Enalapril
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
Enalapril: From Hypertension/Heart Failure to Chronic Pulmonary Heart Disease
One-Sentence Summary
Enalapril is a well-established angiotensin-converting enzyme (ACE) inhibitor originally used to treat hypertension and heart failure. The TxGNN model predicts it may also be effective for Chronic Pulmonary Heart Disease (cor pulmonale), with 4 clinical trials and 20 publications identified, though only a small number directly test enalapril in this specific condition.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Hypertension, Heart Failure (established ACE inhibitor class indication; not verifiable against an EU product label in this Evidence Pack — see Data Gaps below) |
| Predicted New Indication | Chronic Pulmonary Heart Disease (cor pulmonale) |
| TxGNN Prediction Score | 98.91% |
| Evidence Level | L3 |
| EU Market Status | Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in this Evidence Pack. Based on known pharmacology, Enalapril is a member of the ACE inhibitor class, converted in vivo to its active metabolite enalaprilat. Its efficacy in hypertension and chronic heart failure is well established: by inhibiting the renin-angiotensin-aldosterone system, it reduces systemic vascular resistance, afterload, and fluid retention.
Chronic pulmonary heart disease (cor pulmonale) is a condition in which chronic lung disease and hypoxia lead to pulmonary vascular resistance, pulmonary hypertension, and eventual right ventricular strain and failure. Mechanistically, ACE inhibition could plausibly reduce pulmonary vascular resistance and right-heart afterload in the same way it does for the systemic circulation, providing a rationale for the TxGNN prediction.
However, the mechanistic link is not confirmed by strong direct evidence: most of the identified clinical trials study enalapril (or comparator drugs) in general chronic heart failure rather than cor pulmonale specifically, and the literature directly addressing enalapril in pulmonary heart disease consists of small, decades-old studies (11–30 patients, from the early 1990s). The prediction should therefore be treated as mechanistically plausible but clinically unproven.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00292162 | N/A | Completed | 41 | Radiofrequency ablation for atrial fibrillation in advanced chronic heart failure; not an enalapril intervention trial (grade C relevance) |
| NCT00151619 | Phase 2 | Terminated | 7 | Add-on amlodipine in CHF patients already treated with enalapril, furosemide and digoxin; terminated early (grade C relevance) |
| NCT02768298 | Phase 4 | Completed | 201 | LCZ696 (sacubitril/valsartan) vs. enalapril for exercise capacity in HFrEF; enalapril used as active comparator, not specific to cor pulmonale (grade B relevance) |
| NCT06697353 | N/A | Completed | 4936 | Real-world retrospective cohort of vericiguat in Japanese HFrEF patients; does not evaluate enalapril directly (grade C relevance) |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 1405196 | 1992 | Small Clinical Study | Kardiologia polska | Enalapril (10–20 mg/day, 30 days) in 11 patients with cor pulmonale due to COPD improved hemodynamics and exercise tolerance, with a moderate decrease in mean pulmonary arterial pressure |
| 9282581 | 1996 | Small Clinical Study | J Assoc Physicians India | Enalapril added to bronchodilators/diuretics/antibiotics in 30 patients with chronic cor pulmonale improved right ventricular dimensions and renal profile vs. conventional treatment alone |
| 9140694 | 1997 | Animal Model | Cardiovasc Drugs Ther | In rats, enalapril reduced right ventricular collagen/fibrosis during recovery from chronic hypoxia-induced pulmonary hypertension |
| 2210899 | 1990 | Clinical Study (general CHF) | Int J Cardiol | Enalapril monotherapy improved hemodynamics in severe CHF with sodium retention (general heart failure, not cor pulmonale-specific) |
| 6313787 | 1983 | Clinical Study (general CHF) | J Am Coll Cardiol | Early hemodynamic evaluation of enalapril in chronic heart failure; increased cardiac index and reduced pulmonary wedge pressure |
| 33522249 | 2021 | Post-hoc Analysis | J Am Heart Assoc | PARADIGM-HF subgroup analysis showing COPD is a common HFrEF comorbidity associated with undertreatment and worse outcomes |
| 16494512 | 2006 | Review | Paediatr Drugs | Review of ACE inhibitor (including enalapril) use in pediatric heart failure |
| 39210725 | 2024 | Post-hoc Analysis | JAMA Cardiology | Sacubitril/valsartan vs. enalapril effects on all-cause hospitalization, pooled from PARADIGM-HF and PARAGON-HF |
| 30738210 | 2019 | Animal Model | J Pharmacol Toxicol Methods | Mouse HF model with pulmonary edema/pleural effusion validated using standard HFrEF pharmacotherapy |
| 20592661 | 2011 | Review | Am J Ther | Review of immunomodulatory effects of heart failure drug classes, including ACE inhibitors |
EU Market Information
Enalapril is currently recorded as not marketed in this Evidence Pack, with no EU marketing authorizations on file (0 licenses).
Safety Considerations
Please refer to the SmPC for safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanistic rationale for enalapril in chronic pulmonary heart disease is plausible (ACE inhibition lowering pulmonary vascular resistance and right-heart afterload), but the supporting evidence is limited to small, decades-old studies (n=11–30) and observational reports, without any completed RCT specifically targeting cor pulmonale. This corresponds to an L3 evidence level — sufficient to justify a research question, but not to support clinical decision-making.
To proceed, the following is needed:
- EMA/SmPC-sourced warnings, contraindications, and drug interaction data (currently a Blocking data gap — DG001)
- Confirmed mechanism of action documentation from DrugBank (currently a data gap — DG002)
- A contemporary, adequately powered clinical trial or systematic review evaluating enalapril specifically in chronic pulmonary heart disease/cor pulmonale
- Confirmation of original approved indication(s) and EU licensing status, since no license records are currently available for this drug
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.