Eplerenone

證據等級: L5

預測適應症: 10 個

Eplerenone: From Heart Failure to Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia

One-Sentence Summary

Eplerenone is a selective mineralocorticoid receptor (MR) antagonist that is internationally recognised for reducing cardiovascular mortality in heart failure following acute myocardial infarction and in chronic systolic heart failure (HFrEF) — though it is not currently registered in Australia. The TxGNN model predicts it may be effective for pulmonary hypertension owing to lung disease and/or hypoxia with a prediction score of 99.50%; however, the current evidence base comprises 0 clinical trials and 20 general hypoxia biology publications — none of which directly examines Eplerenone in this setting — resulting in an L5 evidence rating.

Quick Overview

Item	Content
Original Indication	Not registered in Australia; internationally established for heart failure post-MI and chronic HFrEF
Predicted New Indication	Pulmonary hypertension owing to lung disease and/or hypoxia
TxGNN Prediction Score	99.50%
Evidence Level	L5
Australia Market Status	Not marketed
Number of ARTG Entries	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data was not retrievable from DrugBank for this report. Based on established pharmacology, Eplerenone is a selective mineralocorticoid receptor (MR) antagonist — it competitively blocks aldosterone binding at the MR in the kidneys, heart, and vasculature, reducing sodium and water retention, attenuating cardiac fibrosis, and preventing the adverse vascular remodelling associated with chronic aldosterone excess. Its selectivity for the MR over androgen and progesterone receptors distinguishes it from the older agent spironolactone.

The mechanistic rationale for Eplerenone in pulmonary hypertension owing to lung disease and/or hypoxia (Group 3 PH) centres on the hypoxia–aldosterone–MR axis. Under sustained hypoxic conditions, HIF-1α signalling may upregulate aldosterone synthesis and increase MR expression in pulmonary vascular smooth muscle cells, potentially driving vasoconstriction and adverse vascular remodelling. Blocking the MR could theoretically interrupt this process and attenuate pulmonary vascular resistance — a hypothesis with biological plausibility given the established role of MR antagonism in systemic cardiovascular remodelling demonstrated in the landmark EPHESUS and EMPHASIS-HF trials.

It is critical to recognise, however, that this mechanistic link remains entirely inferential. Group 3 PH (lung disease and/or hypoxia-driven) is pathophysiologically distinct from left-sided heart failure — the right ventricular pressure overload and pulmonary vascular biology present different pharmacological challenges. The 20 retrieved publications are all general hypoxia biology reviews and basic science studies with no direct relevance to Eplerenone in this setting. No preclinical or clinical studies have tested this hypothesis.

Clinical Trial Evidence

Currently no clinical trials related to Eplerenone in pulmonary hypertension owing to lung disease and/or hypoxia have been registered.

Literature Evidence

The PubMed search returned 20 publications for this drug-disease pairing; however, all are general hypoxia biology reviews or basic science studies and none directly examines Eplerenone or mineralocorticoid receptor antagonism in pulmonary hypertension owing to lung disease and/or hypoxia. The most topically contextual are listed below for background reference only:

PMID	Year	Type	Journal	Key Findings
39841808	2025	Narrative Review	Science Translational Medicine	Preclinical evidence that chronic continuous hypoxia may benefit mitochondrial and autoimmune disease models; major clinical translation barriers discussed
33862277	2021	Review	Ageing Research Reviews	Hypoxia drives neurodegeneration in Alzheimer’s and Parkinson’s disease; moderate altitude hypoxia may paradoxically have protective effects on ageing
28972206	2017	Review	Nature Reviews Immunology	Hypoxia shapes innate and adaptive immunity in physiological niches including bone marrow, lymphoid tissue, and intestinal mucosa
34535359	2021	Review	Clinical Oncology (RCR)	Tumour hypoxia drives resistance to radiotherapy and immunotherapy; strategies for therapeutic modification of hypoxia reviewed
11172576	2000	Review	Respiratory Care Clinics of North America	Foundational review of hypoxaemia mechanisms including V/Q mismatch, shunt, and hypoventilation — relevant physiological context for Group 3 PH

Important: None of these publications provides direct evidence supporting Eplerenone for pulmonary hypertension owing to lung disease and/or hypoxia. They represent background hypoxia physiology context only.

Australia Market Information

Eplerenone is not registered on the Australian Register of Therapeutic Goods (ARTG). There are currently no ARTG entries for this drug.

Healthcare professionals wishing to use Eplerenone for an Australian patient would need to access it via the TGA Special Access Scheme (SAS) Category B or the Authorised Prescriber pathway, noting that this would be entirely off-label and investigational for pulmonary hypertension owing to lung disease.

Safety Considerations

Please refer to the TGA-approved Product Information (PI) for safety information.

Note for clinicians: Although specific safety data was not available in this Evidence Pack for the Australian regulatory context, Eplerenone as a class carries well-recognised risks of hyperkalaemia (particularly in patients with renal impairment, diabetes mellitus, or concurrent use of potassium-sparing agents or ACE inhibitors/ARBs), and requires regular monitoring of renal function and serum electrolytes. Contraindications in approved international labelling typically include severe renal impairment (eGFR <30 mL/min), significant hyperkalaemia at baseline, and use with strong CYP3A4 inhibitors. In the Group 3 PH population — who frequently have comorbid cor pulmonale, hypoxaemia, and renal congestion — these risks warrant careful individual assessment. Please verify all safety information against the applicable approved Product Information prior to any clinical consideration.

Conclusion and Next Steps

Decision: Hold

Rationale: Despite a high TxGNN prediction score (99.50%), the evidence for Eplerenone in pulmonary hypertension owing to lung disease and/or hypoxia is rated L5 — supported only by theoretical mechanistic inference with no dedicated preclinical or clinical studies in this indication. The drug is also not registered in Australia, presenting an additional regulatory barrier before any clinical application could be considered.

To proceed, the following is needed:

Dedicated preclinical studies in validated Group 3 PH animal models (e.g., hypoxia-chamber mouse or rat models) using Eplerenone to establish pharmacological proof-of-concept
Systematic review of MR antagonist class data in pulmonary vascular disease, including spironolactone and the newer agent finerenone, to assess whether a class effect exists
Full MOA data retrieval from DrugBank to confirm the specific aldosterone/MR pathway mechanisms relevant to pulmonary vasculature
Safety profile review from applicable international PI (FDA/EMA-approved labelling) given the absence of TGA registration, with specific assessment of risk in right heart failure and renal congestion
Assessment of TGA Special Access Scheme (SAS) or Authorised Prescriber eligibility requirements for any future clinical investigation in Australia
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.