Effects Of Endothelin Receptor Antagonists Research Articles

#1568 Cardiometabolic benefits of low dose zibotentan and dapagliflozin 10 mg in the ZENITH-CKD study

Abstract Background and Aims Positive effects of endothelin receptor antagonists on blood pressure and urinary albumin excretion have been well described, although their use in a wider population of patients with chronic kidney disease with increased cardiovascular risk has been limited by potential fluid retention. Here we present the effects of low dose zibotentan in combination with dapagliflozin on a range of cardiometabolic risk factors. Method In a post-hoc analysis of the ZENITH-CKD trial, a randomized, double-blind, active-controlled trial conducted in 170 clinical sites in 19 countries, adults with a urinary albumin-creatinine ratio (UACR) of 150 to 5000 mg/g and eGFR ≥20 mL/min/1.73 m2 not on SGLT2i were randomized to zibotentan/dapagliflozin, 0.25 mg/10 mg, zibotentan/dapagliflozin, 1.5 mg/10 mg, or placebo/dapagliflozin 10 mg. Effects on fluid retention events, defined as body weight increase from baseline >3% (of which at least 2.5% from total body water) or BNP increase >100% to >200 pg/mL without atrial fibrillation or 100% increase to >400 pg/mL with atrial fibrillation were assessed (NCT04724837). Results Data from the full analysis set is presented including 91 participants treated with 0.25 mg zibotentan and 10 mg dapagliflozin, and 177 participants treated with 10 mg dapagliflozin and placebo. UACR reduction for 0.25 mg zibotentan and 10 mg dapagliflozin was −47.7%, for 10 mg dapagliflozin alone it was −28.3%, making an adjusted mean difference for the combination versus dapagliflozin alone of −27.0%. Cardiometabolic markers are shown in the table. Conclusion In the ZENITH-CKD study zibotentan used at low dose combined with dapagliflozin had incremental effects versus dapagliflozin alone on a range of cardiometabolic risk markers including blood pressure, LDL cholesterol, HbA1c and uric acid, without a significant increase in fluid retention.

Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease.

Using a lipopolysaccharide model of acute lung injury, we previously showed that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a "gatekeeper" for the influx of inflammatory cells into the lung. These studies provided a rationale for testing the effect of HJP272, an endothelin receptor antagonist (ERA), in hamster models of pulmonary fibrosis induced by intratracheal instillation of either bleomycin (BLM) or amiodarone (AM). To determine the temporal effects of blocking ET-1 activity, animals were given HJP272 either 1 h before initiation of lung injury or 24 h afterward. The results indicated that pretreatment with this agent caused significant reductions in various inflammatory parameters, whereas post-treatment was ineffective. This finding suggests that ERAs are only effective at a very early stage of pulmonary fibrosis and explains their lack of success in clinical trials involving patients with this disease. Nevertheless, ERAs could serve as prophylactic agents when combined with drugs that may induce pulmonary fibrosis. Furthermore, developing a biomarker for the initial changes in the lung extracellular matrix could increase the efficacy of ERAs and other therapeutic agents in preventing the progression of the disease. While no such biomarker currently exists, we propose the ratio of free to peptide-bound desmosine, a unique crosslink of elastin, as a potential candidate for detecting the earliest modifications in lung microarchitecture associated with pulmonary fibrosis.

Comparative Treatment Persistence and Adherence to Endothelin Receptor Antagonists Among Patients with Pulmonary Arterial Hypertension in Japan: A Real-World Administrative Claims Database Study.

Real-world data on the comparative effectiveness of endothelin receptor antagonists (ERAs; macitentan, bosentan, ambrisentan) for pulmonary arterial hypertension (PAH), particularly in Asian countries, are scarce. We evaluated the persistence of these ERAs before and after macitentan approval in Japan (2015). We used real-world data from the Japanese Medical Data Vision administrative claims database between April 2008 and November 2020. Patients with PAH were identified from the dataset. Persistence to ERA treatment before and after approval of macitentan in Japan was defined as the time between start of the index ERA and treatment discontinuation or death. Propensity score adjustment was applied to minimize confounding effects among treatment groups. In the pre-macitentan approval cohort, 153 and 51 patients received bosentan and ambrisentan, respectively. In the post-macitentan approval cohort, 331, 284, and 91 patients received macitentan, bosentan, and ambrisentan, respectively. Unadjusted median persistence for ambrisentan- and bosentan-treated patients was 19 and 10months, respectively (adjusted HR 0.87 [95%CI 0.61-1.24]; P = 0.434 [bosentan as reference]). In the post-macitentan approval cohort, unadjusted median persistence was 18months for macitentan-treated patients versus 6 and 8months for ambrisentan- and bosentan-treated patients, respectively. Adjusted HRs for ambrisentan and bosentan were 1.48 (95%CI 1.12-1.95; P = 0.006) and 1.63 (95%CI 1.30-2.04; P < 0.001 [macitentan as reference]), respectively. Real-world data for Japanese patients with PAH showed that persistence was significantly higher for macitentan, versus ambrisentan and bosentan, since its approval.

The potential benefit of endothelin receptor antagonists' therapy in idiopathic pulmonary fibrosis: A meta-analysis of results from randomized controlled trials.

Background:Fibrotic diseases take a very heavy toll in terms of morbidity and mortality equal to or even greater than that caused by metastatic cancer. This meta-analysis aimed to evaluate the effect of endothelin receptor antagonists on idiopathic pulmonary fibrosis.Method:A systematic search of the clinical trials from the Medline, Google Scholar, Cochrane Library, and PubMed electronic databases was performed. Stata version 12.0 statistical software (Stata Crop LP, College Station, TX) was adopted as statistical software.Result:A total of 5 studies, which included 1500 participants. Our analysis found there is no significant difference between using the endothelin receptor antagonists’ group and placebo groups regarding the lung function via estimating both the change of forced vital capacity from baseline and DLco index. Exercise capacity and serious adverse effects are taken into consideration as well; however, there is still no significant change between the 2 groups.Conclusion:This meta-analysis provides insufficient evidence to support that endothelin receptor antagonists’ administration provides a benefit among included participants who encounter idiopathic pulmonary fibrosis.

The efficacy and safety of macitentan in Fontan-palliated patients: results of the 52-week randomised, placebo-controlled RUBATO trial

Abstract Background The clinical utility and long-term effects of endothelin receptor antagonists (ERAs) in Fontan-palliated patients remain unclear and there are currently no approved therapies. A decline in peak VO2 between consecutive cardiopulmonary exercise tests (CPETs) is highly prognostic for death or transplant in adult Fontan patients, hence its use as a primary endpoint in clinical trials of ERAs in patients with Fontan circulation. Purpose The RUBATO trial aimed to assess the efficacy and safety of macitentan, an endothelin receptor antagonist, in Fontan-palliated patients over 52 weeks. Methods In the multicentre, double-blind, randomised, placebo-controlled, phase 3 RUBATO trial, Fontan-palliated patients were randomised 1:1 to macitentan 10 mg once-daily or placebo for 52 weeks. Eligible patients were aged ≥12 years, in New York Heart Association functional class II or III, had no limitations for CPET (including no pacemakers), had undergone lateral tunnel or extracardiac conduit Fontan (total cavopulmonary connection) &amp;gt;1 year before screening and showed no signs of Fontan failure or clinical deterioration within 3 months before screening. Primary efficacy endpoint was change in peak VO2 from baseline to week 16. Secondary endpoints were change in peak VO2 from baseline over 52 weeks and change in mean count per minute of daily physical activity from baseline to week 16 as measured by an accelerometer. Adverse events were also assessed. Results 137 patients were randomised to macitentan (n=68) or placebo (n=69). 92.7% of patients completed 52 weeks of double-blind treatment: 7 and 3 patients prematurely discontinued study treatment in macitentan and placebo arms, respectively. Patient baseline characteristics are shown in Table 1. At week 16, the mean (SD) change from baseline in peak VO2 was –0.16 (2.86) with macitentan vs –0.67 (2.66) mL/kg/min with placebo (median unbiased estimate of the difference between macitentan and placebo: 0.62 mL/kg/min [99% repeated confidence interval –0.62; 1.85], p=0.1930). No treatment effect was observed in the two secondary endpoints (Table 2): mean (SD) count per minute of daily physical activity decreased from baseline to week 16 by 3.02 (92.44) with macitentan and by 14.34 (117.56) with placebo (p=0.4512). The most common AEs were headache (10.3% vs 8.7% on placebo), nasopharyngitis (5.9% vs 4.3%), and pyrexia (5.9% vs 4.3%). AEs leading to treatment discontinuation were reported in 3 (4.4%) and 1 (1.4%) of macitentan and placebo patients. Conclusion The 52-week RUBATO trial provides an important addition to data on the clinical utility of ERAs in Fontan-palliated patients. The primary efficacy endpoint was not met and no treatment effect was observed for the two secondary endpoints. Macitentan was well tolerated; safety findings were consistent with the known safety profile of macitentan 10 mg. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Actelion Pharmaceuticals Ltd., a Janssen pharmaceutical company of Johnson &amp; Johnson.

P16‐69: Assessment of the effect of endothelin receptor antagonist in patients with less severe or severe pulmonary hypertension associated with interstitial lung disease

P16‐69: Assessment of the effect of endothelin receptor antagonist in patients with less severe or severe pulmonary hypertension associated with interstitial lung disease

Impaired pulmonary vasomotor control in exercising swine with multiple comorbidities

Pulmonary hypertension is common in heart failure with preserved ejection fraction (HFpEF). Here, we tested the hypothesis that comorbidities [diabetes mellitus (DM, streptozotocin), hypercholesterolemia (HC, high-fat diet) and chronic kidney disease (CKD, renal microembolization)] directly impair pulmonary vasomotor control in a DM + HC + CKD swine model. 6 months after induction of DM + HC + CKD, pulmonary arterial pressure was similar in chronically instrumented female DM + HC + CKD (n = 19) and Healthy swine (n = 18). However, cardiac output was lower both at rest and during exercise, implying an elevated pulmonary vascular resistance (PVR) in DM + HC + CKD swine (153 ± 10 vs. 122 ± 9 mmHg∙L−1∙min∙kg). Phosphodiesterase 5 inhibition and endothelin receptor antagonism decreased PVR in DM + HC + CKD (− 12 ± 12 and − 22 ± 7 mmHg∙L−1∙min∙kg) but not in Healthy swine (− 1 ± 12 and 2 ± 14 mmHg∙L−1∙min∙kg), indicating increased vasoconstrictor influences of phosphodiesterase 5 and endothelin. Inhibition of nitric oxide synthase produced pulmonary vasoconstriction that was similar in Healthy and DM + HC + CKD swine, but unmasked a pulmonary vasodilator effect of endothelin receptor antagonism in Healthy (− 56 ± 26 mmHg∙L−1∙min∙kg), whereas it failed to significantly decrease PVR in DM + HC + CKD, indicating loss of nitric oxide mediated inhibition of endothelin in DM + HC + CKD. Scavenging of reactive oxygen species (ROS) had no effect on PVR in either Healthy or DM + HC + CKD swine. Cardiovascular magnetic resonance imaging, under anesthesia, showed no right ventricular changes. Finally, despite an increased contribution of endogenous nitric oxide to vasomotor tone regulation in the systemic vasculature, systemic vascular resistance at rest was higher in DM + HC + CKD compared to Healthy swine (824 ± 41 vs. 698 ± 35 mmHg∙L−1∙min∙kg). ROS scavenging induced systemic vasodilation in DM + HC + CKD, but not Healthy swine. In conclusion, common comorbidities directly alter pulmonary vascular control, by enhanced PDE5 and endothelin-mediated vasoconstrictor influences, well before overt left ventricular backward failure or pulmonary hypertension develop.

For people with pulmonary arterial hypertension, what are the effects of endothelin receptor antagonists (ERAs)?

For people with pulmonary arterial hypertension, what are the effects of endothelin receptor antagonists (ERAs)?

Comparative effectiveness of endothelin receptor antagonists on mortality in patients with pulmonary arterial hypertension in a US Medicare population: a retrospective database analysis

Limited evidence is available on outcomes associated with currently available medications from the endothelin receptor antagonist drug class (bosentan, ambrisentan, and macitentan) in elderly patients with pulmonary arterial hypertension. We evaluated mortality in predominantly elderly patients with pulmonary arterial hypertension in the US taking endothelin receptor antagonists. A retrospective administrative claims study was conducted using the Centers for Medicare and Medicaid Services national Medicare database. Patients with pulmonary arterial hypertension were identified using diagnostic codes. Cohort inclusion required age ≥18 years; ≥1 claim for macitentan, ambrisentan, or bosentan between 1 January 2014 and 31 December 2015 (index date and index endothelin receptor antagonist defined by first such claim); continuous enrollment for ≥12 months before and after the index date; and ≥80% of days covered for the index endothelin receptor antagonist. Follow‐up was from index date until the earliest of Medicare disenrollment, death, or 31 December 2016. Multivariable Cox proportional hazards regression models were used to estimate mortality hazard ratios with 95% confidence intervals for macitentan vs. ambrisentan or bosentan, adjusting for potential confounders. The study cohort included 1628 patients on index macitentan, 2852 on ambrisentan, and 1972 on bosentan. Overall, 69% of patients were aged ≥65 years and most were females (76%). Macitentan was associated with an 18% lower risk for mortality than ambrisentan (hazard ratio: 0.82, 95% confidence interval: 0.72–0.93; P = 0.0026) and a 39% lower risk than bosentan (hazard ratio: 0.61, 95% confidence interval: 0.53–0.71; P &lt; 0.0001). Variables that independently increased the risk of mortality included higher comorbidity index, increasing age, and inpatient hospitalizations at baseline.

Effectiveness and safety of endothelin receptor antagonists, alone and in combination therapy, in the pulmonary arterial hypertension-connective tissue disease subtype: A systematic review and meta-analysis.

There is limited information regarding the effectiveness of endothelin receptor antagonists (ERA) in patients with connective tissue disease-pulmonary arterial hypertension (CTD-PAH), a condition that is characterized by poorer clinical outcomes compared to other PAH subtypes. To conduct a systematic review and meta-analysis of the effectiveness and safety of ERA in CTD-PAH. A literature search, using MEDLINE, COCHRANE, CINAHL and EMBASE databases was conducted, from inception to May 2019 to identify randomized control studies of ERA, as monotherapy or in combination with phosphodiesterase type 5 inhibitors (PDE5i), in CTD-PAH. A protocol was registered in PROSPERO (CRD42019136956). Efficacy outcomes, including the 6-minute walk distance (6MWD) and composite clinical failure endpoints (CFE), and safety outcomes were evaluated. A total of 13 studies, including 784 CTD-PAH participants, were identified. ERA, as monotherapy, did not reduce the risk of CFE compared to placebo (odds ratio [OR] 0.77, 95% CI 0.50-1.19, P = .25). By contrast, combination therapy (ERA+PDE5i) significantly reduced the risk of developing CFE vs monotherapy (OR 0.54, 95% CI 0.32-0.90, P = .02). 6MWD did not improve when comparing monotherapy vs placebo (+17.41m; 95% CI -19.83-54.66) P = .36) or combination therapy vs monotherapy (+13.17m; 95% CI -16.44-42.78, P = .38). ERA-related adverse events rates in CTD-PAH and general PAH cohorts were comparable. ERA, when used in combination with PDE5is, are associated with reduced risk of CFE, but no significant changes in 6MWD, in CTD-PAH. This warrants further studies investigating early combination therapy as a standard of care in this group.

Endothelin-targeted new treatments for proteinuric and inflammatory glomerular diseases: focus on the added value to anti-renin-angiotensin system inhibition.

Chronic kidney disease (CKD) is the main cause of end-stage renal disease worldwide arising as a frequent complication of diabetes, obesity, and hypertension. Current therapeutic options, mainly based of inhibition of the renin-angiotensin system (RAS), provide imperfect renoprotection if started at an advanced phase of the disease, and treatments that show or even reverse the progression of CKD are needed. The endothelin (ET) system contributes to the normal renal physiology; however, robust evidence suggests a key role of ET-1 and its cognate receptors, in the progression of CKD. The effectiveness of ET receptor antagonists in ameliorating renal hemodynamics and fibrosis has been largely demonstrated in different experimental models. A significant antiproteinuric effect of ET receptor antagonists has been found in diabetic and non-diabetic CKD patients even on top of RAS blockade, and emerging evidence from ongoing clinical trials highlights their beneficial effects on a wide range of kidney disorders.

Clinical Implications

Clinical Implications

Clinical and hemodynamic effect of endothelin receptor antagonists in Eisenmenger Syndrome.

Introduction:Endothelin receptor antagonists (ERAs) are widely accepted as a specific treatment for pulmonary arterial hypertension. Unfortunately, consensus and recommendations are lacking for the treatment of patients who suffer from pulmonary arterial hypertension and congenital heart disease, including Eisenmenger syndrome.Objective:This meta-analysis aimed to compare the effect of ERA on patients with Eisenmenger syndrome.Methods:Electronic search on PubMed (MEDLINE), EBSCO, EuropePMC, Clinicaltrials.gov, and Google Scholar was done. Studies involving the use of ERAs on Eisenmenger syndrome patients were included. There were 18 studies included. The primary outcome of interest was the 6-min walking test distance before and after exposure to ERA.Results:There were 517 patients with Eisenmenger syndrome. The subjects had Eisenmenger syndrome secondary to congenital heart disorders, with WHO functional Class ranging from Class I–IV. The follow-up ranges from a mean of 4–60 months. Seventeen studies reported a statistically significant difference between pretreatment and the posttreatment result of 6-min walking test distance. Pooled mean difference comparing pre and posttreatment values yielded an increase of 55.24 m (42.15, 68.33) P < 0.001; moderate heterogeneity I2 51% P = 0.008. Pooled mean pulmonary vascular resistance index difference comparing pre and posttreatment values yielded a decrease of 4.76 woods unit (−6.86, −2.66), P < 0.001 favoring posttreatment; low heterogeneity I2 0%, P = 0.82. Pooled mean mean pulmonary arterial pressure difference comparing pre and posttreatment values yielded a decrease of 5.40 mmHg (−7.53, −3.28), P < 0.001 favoring posttreatment, low heterogeneity I2 0%, P = 0.65.Conclusion:Implementation of ERA in Eisenmenger improves 6-min walking distance and pulmonary vascular pressure indices. Earlier administration of ERA might be beneficial, further studies are needed to assess mortality benefit of this agent.

Transfer and Vascular Effect of Endothelin Receptor Antagonists in the Human Placenta.

Increasing evidence suggests a role for the ET (endothelin) system in preeclampsia. Hence, blocking this system with endothelin receptor antagonists (ERAs) could be a therapeutic strategy. Yet, clinical studies are lacking due to possible teratogenic effects of ERAs. In this study, we investigated the placental transfer of ERAs and their effect on ET-1-mediated vasoconstriction. Term placentas were dually perfused with the selective ETAR (ET type A receptor) antagonists sitaxentan and ambrisentan or the nonselective ETAR/ETBR antagonist macitentan and subsequently exposed to ET-1 in the fetal circulation. ET-1 concentration-response curves after incubation with sitaxentan, ambrisentan, macitentan, or the selective ETBR antagonist BQ-788 were also constructed in isolated chorionic plate arteries using wire-myography, and gene expression of the ET-system was quantified in healthy and early onset preeclamptic placentas. At steady state, the mean fetal-to-maternal transfer ratios were 0.32±0.05 for sitaxentan, 0.21±0.02 for ambrisentan, and 0.05±0.01 for macitentan. Except for BQ-788, all ERAs lowered the response to ET-1, both in the perfused cotyledon and isolated chorionic plate arteries. Placental gene expression of ECE-1, ETAR, and ETBR were comparable in healthy and preeclamptic placentas, while ET-1 expression was higher in preeclampsia. Our study is the first to show direct transfer of ERAs across the term human placenta. Furthermore, ETAR exclusively mediates ET-1-induced constriction in the fetoplacental vasculature. Given its limited transfer, macitentan could be considered as potential preeclampsia therapy. Extending knowledge on placental transfer to placentas of preeclamptic pregnancies is required to determine whether ERAs might be applied safely in preeclampsia.

Transfer and Effect of Endothelin Receptor Antagonists in the Human Placenta: an Ex Vivo Perfusion Study of the Isolated Cotyledon

Transfer and Effect of Endothelin Receptor Antagonists in the Human Placenta: an Ex Vivo Perfusion Study of the Isolated Cotyledon

The protective effect of endothelin receptor antagonists against surgically induced impairment of gastrointestinal motility in rats.

Endothelin (ET) receptor antagonists: BQ-123 (ETA), BQ-788 (ETB), tezosentan (dual ET receptor antagonist) protect against the development of postoperative ileus (POI) evoked by ischemia-reperfusion (I/R). The current experiments explored whether ET antagonists prevent the occurrence of POI evoked by surgical gut manipulation. Intestinal transit was assessed by measuring the rate of dye migration subsequent to skin incision (SI), laparotomy (L), or laparotomy and surgical gut handling (L+M) in diethyl ether anaesthesized rats (E). Experimental animals were randomly sub-divided into two groups depending on the time of recovery following surgery: viz. either 2 or 24 h (early or late phase POI). E and SI did not affect the gastrointestinal (GI) transit. In contrast, L and L+M significantly reduced GI motility in comparison to untreated group (UN). Tezosentan (10 mg/kg), BQ-123 and BQ-788 (1 mg/kg) protected against development of L+M evoked inhibition of intestinal motility in the course of late phase, but not early phase POI. Furthermore, tezosentan alleviated the decrease in the contractile response of the longitudinal jejunal smooth muscle strips to carbachol in vitro induced by L+M. The serum ET(1–21) concentration was not increased in either the early or the late phase POI groups after surgery compared to control animals. This study indicates that delay in the intestinal transit in late phase of surgically induced POI involves an ET-dependent mechanism.

Dysregulation of the endothelin pathway in lymphangioleiomyomatosis with no direct effect on cell proliferation and migration

LAM is a rare low-grade metastasizing lung neoplasm. Inhibitors of mTOR improve clinical outcome of LAM patients by preventing loss of lung function. Nevertheless, other cell targets may be of interest for drug development. Therefore, we explored the potential role of EDN1 (endothelin) in LAM. We report an increased endothelin blood level in LAM patients as well as EDN1 overexpression and EDN1 receptor downregulation in LAM-derived primary cells and in TSC2NEG cells mutated in TSC2. We evidenced EDN pathway dysregulation based on EDN1, EDNRA, EDNRB and ARRB1 mRNA expression in LAM-derived primary cells. We showed overexpression of EDN1 and ARRB1 mRNAs in TSC2NEG cells; these cells lost their ability to respond to stimulation by endothelin. We analyzed the effects of endothelin receptor antagonists alone or in combination with rapamycin, an mTOR inhibitor, on proliferation and migration of LAM cells. Rapamycin treatment of TSC2NEG cells significantly reduced cell proliferation or migration, while none of the tested inhibitors of EDN receptors impaired these functions. We showed that TSC2NEG cells have acquired a transformed phenotype as showed by their ability to grow as spheroids in semi-solid medium and that unlike endothelin receptors antagonists, rapamycin reduced anchorage-independent cell growth and prevented expansion of TSC2NEG spheroids.

What are the effects of endothelin receptor antagonists for people with subarachnoid hemorrhage?

What are the effects of endothelin receptor antagonists for people with subarachnoid hemorrhage?

The effect of endothelin receptor antagonists in the endotoxin-induced uveitis rabbit model

Purpose: To investigate the effect of Bosentan (non-selective endothelin receptor antagonist) and BQ123 (ETA receptor antagonist) on intraocular inflammation in an endotoxin-induced uveitis (EIU) rabbit model.Methods: Uveitis was induced by intravitreal injection of lipopolysaccharide (LPS). The animals were divided into 7 groups and there were six rabbits in each group (saline, saline and ethanol, bosentan, BQ123, lipopolysaccharide (LPS), bosentan and LPS, BQ123 and LPS-injected groups). Bosentan and BQ123 were applied before LPS injection. Aqueous humour was collected at 24th hour post-injections and enucleation was performed for the evaluation of histopathological changes.Results: BQ123 decreased clinical score, cell counts and protein amount more than bosentan and it was significant for cell counts (p = 0.018). Bosentan significantly diminished inflammatory reactions more than BQ123 as shown in histopathological specimens (p = 0.002).Conclusions: ETA receptor blockage is effective on uveitis treatment by its protective effect on blood aqueous barrier.

The Effect of Endothelin Receptor Antagonists in Patients with Eisenmenger Syndrome: A Systematic Review

The efficacy of endothelin receptor antagonists (ERAs) in the management of Eisenmenger syndrome (ES) remains controversial. The aim of this study is to systemically review the safety and effects of ERAs in improving the quality of life and basic cardiac functions of these patients. Twelve databases were searched, including PubMed, Web of Science, Scopus, Virtual Health Library, World Health Organization (WHO) Global Health Library, Google Scholar, POPLINE, Systems for Information of Grey Literature in Europe, New York Academy of Medicine, ClinicalTrials.gov, metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform, through August 2016. We included randomized clinical trials addressing the effect of ERAs on cardiac functions in patients with ES. The quality of studies was assessed using the Cochrane Collaboration tool. We included two trials represented by four papers, of which three papers reported the efficacy of bosentan against placebo and one paper reported the results of a combination of bosentan and sildenafil versus placebo and bosentan. One trial showed a significant effect of bosentan treatment over placebo on indexed pulmonary vascular resistance and mean pulmonary artery pressure, but a non-significant increase in 6-min walk distance and a non-significant effect on systemic pulse oximetry. The other trial reported the safe but non-significant effect of combination therapy of bosentan and sildenafil compared with bosentan and placebo. This study demonstrated safety and improved hemodynamic effects of bosentan in ES, with a controversial effect on exercise capacity. Further randomized controlled trials with longer follow-up duration are needed to confirm these results.