Post-Discharge Initiation of Angiotensin Receptor-Neprilysin Inhibitor in an Inotrope-Dependent Patient in the Outpatient Setting: A Case Report

Abstract

Purpose: Angiotensin receptor-neprilysin inhibitor (ARNI) therapy has been reported to be initiated in patients on vasoactive medications during acute decompensated heart failure. However, there is no report regarding the safety of initiating ARNI therapy in patients receiving inotrope infusion in an outpatient setting. Summary: We described a case of initiating post-discharge ARNI therapy in a 41-year-old man with inotrope-dependent heart failure in an outpatient setting. Two weeks after the initiation of low dose sacubitril/valsartan, milrinone was successfully discontinued without any adverse effects. Conclusion: With close monitoring, ARNI therapy could be safely initiated in hemodynamically stable patients receiving intravenous inotrope, and further investigation is needed to confirm our findings.

Introduction

In the recently published PIONEER-HF trial, the initiation of sacubitril/valsartan during acute decompensated heart failure (ADHF) was reported to be associated with reduced N-terminal pro b-type natriuretic peptide (NT-proBNP) to a greater degree than enalapril. ¹ However, patients with use of intravenous inotropes during the preceding 24 hours were excluded from the PIONEER-HF trial. Therefore, the role of initiating sacubitril/valsartan in patients receiving intravenous inotrope remains unclear. In a study reported by Martyn et al, ² they retrospectively reviewed all patients with ejection fraction <40% who were started on sacubitril/valsartan in cardiac intensive care units (ICU). Twenty patients were found to have a cardiac index below 2.2 L/min/m² and were on vasoactive medications at the time of sacubitril/valsartan initiation. Among them, 15 patients were receiving sodium nitroprusside alone, 4 were receiving an inotrope (milrinone or dobutamine) plus sodium nitroprusside, and 1 was on dobutamine alone. All patients were successfully weaned off intravenous vasoactive therapy before transfer from the cardiac ICU. The authors concluded that selected patients with heart failure with reduced ejection fraction (HFrEF) characterized by low cardiac output, elevated filling pressures, and preserved renal function could be safely transitioned to angiotensin receptor-neprilysin inhibitor (ARNI) therapy in the cardiac ICUs. Having said that, however, there is no report regarding the safety of initiating post-discharge ARNI therapy ARNI therapy in patients receiving inotrope infusion in an outpatient setting. There are substantial ambulatory patients on chronic inotropic therapy who may potentially benefit from ARNI therapy. Here, we presented a case of initiating post-discharge low dose sacubitril/valsartan in a 41-year-old man with inotrope-dependent heart failure at our heart failure clinic.

Case Summary

A 41-year-old man presented at the heart failure clinic for post-hospital follow-up visits. The patient had a history of the American College of Cardiology (ACC) and American Heart Association (AHA) stage C HFrEF secondary to idiopathic dilated cardiomyopathy. He was hospitalized due to ADHF. The echocardiogram study during hospital stay showed ejection fraction <20%, right ventricle moderately dilated, right ventricular systolic pressure moderately reduced, and severe mitral valve regurgitation. After the initiation of milrinone during the hospital stay, 2 attempts to wean off milrinone were made but failed due to malperfusion and symptomatic hypotension with significant drops of the cardiac index to 1.3 L/min/m² and 1.76 L/min/m², respectively. As such the patient was discharged on inotropic support with milrinone 0.25 µg/kg/min; cardiac index was 1.8 L/min/m². The patient was also discharged with guideline-directed medical treatment (GDMT) including weight-based diuretics with torsemide 20 mg as needed, metoprolol succinate 25 mg daily, spironolactone 25 mg daily, and digoxin 250 µg daily. Lisinopril was held right before discharge due to hypotension.

The first follow-up clinic visit was 2 days after discharge. His blood pressure was 108/74 mm Hg with a heart rate of 119 beats/min. The dose of milrinone infusion remained at 0.25 µg/kg/min. Due to the elevated heart rate, the dose of metoprolol succinate was increased to 37.5 mg daily during this visit. In a subsequent visit, his NT-proBNP level was found to decrease from 3084 ng/L to 1235 ng/L within 12 days after discharge. The overall treatment goal for this patient at the time was for slow titration of GDMT and hopefully weaning him from milrinone over time. The second clinic visit was 1 month after discharge. The blood pressure was 136/98 mm Hg with a heart rate of 90 beats/min. He was generally well and had no major/new complaints. He was adherent to his medication regimen as prescribed and denied any side effects. He was also compliant with a low sodium diet. His daily weights had been stable. The NT-proBNP level was further reduced to 426 ng/L. Given the considerable improvement of his clinical status, sacubitril/valsartan 24/26 mg twice daily was initiated. No hypotension was reported thereafter.

Two weeks after the initiation of ARNI therapy, the NT-proBNP further normalized from 426 ng/L to 155 ng/L and the patient was admitted to the cardiac observation unit as planned to discontinue milrinone, followed by same-day discharge. His mixed venous oxygen saturation 6 hours after discontinuation of milrinone was 64.1%. His blood pressure was 122/87 mm Hg before the admission and remained stable during the observation with systolic blood pressures in the low 120s, and heart rate of 70. During the exam, he was warm and well-perfused without clinical evidence of hypoperfusion. The patient returned to the clinic 1 week later for the scheduled third clinic visit. He was euvolemic on the exam with New York Heart Association Functional Classification II ACC/AHA stage C HFrEF. Thus, this patient was successfully weaned from milrinone. The trend in NT-proBNP levels during treatment is shown in Figure 1.

Figure 1.

NT-proBNP levels. The trend in NT-proBNP levels during treatment.

Sacubitril/valsartan dose was slowly titrated to 97/103 mg twice daily over the course of therapy. Patient was evaluated at another institution shortly afterwards but was not considered a candidate for heart transplantation. The latest echocardiogram in the eighth month after discharge showed that left ventricular internal diameter in diastole (LVIDd) decreased to 5.91 cm from 8.35 cm measured before discharge (Figure 2). Left atrial cavity size diminished from severely increased to mildly increased with a reduction of left atrial dimension from 5.5 cm to 4.3 cm. Mitral valve regurgitation improved from moderate to mild. Left ventricular systolic function remained severely reduced with estimated ejection fraction <20%.

Figure 2.

The results of echocardiogram study. Measurement of left ventricular parameters before (a) and 8 months after (b) the initiation of ARNI therapy. Measurement of left atrium parameters before (c) and 8 months after (d) the initiation of ARNI therapy. Echocardiographic four-chamber view before (e) and 8 months after (f) the initiation of ARNI therapy.

Discussion and Conclusion

Our case echoes the Martyn et al’s findings, as sacubitril/valsartan was successfully initiated with concurrent use of intravenous milrinone, and this patient achieved stable hemodynamic improvement without any adverse effects in the outpatient setting. Additional reduction of NT-proBNP levels after the initiation of ARNI therapy was observed. Although improvement in the estimated ejection fraction was not observed, the echocardiogram study found signs of reverse cardiac remodeling in this patient, which could be attributed to the reduction of NT-proBNP levels. ³ In conclusion, this approach has the potential to expand the use of sacubitril/valsartan in patients on intravenous inotropic therapy in the outpatient setting. We hypothesize that, with close monitoring, ARNI therapy could be safely initiated in hemodynamically stable patients receiving intravenous inotrope, and further investigation is needed to confirm our findings.