Successful treatment of late-onset pulmonary hypertension after atrial septal defect operation with macitentan: Our center experience
Tarik Kivrak1*, Zeynep Ulutas2, Sena Sert3 and Bulent Mutlu41Firat University, Department of Cardiology, Elazig, Turkey
2Elazig State Hospital, Department of Cardiology, Elazig, Turkey
3Corlu State Hospital, Departement of Cardiology, Tekırdag, Turkey
4Marmara University, Departement of Cardiology, Istanbul, Turkey
*Address for Correspondence: Tarik Kivrak, Firat University, Department of Cardiology, Elazig, Turkey, Tel: 05053729945; Email: firstname.lastname@example.org
Dates: Submitted: 04 August 2018; Approved: 16 August 2018; Published: 17 August 2018
How to cite this article: Kivrak T, Ulutas Z, Sert S, Mutlu B. Successful treatment of late-onset pulmonary hypertension after atrial septal defect operation with macitentan: Our center experience. J Pulmonol Respir Res. 2018; 2: 001-003. DOI: 10.29328/journal.jprr.1001006
Copyright: © 2018 Kivrak T, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Macitentan; Atrial septal defect; Acquired pulmonary hypertension
Background: Macitentan significantly improves pulmonary hemodynamics and survival in patients with primary pulmonary hypertension (PPH). Its beneficial effect, however, may be blunted due to the adverse impacts such as anemia and peripheral edema. Pulmonary arterial hypertension (PAH) is a significant consequence of congenital heart disease (CHD). Its presence and severity are associated with increased morbidity and mortality. We tried to evaluate that the effectiveness of the macitentan in patients with late-onset pulmonary hypertension after atrial septal defect operation in our center.
Methods: The effect of a single dose of macitentan (10 mg) on pulmonary hemodynamics, functional capacity was examined in four patients with late-onset pulmonary hypertension after atrial septal defect operation.
Results: The macitentan significantly improved mean pulmonary artery pressure (MPAP), cardiac output (CO), tricuspid annular plane systolic excursion (TAPSE), right ventricle systolic wave(RVS’), 6-minute walking test and NT-proBNP levels compared with before treatment.
Conclusions: Macitentan can be used in patients with late-onset pulmonary hypertension after shunt operation especially atrial septal defect.
Pulmonary arterial hypertension (PAH) associated with congenital heart disease is usually the result of a sizeable systemic-to-pulmonary shunt. It often leads to right ventricular failure and early death . The prevalence of this phenomenon differs in various reports. The Euro Heart Survey on adult congenital heart disease (CHD), which is a retrospective cohort study with a five-year follow-up, reported PAH in 28% of patients , while a Dutch registry showed a PAH prevalence of only 4.2% . The guidelines ensure recommendations for the management of PAH-CHD [4,5]. However, evidence to support the use of PAH-specific therapies in CHD is limited, and the administration is not standardized, with variation between treating centers and clinicians. The dual endothelin-receptor antagonist macitentan was developed by modifying the structure of bosentan to increase efficacy and safety . Macitentan is characterized by sustained receptor binding and enhanced tissue penetration [6,7]. It can be used as pulmonary arterial hypertension . Two dose levels (3 and 10 mg) were studied; macitentan reduced the risk of a morbidity/mortality event vs. placebo (10 mg dose, risk reduction 45 %, p>0.001; 3mg dose, risk reduction 30%, p=0.01) . This study aimed to evaluate the macitentan therapy of adults with corrected congenital heart diseases(especially atrial septal defect) and pulmonary arterial hypertension in a single center in our center.
Four patients with late-onset pulmonary hypertension after shunt operation were evaluated after 3 months of macitentan therapy. Macitentan had been given as a result of nonresponsiveness to vasoreactivity test. Each patient gave written informed consent to participate in the study which was approved by the local ethical committee Firat. The diagnosis pulmonary arterial hypertension was based on a raised MPAP of ≥25mm Hg and the diagnostic criteria published by . There were atrial septal defect operation stories all of the patients. All of the patients were diagnosed with pulmonary arterial hypertension by pulmonary hypertension council (included cardiologist, and pulmonologist). The disease is defined as late-onset pulmonary hypertension after atrial septal defect operation (acquired pulmonary arterial hypertension) (Table 1). All patients were treated with macitentan 10 mg. They were reevaluated after three months.
Data were analyzed descriptively using the IBM SPSS 23.0. Baseline variables were recorded and are presented as mean. Intraindividual comparison of the hemodynamic variables measured at baseline and after macitentan was made using the two-sided Wilcoxon U test for paired data. P values below 0.05 were considered statistically significant.
The effect of macitentan on pulmonary hemodynamics was tested in four patients (female) with a proven diagnosis of pulmonary arterial hypertension(acquired pulmonary arterial hypertension after atrial septal defect operation) for a mean period of 6 months. Patients participated in a hemodynamic study that included right heart catheterization at baseline and month 6. Patients had significant decreases in pulmonary vascular resistance, and significant increases in the cardiac output, as compared with the basal term. The 6-minute walk distance had increased in all patients (p<0.05) (Table 1).
Macitentan considerably diminished morbidity and mortality among patients with pulmonary arterial hypertension. Because pulmonary arterial hypertension is a chronic, life-threatening disease, data from long-term outcome studies are required to assess the impact of therapy on disease progression. Updated guidelines for clinical research on pulmonary arterial hypertension support the use of these long-term outcome studies . Our trial showed that macitentan therapy significantly improved pulmonary hemodynamics in four patients with late-onset pulmonary hypertension after shunt operation within six months. More importantly, the macitentan theraphy enhanced parameters closely linked to long-term effects of treatment and survival in pulmonary arterial hypertension such as MPAP and CO . These results suggest that macitentan at 10mg dose allows for stable treatment of this patient group.This is the first trial in these patient group.
- Kidd L, Driscoll DJ, Gersony WM, Hayes CJ, Keane JF, et al. Second natural history study of congenital heart defects. Results of treatment of patients with ventricular septal defects. Circulation. 1993; 87: I38-151. Ref.: https://tinyurl.com/y8sn2nmy
- Engelfriet PM, Duffels MG, Möller T, Boersma E, Tijssen JG, et al. Pulmonary arterial hypertension in adults born with a septal heart defect: the Euro Heart Survey on adult congenital heart disease. Heart. 2007; 93: 682-687. Ref.: https://tinyurl.com/y7p9fj4s
- Duffels MG, Engelfriet PM, Berger RM, van Loon RL, Hoendermis E, et al. Pulmonary arterial hypertension in congenital heart disease: an epidemiologic perspective from a Dutch registry. Int J Cardiol. 2007; 21: 198-204. Ref.: https://tinyurl.com/y7xyzofa
- Galie N. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2015; 46: 903-975.
- Bolli MH, Christoph Boss, Christoph Binkert, Stephan Buchmann, Daniel Bur, et al. The discovery N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide (macitentan), an orally active, potent, dual endothelin receptor antagonist. J Med Chem. 2012; 55: 7849-7861. Ref.: https://tinyurl.com/ycdbnrz3
- Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008; 327: 736-745. Ref.: https://tinyurl.com/yb9b767o
- Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One. 2012; 7: e47662. Ref.: https://tinyurl.com/yd7xun9p
- Tomás Pulido, Adzerikho I, Channick RN, Delcroix M, Galiè N, et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med. 2013; 369: 809-818. Ref.: https://tinyurl.com/ybu5tguz
- Bedan M, Grimm D, Wehland M, Simonsen U, Infanger M, et al. A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. Basic Clin Pharmacol Toxicol. 2018; 123: 103-113. Ref.: https://tinyurl.com/ycmget86
- Galiè N, Simonneau G, Barst RJ, Badesch D, Rubin L. Clinical worsening in trials of pulmonary arterial hypertension: results and implications. Curr Opin Pulm Med 2010; 16: 11-19. Ref: https://tinyurl.com/ycx5ftxe
- Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997; 336: 111-1117. Ref.: https://tinyurl.com/yd42u2qu