ARNI in PAH-Related Right Heart Failure with Normal LVEF
ARNI (sacubitril/valsartan) is not recommended for PAH-related right heart failure with preserved LVEF, as current evidence and guidelines address only left-sided heart failure, not primary pulmonary arterial hypertension.
Critical Distinction: PAH vs. Left Heart Disease
The fundamental issue is that all available evidence for ARNI pertains to left-sided heart failure (HFrEF or HFpEF), not primary pulmonary arterial hypertension 1. The FDA approval for sacubitril/valsartan specifically covers chronic heart failure with reduced ejection fraction and does not extend to PAH-related right heart failure 2.
Why This Matters
- PAH is a distinct disease entity where the primary pathology originates in the pulmonary vasculature, causing right ventricular failure secondary to increased afterload 1
- Left-sided HFpEF with secondary pulmonary hypertension (PH-LHD) is mechanistically different from PAH, where elevated left-sided filling pressures drive pulmonary pressure increases 3, 4
- The 2022 AHA/ACC/HFSA guidelines only address ARNI use in left-sided heart failure with preserved or reduced ejection fraction, making no recommendations for primary right heart failure or PAH 1
Evidence Limitations
What the Guidelines Say
The PARAGON-HF trial evaluated sacubitril/valsartan in HFpEF (LVEF ≥45%) but did not meet its primary endpoint for cardiovascular death or heart failure hospitalizations (rate ratio 0.87; 95% CI 0.75-1.01; P=0.06) 1. Even in this left-sided HFpEF population:
- No mortality benefit was demonstrated (HR 0.95 for cardiovascular death, HR 0.97 for total mortality) 1
- Only exploratory subgroup analyses suggested potential benefit in patients with LVEF 45-57% and in women 1
- This resulted in only a Class 2b recommendation (may be considered) for selected HFpEF patients 5
Observational Data in PH-LHD (Not PAH)
Several small observational studies showed improvements in pulmonary pressures with ARNI, but these were in left-sided heart failure patients with secondary pulmonary hypertension, not primary PAH:
- Studies by 3, 6, 4 demonstrated reduced pulmonary artery pressures in HFpEF patients with PH-LHD after switching to sacubitril/valsartan
- A meta-analysis 7 of 875 HFrEF patients showed improved right ventricular function and reduced systolic pulmonary arterial pressure (weighted mean difference 7.21 mm Hg)
- However, all these studies involved left-sided heart failure as the primary pathology, not PAH 3, 6, 4, 8, 7
Clinical Approach for PAH-Related RHF
Appropriate Management
For patients with PAH-related right heart failure and normal LVEF, focus on:
- PAH-specific therapies: endothelin receptor antagonists, phosphodiesterase-5 inhibitors, prostacyclin analogs, and soluble guanylate cyclase stimulators (not discussed in provided evidence but standard PAH management)
- Diuretics for volume management to relieve congestion 1
- Treatment of underlying PAH etiology 1
Common Pitfall to Avoid
Do not extrapolate HFpEF data to PAH patients. The mechanism of right heart failure in PAH (primary pulmonary vascular disease causing RV pressure overload) differs fundamentally from HFpEF with secondary pulmonary hypertension (elevated left-sided pressures transmitted backward) 3, 4.
When ARNI Might Be Considered (With Extreme Caution)
If a patient has both PAH and concurrent left-sided HFpEF (a complex scenario), ARNI might be considered for the left-sided component, but this would require:
- Documented elevated left-sided filling pressures contributing to pulmonary hypertension 3, 4
- LVEF in the 45-57% range where subgroup benefit was suggested 1
- Female sex (another subgroup showing potential benefit) 1
- Close monitoring for hypotension and angioedema 1
- Recognition that this is off-label use without guideline support for the PAH component 1
In isolated PAH-related RHF with normal LVEF and no left-sided pathology, ARNI has no established role and should not be used.