Today’s VA pearls are all about entresto!
Nathaniel shared a case in morning report of a 67M with history of CAD s/p CABG, HFrEF (EF25-30%) s/p ICD placement, atrial flutter, and DM2 who presented with dizziness and hypotension.
The patient reported feeling lightheaded on standing for the past 4-5 days, and home telehealth SBPs were in the 70s-80s, prompting him to present to the ED. He denied any n/v/d, no change in medication doses, and no symptoms of systemic illness.
Medications for HF included metoprolol, eplerenone, and entresto (sacubitril/valsartan), as well as lasix PRN for volume overload. He was also on tamsulosin, sildenafil, and metformin.
The patient was found to be in atrial flutter with rates 80-110s, BP 90/50, and hypovolemic with collapsing IVC on bedside ultrasound and mild AKI.
The patient’s hypotension resolved over 12 hours with 3L IVF and holding all home meds.
In reviewing this case, the primary team and cardiology had a high suspicion for entresto-related hypotension. Since entresto is becoming an increasingly popular medication in the toolkit of HFrEF management, let’s dive a little deeper into how this medication works, and why we need to look out for hypotension!
Entresto mechanism of action
Neurohormonal blockade has been a longstanding component of heart failure therapy, by blocking harmful effects of the renin-angiotension-aldosterone (RAAS) system. In addition, augmentation of beneficial counter-regulatory systems such as natriuretic peptides is thought to further promote cardiac function.
Sacubitril is a neprilysin inhibitor, which raises levels of vasoactive peptides (including BNP, bradykinin, and adrenomedullin) by inhibiting their degradation. Unfortunately, neprilysin is also responsible for degrading the harmful hormone angiotensin II. Thus, a neprilysin inhibitor alone was found to be not beneficial in HF.
In order to raise levels of helpful peptides but continue RAAS inhibition, sacubitril was paired with valsartan to create entresto (an angiotensin receptor-neprilysin inhibitor, or ARNI).
The landmark trial that suggested benefit of entresto in HFrEF was PARADIGM-HF, an RCT comparing entresto vs enalapril in patients with EF < 40% and NYHA functional class II-IV. The study was stopped early due to significant benefit in the entresto group with primary outcome of reduced mortality and reduced HF hospitalizations [HR 0.80, 95% CI 0.73-0.87]. Since publication of this trial in 2014, entresto has been incorporated as a first-line alternative to ACEi in HFrEF.
Precautions with Entresto
The most common adverse effect with entresto is hypotension. This was observed in PARADIGM-HF (18% in entresto group vs 12% in enalapril group) and has continued to be noted in clinical practice. Entresto can have profound hypotensive effect due to its combination med effect, and may be expected to cause hypotension even in patients who were previously stabilized on an ACE/ARB. Current recommendations are to allow for a lead-in period with 36-hour washout when switching from ACEi to entresto to avoid duplicated effect.
Other side effects largely mirror previously observed ACE/ARB effects: hyperkalemia, cough, and angioedema. Entresto is contraindicated in patients with history of angioedema, but this side effect is rare overall.
Finally, an important pearl from Dr. Greg Judson in AM report – entresto elevates BNP levels, making this lab test unreliable as a measure of volume overload. However, neprilysin does not affect NT-proBNP, so this precursor is recommended as the alternative for monitoring in patients on entresto.
In the case of our patient, hypotension and lightheadedness resolved after fluid and holding meds. BNP level was initially 1200 and decreased to 600 when holding entresto. Plan is to discharge on a lower dose of entresto with outpatient titration of diuretics.
- Entresto (sacubitril-valsartan) is a combination of neprilysin inhibitor and angiotensin receptor blocker that has demonstrated mortality benefit in HFrEF, now considered a first-line alternative to ACEi. Sacubitril works by preventing breakdown of protective peptides such as BNP, but since it also elevates angiotensin II, it needs to be paired with an ARB!
- The most common adverse effect of entresto is hypotension, which can be profound even in patients previously stabilized on ACE/ARB; consider med effect as a cause of hypotension, particularly on initiation or uptitration of dose.
- Entresto elevates BNP levels, making this lab test unreliable as a measure of volume overload. Use NT-proBNP instead in patients on entresto, as this precursor is not affected.