Ambrisentan for Early-Stage Low-Risk Pulmonary Arterial Hypertension

Abstract

Background

Early-stage pulmonary arterial hypertension (PAH) with mild hemodynamic abnormalities is increasingly being concerned because of the revised PAH definition. However, there is a lack of randomized controlled trials evaluating the efficacy of currently available medications in this population.

Objectives

The ALEPH (Ambrisentan for Early Low-Risk Pulmonary Arterial Hypertension) trial is designed to investigate the efficacy and safety of ambrisentan in early-stage low-risk PAH patients.

Methods

The ALEPH trial is a multicenter, randomized, double-blind, placebo-controlled clinical study. Eligible patients are diagnosed with PAH according to 2022 European Society of Cardiology and the European Respiratory Society guidelines, with mean pulmonary artery pressure >20 and <25 mm Hg, pulmonary vascular resistance >2 and ≤3 WUs, and PAWP ≤15 mm Hg by right heart catheterization, classified as low-risk, and have not previously received PAH-specific therapy. Participants are randomly assigned to receive either ambrisentan or placebo for 12 months. The primary endpoint is a composite of PAH progression. Secondary endpoints include changes in hemodynamic and echocardiographic parameters, N-terminal pro–B-type natriuretic peptide levels, World Health Organization functional class, 6-minute walk distance, and time to clinical events such as hospitalization or death. Primary analysis will be performed in the intention-to-treat population, with sensitivity analysis in the per-protocol population. Statistical analyses include Z-test for the primary endpoint, Cox proportional hazards models for time-to-event data, and analysis of covariance or Mann-Whitney U test for continuous variables.

Conclusions

The ALEPH trial aims to generate high-quality evidence regarding the efficacy and safety of ambrisentan monotherapy in early-stage, low-risk PAH. This study may provide valuable insight into early therapeutic intervention for patients with mild hemodynamic disorder. (Ambrisentan for Early Low-Risk Pulmonary Arterial Hypertension [ALEPH]; NCT06987097)

Central Illustration

Pulmonary hypertension (PH) is a clinical and pathophysiological syndrome caused by pulmonary vasculature dysfunction or remodeling secondary to various diseases and mechanisms.¹ Vascular remodeling typically involves intimal thickening and/or medial thickening of muscular arteries and distal muscularization, ultimately leading to increased pulmonary vascular resistance (PVR), right heart failure, and even death. Clinically, PH is classified into 5 groups based on etiology: pulmonary arterial hypertension (PAH); PH caused by left heart disease; PH caused by lung diseases and/or hypoxia; chronic thromboembolic PH and/or other pulmonary artery obstructions; and PH caused by unclear and/or multifactorial mechanisms.

Among these, PAH is a progressive and life-threatening condition. Current guidelines emphasize risk stratification and recommend early combination therapy targeting multiple pathways—endothelin, nitric oxide, and prostacyclin—for treatment-naïve patients. Specifically, for low-risk patients, initial oral dual therapy (eg, an endothelin receptor antagonist [ERA] and a phosphodiesterase type 5 inhibitor) is the standard strategy to delay disease progression.

Previous guidelines defined PH as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg, measured at rest by right heart catheterization (RHC).^2,3 However, several studies have demonstrated that patients with mild PH (19-24 mm Hg) already exhibit increased risk of adverse outcomes.^4,5 In 2018, the 6th World Symposium on Pulmonary Hypertension proposed revising the diagnostic threshold to mPAP >20 mm Hg, a criterion subsequently adopted in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for all forms of PH.⁶ These updates underscore the importance of early screening, regular follow-up, and timely intervention in patients with early-stage PAH. Nonetheless, current clinical trials and approved therapies were based on the former definition (mPAP ≥25 mm Hg), leaving a significant evidence gap for newly reclassified patients with mild hemodynamic abnormalities (eg, mPAP 21-24 mm Hg, PVR 2-3 WU). As a result, the optimal management strategy for this subgroup remains uncertain under the current guidelines.

ERAs have been widely used in the treatment of PAH. Ambrisentan, a selective ET_A receptor antagonist, has been shown in multiple studies to improve exercise capacity and is associated with a low risk of aminotransferase elevations. Moreover, long-term treatment with ambrisentan has generally been well tolerated.7, 8, 9 However, its efficacy in patients with early-stage, low-risk PAH remains unclear.

Patients with early-stage PAH often present with mild or nonspecific symptoms and are typically categorized as low risk. The efficacy of pharmacological treatment in this population remains to be established through large-scale, high-quality clinical evidence.⁶ Existing studies evaluating intervention in early-stage, low-risk PAH are primarily small, single-center trials. The Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH) A Randomized, Controlled, Double-blind, Parallel Group, Proof-of-concept Trial (EDITA) randomized controlled trial (RCT) assessed ambrisentan in patients with mild PAH associated with systemic sclerosis and reported improvements in cardiac index and PVR after 6 months. Furthermore, long-term follow-up from the EDITA study suggested that early initiation of ambrisentan may delay disease progression.^10,11 Similar findings were reported by Kovacs et al¹² in a small cohort of 10 patients with systemic sclerosis, where bosentan—another ERA—was shown to improve pulmonary hemodynamics. Despite their value, these trials were limited by sample size and narrow inclusion criteria.

Initiating early pharmacological therapy may be beneficial for patients in this early-stage, low-risk group. However, current clinical trials have predominantly focused on patients with mPAP ≥25 mm Hg, leaving the efficacy of early treatment in low-risk PAH uncertain. Whether targeted therapies can delay disease progression, reduce mortality, and improve long-term outcomes in this population warrants further high-quality, multicenter clinical trials.

Methods

Study hypothesis

This study hypothesizes that ambrisentan will improve pulmonary hemodynamics and reduce composite clinical worsening events in patients with early-stage, low-risk PAH. The primary objective is to compare the composite clinical worsening outcomes between ambrisentan and placebo over a 12-month treatment period in this patient population.

The current study is funded by the Chinese Society of Cardiology's Foundation (CSCF2024A01) and the Beijing Great Physician Commonweal Foundation. The trial has been registered under number NCT06987097.

Study design

The ALEPH trial is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical study designed to enroll 478 patients with early-stage low-risk PAH across 25 participating centers. Patients will be enrolled over a 24-month accrual period. Early-stage low-risk PAH is defined as an mPAP between 20 and 25 mm Hg at rest (measured by RHC), attributed to Group 1 PH etiologies, and classified as low risk according to the 2022 ESC PH guidelines. Following screening, eligible participants will be randomized in a 1:1 ratio to receive either ambrisentan (treatment group) or placebo (control group) and will undergo continuous treatment for 12 months. Study follow-up visits will be conducted at months 1, 6, and 12, with extended follow-up continuing for up to 3 years. The schematic diagram is shown in the Central Illustration. Wuhan Humanwell Pharmaceutical Co, Ltd provided the study drug and placebo, but will not be involved in the study design, conduct, data collection, analysis, interpretation, or manuscript preparation.

Central Illustration.

Study Design and Follow-Up Schedule

∗Patients in the Ambrisentan group receive 5 mg daily for 2 weeks, followed by dose escalation to 10 mg once daily if tolerated. Down-titration to 5 mg is allowed based on adverse event profile.

Inclusion and exclusion criteria

Participants would be eligible if they aged ≥18 years with Group 1 PH, defined as mPAP 21 ∼24 mm Hg, PVR >2 WUs and ≤3 WUs, and pulmonary arterial wedge pressure (PAWP) ≤15 mm Hg as measured by RHC. Patients must also meet low-risk criteria according to the 2022 ESC PH guidelines (3-strata risk assessment model).

All patients (or their legally authorized representatives) must understand the study requirements, agree to the treatment procedures, provide written informed consent before any study-specific procedures, and demonstrate the willingness and ability to comply with all protocol requirements.

A potential subject who meets any of the following criteria will be excluded from the current study:

• 1.Patients currently receiving PAH drugs, regardless of whether mPAP is between 20 and 25 mm Hg. PAH drugs include ERAs (eg, bosentan, ambrisentan, macitentan), phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil, vardenafil), prostacyclin analogs (eg, iloprost, epoprostenol, treprostinil, beraprost), soluble guanylate cyclase stimulators (eg, riociguat), and activin-signaling inhibitor (sotatercept). Intermittent use of phosphodiesterase type 5 inhibitors for the treatment of male erectile dysfunction is permitted.
• 2.Intolerance to ambrisentan or its excipients.
• 3.Pulmonary veno-occlusive disease.
• 4.Pulmonary capillary hemangiomatosis.
• 5.Within 12 months after congenital heart disease surgical repair or percutaneous closure procedure.
• 6.Groups 2 to 5 PH. To exclude Group 2 PH, patients with PAWP >15 mm Hg on RHC, echocardiographic evidence of left ventricular systolic/diastolic dysfunction, significant left-sided valvular disease, or elevated natriuretic peptides in this context was ineligible. Group 3 PH was excluded if pulmonary function tests, high-resolution computed tomography, or arterial blood gas/pulse oximetry revealed significant parenchymal lung disease or chronic hypoxia.
• 7.Clinically significant anemia, defined as hemoglobin concentration below 75% of the lower limit of normal.
• 8.Renal insufficiency, defined as estimated glomerular filtration rate <30 mL/min/1.73 m² within 3 months before enrollment.
• 9.Elevated alanine aminotransferase and/or aspartate aminotransferase exceeding 3 times the upper limit of normal.
• 10.Severe hypotension (<90/50 mm Hg).
• 11.Uncontrolled hypertension (≥180/110 mm Hg at rest).
• 12.Participation in any clinical drug trial within 4 weeks before screening and/or planned participation in another clinical drug trial during this study.
• 13.Life expectancy of <1 year.
• 14.Pregnant or breastfeeding women.

Randomization and follow-up

Patients meeting the eligibility criteria will be randomized in a 1:1 ratio to either the experimental group (ambrisentan group) or the control group (placebo group). The randomization sequence will be generated by an independent statistician using SAS software (version 9.4), stratified by participating sites and etiology. The sequence will be implemented and concealed via an Interactive Web Response System (IWRS) before study drug initiation. The use of identical drug packs and the IWRS ensures maintained blinding of investigators and patients throughout the study.

All participants receiving an IWRS-assigned treatment will undergo scheduled clinical assessment at 1 month, 6 months, 12 months, 2 years, and 3 years after treatment initiation. V1 (screening), V2 (enrollment), V3 (the first month), V4 (the sixth month), and V5 (the 12th month) will be conducted as in-person clinic visits. V6 (year 2) and V7 (year 3) will be completed via telephone, internet-based teleconsultation, or in-person consultations, depending on patient availability and site resources. Data collected during follow-up visits will adhere to the specifications outlined in Table 1.

Table 1.

Schedule of Data Collection

	Screening −7 to 0 d	Enrollment 1 d	1-mo Visit 30 ± 7 d	6-mo Visit 182 ± 30 d	12-mo Visit 365 ± 30 d	2-y Visita 730 ± 30 d	3-y Visita 1,095 ± 30 d	EOT Visit
Visit	1	2	3	4	5	6	7
Obtain written informed consent	X
Eligibility criteria	X
Demographic data	X
Medical history	X
Physical examination	X				X
Vital signs	X				X
WHO-FC	X		X	X	X	X	X	X
Laboratory evaluationb	X		X		X
BNP or NT-proBNP	X		X	X	X	X	X	X
6-min walk distance	X		X	X	X	X	X	X
Echocardiography	X				X
Right heart catheterizationc	X				X
Randomization		X
Adverse events		X	X	X	X	X	X	X
Concomitant medications	X		X	X	X	X	X	X
Study drug dispensing and reconciliation		X	X	X	X

Visit: clinic visit.

BNP = B-type natriuretic peptide; FC = functional class; NT-proBNP = N-terminal pro–B-type natriuretic peptide; WHO = World Health Organization.

^aOpen-label phase after unblinding, format: phone/online/clinic.

^bLaboratory evaluations include hemoglobin and serum creatinine. For safety reasons, the treating physician will perform additional laboratory evaluations for transaminases and hemoglobin.

^cThe right heart catheterization used for screening should be performed within 7 d before enrollment and may serve as the baseline examination for this study.

Blinding and masking

This study adopts a double-blind design utilizing ambrisentan and a matching placebo. The participants, site investigators, academic research center staff, and treating physicians involved in the treatment and/or clinical evaluation will not be aware of the assigned treatment groups. An independent Data Safety Monitoring Board (DSMB) will conduct periodic safety and efficacy reviews. A dedicated statistician, independent of the study team, will prepare unblinded interim analysis reports and submit them to the DSMB in accordance with the DSMB charter.

Study treatment and medications

Study treatment includes administration of ambrisentan 5 to 10 mg (1-2 tablets) or a visually and physically matched placebo at the same dosage. The initial treatment will begin at 5 mg once daily for 2 weeks, followed by dose escalation to 10 mg once daily (2 tablets) if tolerated. In cases of poor tolerance (eg, headache, dizziness, palpitations, hypotension, or other symptoms/signs related to the study drug), the dosage may be reduced to 5 mg daily. If a patient on the maximum tolerated dose (10 mg/d) experiences worsening PH or signs of right heart failure, physicians may prescribe additional diuretic therapy, with the specific agent and dosage left to the clinician’s discretion. Background medications that patients are using before the study will remain unchanged throughout the trial period.

This study will include a 1-year course of ambrisentan or placebo. After 12 months of treatment and unblinding, patients who reach the predefined primary endpoint will continue receiving targeted therapy. Patients who do not meet the primary endpoint will have their subsequent management determined by a PH specialist. After the last enrolled subject completes 1 year of follow-up, an additional 2 years of follow-up will be conducted to collect clinical data, including all-cause mortality, hospitalizations caused by PAH exacerbation, and PAH clinical deterioration.

All investigational medications used in this study are approved and commercially available in China.

Study endpoints

Primary endpoints

The primary endpoint of the ALEPH is the first occurrence of a composite event indicating PAH progression, as assessed by 2 complementary criteria: 1) mPAP ≥25 mm Hg or PVR >3 WUs measured by RHC; and 2) worsening of risk stratification compared with baseline (eg, progressing to intermediate-low, intermediate-high, or high risk), according to the simplified 4-tier model of the 2022 ESC PH guidelines.

All potential primary endpoint events will be adjudicated by an independent clinical events committee. If no qualifying events is observed by the analysis date, the subject will be censored at the date of last contact or at the time of death, whichever occurs first. Suspected events that are not confirmed by the clinical events committee will be excluded from the primary endpoint analysis but will be detailed in a separate report.

Assessment of primary endpoint components

The timing of the follow-up RHC assessment is stratified based on the order of patient enrollment to optimize operational feasibility without prolonging the total study duration. For patients enrolled during the first half of the accrual period, the RHC may be performed within an extended window of 12 to 16 months postrandomization. For patients enrolled during the second half of the accrual period, the RHC should be performed within a standard window of 11.5 to 12.5 months postrandomization to ensure timely study completion.

Regardless of the assigned window, the event time for hemodynamic progression is the actual date of the RHC procedure that first confirms the progression criteria. For clinical deterioration, the event date is the visit date when worsening is first documented. The earliest date among all component events defines the composite endpoint time. All RHC assessments must be completed before the final study close-out date.

Secondary endpoints

Secondary endpoints of the study include the following:

• 1.Hemodynamic measurements at 12 months: systolic pulmonary artery pressure, mPAP, cardiac output, cardiac index, PVR, PVR index, PAWP, right atrial pressure, and pulmonary arterial compliance.
• 2.Echocardiographic measurements at 12 months: diameter of chambers, ejection fraction, right ventricular fraction of area change, tricuspid annular plane systolic excursion, pulmonary artery acceleration time, regurgitation of tricuspid or pulmonary valve, systolic pulmonary artery pressure, right atrial pressure, cardiac output, cardiac index, and so on.
• 3.World Health Organization functional class and Borg index.
• 4.N-terminal pro–B-type natriuretic peptide or B-type natriuretic peptide.
• 5.6-minute walk distance (6MWD).
• 6.Time to the first occurrence of the following events: all-cause mortality; hospitalization caused by PAH worsening; clinical deterioration of PAH, defined as the need for diuretic agents or digoxin (oral or intravenous), or the need of combination therapy with PAH drugs; and 6MWD decreases by 10% or 30 m.
• 7.Clinical events collected during the additional 2-year real-world follow-up period, including all-cause mortality, PAH-related hospitalizations, and PAH clinical deterioration, to evaluate the long-term effectiveness and safety of ambrisentan.

Ethical approval

The study has been approved by the Institutional Review Board of Nanjing First Hospital (KY20250327-11).

Statistical analysis

Sample size

The sample size was calculated based on the primary endpoint of the 1-year incidence of PAH progression. The assumed event rates were 16% in the placebo group, a conservative estimate supported by the high 6-month progression rate observed in the EDITA trial placebo group and the 1-year hard event rate in the GoDeep registry, and 7% in the ambrisentan group.^10,13 A corresponding 56% relative risk reduction was obtained, representing a clinically meaningful effect we aim to detect. The calculation was performed using a 2-sided, 2-sample Z-test for proportions, with a type I error rate (α) of 0.045 and a power of 80%. $\text{The}\text{following}\text{formula}\text{was}\text{used:}$

$$n_{\text{per}\text{group}}=\frac{{\left[Z_{1-\alpha /2}\sqrt{2\stackrel{\_}{p}\left(1-\stackrel{\_}{p}\right)}+Z_{1-\beta }\sqrt{p_1\left(1-p_1\right)+p_2\left(1-p_2\right)}\right]}^2}{{\left(p_1-p_2\right)}^2}$$

where $\stackrel{\_}{p}=\frac{p_1+p_2}{2}$, $p_1$ indicates control/group A event rate, $p_2$ indicates treatment/group B event rate, $\alpha$ indicates type-I error (2-sided usually 0.05), $\beta$ indicates type-II error; and power $=1-\beta \text{.}$ This yielded a requirement of 203 patients per group. To account for an estimated 15% rate of loss to follow-up or missing data, the total sample size was inflated to 478 subjects (239 per group). A supporting sample size estimation was performed using the log-rank test. This calculation was based on a 24-month accrual period, a total study duration of 36 months.

Statistical analyses

Categorical variables are reported as numbers and percentages and were compared using the chi-square test or Fisher exact test. Continuous variables are reported as mean ± SD or median (Q1-Q3) if not normally distributed and were compared using the Student’s t-test or the Mann-Whitney U test, respectively. Event rates were estimated using the Kaplan-Meier method and were compared using the log-rank test. Treatment effects were estimated using Cox proportional hazards regression, with results presented as HRs and corresponding 95% CIs. The treatment effects for the primary analyses were adjusted for the type of heart failure (ie, heart failure with reduced, preserved, or mildly reduced ejection fraction), type of PH (ie, isolated postcapillary PH and combined postcapillary and precapillary PH), and geographical region (western, eastern, southern, or northern China). Adjustment for multiplicity was not done for any secondary endpoints, and these should therefore be considered hypothesis-generating only. All events experienced by each patient (if necessary) were included in the analysis performed using the semiparametric proportional rates method of Wei-Lin-Weissfeld.¹⁴ Between-group differences in 6MWD from baseline were analyzed using mixed-model repeated measures methods¹⁵ assuming that missing data were missing at random. Treatment group, days to the follow-up test, and treatment-by-day interaction were included in the model as fixed effects, with baseline 6MWD as a covariate. Sensitivity analyses for 6MWD using the mixed-model repeated measures model were performed adjusting for sites and etiology and using multiple imputation using the Markov-chain Monte Carlo method. Wilcoxon signed-rank test was used to compare the changes from baseline in continuous variables, with Hodges-Lehmann estimation for calculation of 95% CI. Both the intention-to-treat (ITT) and per-protocol (PP) cohorts will be statistically analyzed. The ITT population includes all randomized subjects, with treatment allocation recorded in the electronic data capture system, regardless of protocol adherence. The PP population consists of randomized subjects who complete the study without major protocol deviations. The relative treatment effects of the primary endpoint in prespecified subgroups were assessed using interaction terms in the Cox proportional hazard model. Prespecified subgroups comparisons included PAH associated with connective tissue disease, PAH associated with congenital heart disease, idiopathic PAH, presence of cardiopulmonary comorbidities (yes vs no), age ≤40 years vs >40 years, male vs female, baseline 6MWD <420 m vs ≥420 m, and duration of PAH <12 months vs ≥12 months. The results of the subgroup analyses will be presented by forest plots. Interaction testing will be performed using subgroup treatment allocation as an additional term in the Cox model.

Interim analysis

A single formal interim analysis for efficacy and futility is prespecified and will be conducted when approximately 50% of the planned total population (N = 239) have completed 12-month follow-up. This analysis will be performed by the DSMB. To control the overall type I error rate at a 2-sided alpha of 0.05, the O'Brien-Fleming spending function will be used. The significance levels for early stopping for efficacy at the interim analysis will be set at a 2-sided P < 0.005. Based on the observed event rates and variability at the interim analysis, the DSMB will be empowered to recommend a sample size re-estimation to ensure that the trial maintains adequate power, following prespecified conditional power or promising zone methods. The final analysis of the primary endpoint at the conclusion of the study will be declared statistically significant if the 2-sided P value is <0.045.

Discussion

The ALEPH trial is a multicenter, randomized, double-blind, placebo-controlled clinical study designed to evaluate the efficacy and safety of ambrisentan in patients with early-stage, low-risk PAH. The center hypothesis of this ALEPH is that ambrisentan will improve pulmonary hemodynamics and reduce composite clinical worsening events in this patient population. The rate of composite of PH progression will be analyzed in both the ITT and PP population. The analyses of other hemodynamic, echocardiographic, and laboratory measurements and clinical events will be conducted in the ITT population.

The study is particularly relevant given the recent changes in the hemodynamic definition of PAH. According to the updated guidelines, patients with mPAP >20 mm Hg and PVR >2 WU can be diagnosed with PH. However, all existing RCTs of approved PAH therapies have used the former diagnostic criteria—mPAP ≥25 mm Hg and PVR ≥3 WU. Although a recent observational study suggested early initiation of PH-targeted therapy, there is currently a lack of robust evidence regarding the efficacy and safety of PAH drugs in patients with mild hemodynamic abnormalities, such as mPAP 21 to 24 mm Hg or PVR 2 to 3 WU.^13,16 Only limited small RCTs and post hoc analyses have suggested a potential benefit of ERAs such as ambrisentan or bosentan in patients with World Health Organization Group 1 or 4 PH.10, 11, 12^,15

This study addresses several important knowledge gaps. First, the ALEPH trial is an RCT with a larger sample size and multicenter design, enhancing both the statistical power and generalizability of the results. Second, the current study enrolls PAH patients, and is not restricted to PAH associated with systemic sclerosis like the former studies. The lack of supporting evidence or even indication for early PAH treatment will be filled. The subgroup analysis part will further explore the potential efficacy differences of ambrisentan among PAH subclasses. Importantly, most validated risk stratification models, including ESC/ERS 4-strata and REVEAL 2.0 lite, do not incorporate patients with mPAP 21 to 24 mm Hg and PVR between 2 and 3 WU, leaving a critical gap in prognostic evaluation for early PAH.¹⁷

Results from the ARIES-1 recommended an initial administration of ambrisentan monotherapy for PAH patients, leading to improvements in catheterization and 6MWD.¹⁸ Furthermore, Galiè et al¹⁹ showed in a randomized, double-blind study that initial combination therapy with ambrisentan and tadalafil significantly reduced the risk of clinical failure events compared with monotherapy, albeit with a higher incidence of adverse effects. Furthermore, an initial triple-combination therapy was found to be associated with a higher survival rate in high-risk PAH population.²⁰ These findings imply that early initiation of ambrisentan-containing regimens may improve outcomes, and monotherapy in low-risk patients, as tested in ALEPH, may strike a balance between efficacy and safety.

The pathogenesis of PAH is complex, involving dysregulation of multiple pathways including TGF-β, activin, and the endothelin-signaling axis.²¹ Plasma endothelin-1 levels are consistently elevated in PAH regardless of etiology, and genetic polymorphisms in the endothelin pathway have been linked to clinical outcomes.^22,23 Therapeutically, targeting the endothelin pathway has proven effective. Currently approved ERAs such as ambrisentan, bosentan, and macitentan have demonstrated clinical benefit. In addition, novel strategies such as targeted vaccines are under investigation, offering further avenues to suppress PAH progression.²⁴

Given the progressive nature of PAH and the lack of tailored treatment algorithms or validated risk models for this subgroup, our study offers a timely opportunity to investigate whether initiating ambrisentan therapy in early-stage, low-risk PAH can delay clinical worsening and improve hemodynamic parameters.

Study limitations

First, the primary endpoints rely on RHC reassessment and risk stratification at 12 months, which may be subject to incomplete follow-up or variability in clinical assessment. Second, the trial adopts ambrisentan monotherapy, although current guidelines increasingly recommend initial combination therapy for PAH, which may restrict the applicability of our results in broader clinical practice. Third, given the relatively low expected event rates in this population, the study may be underpowered to detect differences in long-term clinical outcomes such as mortality or hospitalization. Finally, although extended follow-up to 3 years is planned, the primary analysis at 12 months may not fully capture the long-term prognosis of this patient population.

Conclusions

The ALEPH trial is poised to fill critical evidence gaps regarding early intervention in low-risk PAH patients, potentially supporting the use of ambrisentan monotherapy as an effective and tolerable first-line treatment in this emerging population.

Funding Support and Author Disclosures

This work is supported by from the Chinese Society of Cardiology's Foundation (CSCF2024A01), the Beijing Great Physician Commonweal Foundation, the Jiangsu Provincial Medical Innovation Center (grant number CXZX202215), the Nanjing Municipal Center for Translational Medicine in Cardiopulmonary and Vascular Diseases, and the Nanjing Municipal Clinical Research Center for Cardiovascular Diseases. And jointly supported by Wuhan Humanwell Pharmaceutical Co, Ltd (Wuhan, China). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.