Mechanisms and Prognosis of Intolerance to Angiotensin Receptor-Neprilysin Inhibitors in Advanced Heart Failure: Insights From Vasodilator Challenge

Abstract

Background

Angiotensin receptor-neprilysin inhibitor (ARNI) intolerance is common in patients with advanced heart failure (AdHF) and may be associated with worse prognosis. During right heart catheterization (RHC), afterload reduction induced by vasodilator challenge may reproduce the hemodynamic effects of ARNI. Through sodium nitroprusside (NTP) infusion, we characterized the hemodynamic mechanisms of ARNI intolerance and explored its prognostic relevance in AdHF.

Methods

We performed a retrospective, multicenter study evaluating AdHF patients undergoing RHC with NTP infusion. Hemodynamic ARNI intolerance was defined as symptomatic hypotension requiring ARNI cessation. We collected clinical, echocardiographic, and hemodynamic parameters at baseline and after vasodilator challenge and evaluated their association with ARNI intolerance and a composite clinical outcome of 1-year all-cause death, urgent heart transplantation, or LVAD implantation.

Results

Of the 116 consecutive patients, hemodynamic ARNI intolerance was seen in 26 (22.4%). Baseline hemodynamics were not associated with ARNI intolerance. After NTP infusion, a smaller increase in stroke volume index (ΔSVi; adjusted odds ratio [adj-OR] per mL increase: 0.89, 95% confidence interval [CI] 0.81-0.99, P = 0.031) and higher pulmonary elastance (post-NTP arterial elastance; adj-OR per mm Hg per mL increase: 6.49, 95% confidence interval [CI] 1.04-40.46, P = 0.045) were independently associated with hemodynamic ARNI intolerance. Patients with ARNI intolerance were more likely to experience the primary outcome (Kaplan-Meier estimates: 73.0% vs 36.2%, P = 0.021). Higher baseline right atrial pressure/pulmonary artery wedge pressure (hazard ratio [HR] 8.57, 95% CI 2.23-32.89, P = 0.002) and lower post-NTP SVi (HR 0.95, 95% CI 0.92-0.99, P = 0.015) were independent predictors of adverse events.

Conclusions

Among AdHF patients, ARNI intolerance is common and associated with worse outcomes. NTP infusion unveils exhausted hemodynamic reserve as its underlying mechanism and prognostic determinant.