg and pulmonary vascular resistance (PVR) ≥3 Wood Units.11. 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):1801913. doi: 10.1183/13993003.01913-2018. Although CTEPH originates from a chronic pulmonary thromboembolism, PAH and CTEPH diseases present loss and obstructive remodeling of the pulmonary vascular bed, resulting in elevated pulmonary arterial pressure and PVR, progressive right heart failure, and death.66. 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. doi: 10.1183/13993003.01887-2018.
In addition to presenting pathophysiological similarities, PAH and CTEPH also have similarities in pharmacological treatment. Pulmonary endarterectomy remains the treatment of choice for patients with surgical CTEPH; however, for those considered inoperable, scientific evidence supports the initiation of medical therapy and the consideration of balloon pulmonary angioplasty.77. Kim NH, Delcroix M, Jais X, Madani MM, Matsubara H, Mayer E, et al. Chronic Thromboembolic Pulmonary Hypertension. Eur Respir J. 2019;53(1):1801915. doi: 10.1183/13993003.01915-2018.
The soluble guanylate cyclase stimulator (riociguat) has a dual mode of action: 1) it directly stimulates soluble guanylate cyclase independently of nitric oxide and 2) it increases the sensitivity of soluble guanylate cyclase to nitric oxide.88. Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bölkow D, et al. First Acute Haemodynamic Study of Soluble Guanylate Cyclase Stimulator Riociguat in Pulmonary Hypertension. Eur Respir J. 2009;33(4):785-92. doi: 10.1183/09031936.00039808. , 99. Stasch JP, Pacher P, Evgenov OV. Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease. Circulation. 2011;123(20):2263-73. doi: 10.1161/CIRCULATIONAHA.110.981738. As it is known that patients with PAH or CTEPH have reduced levels of nitric oxide,1010. Ghofrani HA, Humbert M, Langleben D, Schermuly R, Stasch JP, Wilkins MR, et al. Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension. Chest. 2017;151(2):468-80. doi: 10.1016/j.chest.2016.05.024. this mode of action is very important to improve the dynamics of the pulmonary vasculature. Previous studies have shown that riociguat significantly improved exercise capacity, as well as secondary endpoints, such as PVR, the World Health Organization (WHO) functional class, and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with PAH1111. Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2013;369(4):330-40. doi: 10.1056/NEJMoa1209655. and CTEPH.1212. Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2013;369(4):319-29. doi: 10.1056/NEJMoa1209657. Based on these results, riociguat was approved for the treatment of adults with PAH in monotherapy or in combination,55. 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. doi: 10.1093/eurheartj/ehv317. and it is the only medication approved by American, European, and Brazilian regulatory agencies for the treatment of inoperable CTEPH or residual PH.1313. Fernandes CJCS, Ota-Arakaki JS, Campos FTAF, Corrêa RA, Gazzana MB, Jardim C, et al. Brazilian Thoracic Society Recommendations for the Diagnosis and Treatment of Chronic Thromboembolic Pulmonary Hypertension. 2020;46(6): e20200204. doi:10.36416/1806-3756/e20200204.
https://doi.org/10.36416/1806-3756/e2020...
, 1414. Klinger JR, Chakinala MM, Langleben D, Rosenkranz S, Sitbon O. Riociguat: Clinical Research and Evolving Role in Therapy. Br J Clin Pharmacol. 2021;87(7):2645-62. doi: 10.1111/bcp.14676. In this context, the aim of this study was to describe real-life data on the treatment of patients with PH from group 1 (PAH) and group 4 (CTEPH) with riociguat in Brazil, measuring current risk assessment parameters.
Methods
Selection of patients
All patients with PAH and CTEPH who started the treatment with riociguat between 2010 and 2020 at the Centro de Hipertensão Pulmonar, Complexo Hospitalar Santa Casa de Porto Alegre were included and analyzed retrospectively ( Figure 1 ). This is a Reference Center for PH treatment, which participates in the main multicenter clinical studies in the area since 2005. This study was approved by the local ethics committee (number: 30199714.6.0000.5335). Diagnosis of PH was confirmed by right heart catheterization (RHC) in all patients.
– Flowchart of patients throughout the study. PAH: pulmonary arterial hypertension; CTEPH: chronic thromboembolic pulmonary hypertension.
Procedures
Demographic and clinical characteristics were collected at baseline, 3 months, 1 year, and 3 years of follow-up. These parameters included the determination of PH etiology, the WHO functional class, the 6-minute walking test (6MWT), NT-proBNP, and hemodynamic measurements.
Baseline was defined as the time of stable medication before starting treatment with riociguat. The WHO functional class was determined by the treating physician at each visit. The 6MWT was carried out according to ATS guidelines.1515. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS Statement: Guidelines for the Six-minute Walk Test. Am J Respir Crit Care Med. 2002;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. RHC was performed using a Swan-Ganz catheter. Cardiac output was measured by thermodilution. Survival was established based on the electronic medical records.
Statistical analysis
Normal distribution was checked using the Shapiro-Wilk test. The continuous variables with normal distribution are presented as mean ± standard deviation (SD). Variables with skewed distribution were log-transformed before analyses and are presented as medians (25th – 75th percentiles).1616. Winter JCF. Using the Student’s t-test with Extremely Small Sample Sizes. Practical Assessment, Research & Evaluation. 2013;18(10):1-11. doi: 10.7275/e4r6-dj05. Categorical data are shown as absolute number and percentages.
Clinical, laboratorial, and hemodynamics characteristics were compared between groups (PAH and CTEPH), using the unpaired Student’s t -test1616. Winter JCF. Using the Student’s t-test with Extremely Small Sample Sizes. Practical Assessment, Research & Evaluation. 2013;18(10):1-11. doi: 10.7275/e4r6-dj05. or χ2tests, as appropriate. Differences between baseline, 3 months, 1 year, and 3 years of follow-up were compared using the paired Student’s t -test. Correlation analyses were performed using Pearson’s correlation tests. Statistical analyses were performed using the SPSS 18.0 software (SPSS, Chicago, IL), and p-values < 0.050 were considered statistically significant.
Results
A total of 41 patients who had been treated with riociguat were eligible for the analysis. Of these, 31 had completed 3 years of follow-up and were selected for the following analysis ( Figure 1 ).
Baseline demographic and clinical characteristics of the study population are shown in Table 1 . Of the 41 patients enrolled in this study, 24 patients were classified as PAH (group 1) and 17 patients as CTEPH (group 4). The most common PAH etiologies were idiopathic (67%). Patients were predominantly female (70.7%), with a mean age at PH diagnosis of 42.2 ± 3.5 years. Most participants showed moderate to severe disease manifestations at baseline, with 70.7% of the patients presenting WHO functional class III or IV. Overall, the median levels of NT-proBNP were 655 pg/ml, and the mean 6MWT was 386 meters. Hemodynamically, patients showed mPAP of 45.5 ± 11.7 mmHg; PVR of 9.8 ± 1.0 Wood; and a cardiac index (CI) of 2.7 ± 0.1 L/min ( Table 1 ). It is important to note that no difference was found between the PAH and CTEPH groups regarding the analyzed characteristics ( Table 1 ).
During a 3-year patient follow-up, a functional capacity improvement was noted, as illustrated in Figure 2 . During the follow-up, the number of patients in functional class III decreased, and that of functional class II increased ( Figure 2a ). Considering only the patients who completed 3 years of follow-up (n= 31), at baseline, 61% patients were functional class III, and after 3 years of treatment with riociguat, 10% of patients continued as functional class III. In the same way, at baseline, 32% of the patients were functional class II, and after treatment, 71% of the patients were in functional class II. In particular, the number of patients in functional class I increased from 0 at baseline to 5 patients after 3 years of treatment ( Figure 2b ).
– Change of WHO functional class over time in patients with pulmonary hypertension. A) Data from all 41 patients in baseline and follow-up periods. B) Data from the 31 patients who completed 3 years of follow-up.
Clinical characteristics of the 31 patients who completed the 3 years of follow-up are described in Table 2 . Our results showed a significant improvement of 64 m after 3 years of treatment with riociguat when compared to the baseline (p= 0.014). After stratification by PH etiology, a reduction of 59 m was observed in PAH (p= 0.045) and of 70 m in CTEPH patients (p= 0.080). Moreover, as shown in Figure 3 , 6MWT significantly improved in 3 months, 1 year, and 3 years when compared to baseline results. Although the decrease in NT-proBNP levels is not statically significant, a clinically important reduction of 663 pg/ml could be observed in NT-proBNP levels after treatment with riociguat ( Table 2 and Figure 4 ). Moreover, there is a negative correlation between 6MWT and NT-proBNP levels after 3 years of follow-up (r= -0.520, p= 0.027). No significant changes were observed in RAP and CI in baseline measurements when compared to 3 years of follow-up. According to the French non-invasive risk stratification, no patient was at low risk at baseline and 7 patients achieved low risk status after 3 years of treatment. During the follow-up period, a total of one (3.2%) patient died of PH-related causes; and this death occurred in patient with functional class III at baseline.
– Change of 6-min walking test (6MWT) over time in patients with pulmonary hypertension. *p-value< 0.05; +p-value< 0.10; Paired Student’s t-test compared to Baseline.
– Change of N-terminal pro-brain natriuretic peptide (NT-proBNP) over time in patients with pulmonary hypertension.
Additionally, our center also observed the results of a sub-group of 10 patients who have completed 10-years using riociguat. In the same line of 3 years of follow-up results, the clinical status of these patients was also satisfactory, with low risk and good treatment tolerability.
Discussion
To the best of our knowledge, this is the first study to detail the real-life experience of treating PAH and CTEPH with riociguat for at least 3 years. In this real-life cohort, we show an improvement in 6MWT and WHO functional class in both groups, PAH and CTEPH.
The 6MWT is a simple tool for the evaluation of functional exercise capacity, which reflects the capacity of the individual to perform activities of daily living. Moreover, it is familiar to patients55. 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. doi: 10.1093/eurheartj/ehv317. and has been the most employed primary endpoint in clinical trials of PH therapies.1717. Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, et al. Risk Assessment, Prognosis and Guideline Implementation in Pulmonary Arterial Hypertension. Eur Respir J. 2017;50(2):1700889. doi: 10.1183/13993003.00889-2017. Among exercise tests, the 6MWT has proven to have the best ability to capture changes in exercise capacity and has regularly proven to be an independent predictor of morbidity and mortality in PH.1818. Mainguy V, Malenfant S, Neyron AS, Bonnet S, Maltais F, Saey D, et al. Repeatability and Responsiveness of Exercise Tests in Pulmonary Arterial Hypertension. Eur Respir J. 2013;42(2):425-34. doi: 10.1183/09031936.00107012.
19. Deboeck G, Scoditti C, Huez S, Vachiéry JL, Lamotte M, Sharples L, et al. Exercise Testing to Predict Outcome in Idiopathic Versus Associated Pulmonary Arterial Hypertension. Eur Respir J. 2012;40(6):1410-9. doi: 10.1183/09031936.00217911. - 2020. Nagel C, Prange F, Guth S, Herb J, Ehlken N, Fischer C, et al. Exercise Training Improves Exercise Capacity and Quality of Life in Patients with Inoperable or Residual Chronic Thromboembolic Pulmonary Hypertension. PLoS One. 2012;7(7):e41603. doi: 10.1371/journal.pone.0041603.
Our results showed a significant improvement of 64 m after 3 years of treatment with riociguat, which is in accordance with the findings of improvements in 6MWT of many studies, both randomized controlled trials1111. Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2013;369(4):330-40. doi: 10.1056/NEJMoa1209655. , 1212. Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2013;369(4):319-29. doi: 10.1056/NEJMoa1209657. as well as extension,2121. Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F, Hoeper MM, Jansa P, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension: A Long-term Extension Study (CHEST-2). Eur Respir J. 2015;45(5):1293-302. doi: 10.1183/09031936.00087114. , 2222. Souza R, Kawut SM. What is New About Rio? Eur Respir J. 2015;45(5):1211-3. doi: 10.1183/09031936.00032715. open-label2323. Hoeper MM, Simonneau G, Corris PA, Ghofrani HA, Klinger JR, Langleben D, et al. RESPITE: Switching to Riociguat in Pulmonary Arterial Hypertension Patients with Inadequate Response to Phosphodiesterase-5 Inhibitors. Eur Respir J. 2017;50(3):1602425. doi: 10.1183/13993003.02425-2016. , 2424. Frantz RP. REPLACE and the Role of Riociguat in Pulmonary Arterial Hypertension Therapy. Lancet Respir Med. 2021;9(6):546-7. doi: 10.1016/S2213-2600(20)30567-1. and real-life studies.2525. McLaughlin VV, Jansa P, Nielsen-Kudsk JE, Halank M, Simonneau G, Grünig E, et al. Riociguat in Patients with Chronic Thromboembolic Pulmonary Hypertension: Results from an Early Access Study. BMC Pulm Med. 2017;17(1):216. doi: 10.1186/s12890-017-0563-7. In addition, our data presented a gradual increase in 6MWT distance, from 3 months to 3 years after the start of treatment, with a final median greater than 440m, which is considered a low-risk status for patients.55. 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. doi: 10.1093/eurheartj/ehv317.
The 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) treatment guidelines recommend regular risk assessment in PAH patients, to manage the patients, focusing on low risk.55. 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. doi: 10.1093/eurheartj/ehv317. This risk assessment is performed using a multidimensional approach, but there are abbreviated versions, such as the French registry non-invasive method, which evaluate 6MWT, NT-ProBNP, and WHO functional class.1717. Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, et al. Risk Assessment, Prognosis and Guideline Implementation in Pulmonary Arterial Hypertension. Eur Respir J. 2017;50(2):1700889. doi: 10.1183/13993003.00889-2017. In this context, we also found improvements in NT-ProBNP and WHO functional class in our patients treated with riociguat. Moreover, seven patients achieved the low-risk status. These results emphasize the benefits of medication to the achievement of treatment goals and, perhaps, to reduce the estimated 1-year mortality. Previous reports found significant improvements in these parameters1111. Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2013;369(4):330-40. doi: 10.1056/NEJMoa1209655. , 1212. Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2013;369(4):319-29. doi: 10.1056/NEJMoa1209657. and in the low-risk score achievement1717. Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, et al. Risk Assessment, Prognosis and Guideline Implementation in Pulmonary Arterial Hypertension. Eur Respir J. 2017;50(2):1700889. doi: 10.1183/13993003.00889-2017. after treatment with riociguat. It is likely that our data did not reach statistical significance because of the small sample size.
Our study has some limitations. First, due to the real-life cohort design of this study, the number of patients at each visit varied. Second, this is a retrospective study with a reduced sample size. Third, the results are from a single center. Therefore, these limitations should be considered when interpreting the results.
Conclusion
In our real-life cohort, most patients with PH treated with riociguat showed stable or improved risk parameters, especially the 6MWT, at 3 years of follow-up. Moreover, our data was able to reproduce the results of pivotal studies during our follow-up.
Acknowledgments
Gabriela Roncato was an employee of Bayer SA during the writing of the study as a former researcher at Centro de Hipertensão Pulmonar, Complexo Hospitalar Santa Casa de Porto Alegre.
Referências
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1Simonneau 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):1801913. doi: 10.1183/13993003.01913-2018.
-
2D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in Patients with Primary Pulmonary Hypertension. Results from a National Prospective Registry. Ann Intern Med. 1991;115(5):343-9. doi: 10.7326/0003-4819-115-5-343.
-
3Poch D, Mandel J. Pulmonary Hypertension. Ann Intern Med. 2021;174(4):49-64. doi: 10.7326/AITC202104200.
-
4Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An Evaluation of Long-term Survival from Time of Diagnosis in Pulmonary Arterial Hypertension from the REVEAL Registry. Chest. 2012;142(2):448-56. doi: 10.1378/chest.11-1460.
-
5Galiè 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. doi: 10.1093/eurheartj/ehv317.
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6Humbert 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. doi: 10.1183/13993003.01887-2018.
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7Kim NH, Delcroix M, Jais X, Madani MM, Matsubara H, Mayer E, et al. Chronic Thromboembolic Pulmonary Hypertension. Eur Respir J. 2019;53(1):1801915. doi: 10.1183/13993003.01915-2018.
-
8Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bölkow D, et al. First Acute Haemodynamic Study of Soluble Guanylate Cyclase Stimulator Riociguat in Pulmonary Hypertension. Eur Respir J. 2009;33(4):785-92. doi: 10.1183/09031936.00039808.
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9Stasch JP, Pacher P, Evgenov OV. Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease. Circulation. 2011;123(20):2263-73. doi: 10.1161/CIRCULATIONAHA.110.981738.
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10Ghofrani HA, Humbert M, Langleben D, Schermuly R, Stasch JP, Wilkins MR, et al. Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension. Chest. 2017;151(2):468-80. doi: 10.1016/j.chest.2016.05.024.
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11Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2013;369(4):330-40. doi: 10.1056/NEJMoa1209655.
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12Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2013;369(4):319-29. doi: 10.1056/NEJMoa1209657.
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13Fernandes CJCS, Ota-Arakaki JS, Campos FTAF, Corrêa RA, Gazzana MB, Jardim C, et al. Brazilian Thoracic Society Recommendations for the Diagnosis and Treatment of Chronic Thromboembolic Pulmonary Hypertension. 2020;46(6): e20200204. doi:10.36416/1806-3756/e20200204.
» https://doi.org/10.36416/1806-3756/e20200204 -
14Klinger JR, Chakinala MM, Langleben D, Rosenkranz S, Sitbon O. Riociguat: Clinical Research and Evolving Role in Therapy. Br J Clin Pharmacol. 2021;87(7):2645-62. doi: 10.1111/bcp.14676.
-
15ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS Statement: Guidelines for the Six-minute Walk Test. Am J Respir Crit Care Med. 2002;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102.
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16Winter JCF. Using the Student’s t-test with Extremely Small Sample Sizes. Practical Assessment, Research & Evaluation. 2013;18(10):1-11. doi: 10.7275/e4r6-dj05.
-
17Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, et al. Risk Assessment, Prognosis and Guideline Implementation in Pulmonary Arterial Hypertension. Eur Respir J. 2017;50(2):1700889. doi: 10.1183/13993003.00889-2017.
-
18Mainguy V, Malenfant S, Neyron AS, Bonnet S, Maltais F, Saey D, et al. Repeatability and Responsiveness of Exercise Tests in Pulmonary Arterial Hypertension. Eur Respir J. 2013;42(2):425-34. doi: 10.1183/09031936.00107012.
-
19Deboeck G, Scoditti C, Huez S, Vachiéry JL, Lamotte M, Sharples L, et al. Exercise Testing to Predict Outcome in Idiopathic Versus Associated Pulmonary Arterial Hypertension. Eur Respir J. 2012;40(6):1410-9. doi: 10.1183/09031936.00217911.
-
20Nagel C, Prange F, Guth S, Herb J, Ehlken N, Fischer C, et al. Exercise Training Improves Exercise Capacity and Quality of Life in Patients with Inoperable or Residual Chronic Thromboembolic Pulmonary Hypertension. PLoS One. 2012;7(7):e41603. doi: 10.1371/journal.pone.0041603.
-
21Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F, Hoeper MM, Jansa P, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension: A Long-term Extension Study (CHEST-2). Eur Respir J. 2015;45(5):1293-302. doi: 10.1183/09031936.00087114.
-
22Souza R, Kawut SM. What is New About Rio? Eur Respir J. 2015;45(5):1211-3. doi: 10.1183/09031936.00032715.
-
23Hoeper MM, Simonneau G, Corris PA, Ghofrani HA, Klinger JR, Langleben D, et al. RESPITE: Switching to Riociguat in Pulmonary Arterial Hypertension Patients with Inadequate Response to Phosphodiesterase-5 Inhibitors. Eur Respir J. 2017;50(3):1602425. doi: 10.1183/13993003.02425-2016.
-
24Frantz RP. REPLACE and the Role of Riociguat in Pulmonary Arterial Hypertension Therapy. Lancet Respir Med. 2021;9(6):546-7. doi: 10.1016/S2213-2600(20)30567-1.
-
25McLaughlin VV, Jansa P, Nielsen-Kudsk JE, Halank M, Simonneau G, Grünig E, et al. Riociguat in Patients with Chronic Thromboembolic Pulmonary Hypertension: Results from an Early Access Study. BMC Pulm Med. 2017;17(1):216. doi: 10.1186/s12890-017-0563-7.
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Study AssociationThis study is not associated with any thesis or dissertation work.
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Sources of Funding: There were no external funding sources for this study.
Publication Dates
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Publication in this collection
09 May 2022 -
Date of issue
2022
History
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Received
02 June 2020 -
Reviewed
09 Aug 2021 -
Accepted
01 Sept 2021