Shock and Awe: Sacubitril/Valsartan for Severe HF Safely Started in ICU in Early Cases

September 17, 2019

PHILADELPHIA — Even the sickest of patients with acute heart failure (HF) can be safely started on sacubitril/valsartan (Entresto, Novartis) in the intensive-care unit (ICU) as part of their careful transition from IV vasodilators and inotropes to oral therapy, suggests an early experience of fewer than 2 dozen cases.

Despite concerns that some patients can develop hypotension when starting on sacubitril/valsartan, 17 of the 22 patients in whom the strategy was attempted tolerated the drug and left the ICU on 1 of its 3 standard dosage levels.

Dr Trejeeve Martyn

The total group's cardiac index (CI) averaged 1.67 L/min/m2 before initiation of sacubitril/valsartan, "which is quite low, 2.2 being our cut-off for cardiogenic shock," observed Trejeeve Martyn, MD, Cleveland Clinic, Ohio, speaking to | Medscape Cardiology.

"When they left the ICU, on average they had a significant improvement," to 2.43 L/min/m2, said Martyn, who presented the experience here at the Heart Failure Society of America (HFSA) 23rd Annual Scientific Meeting.

The 22 patients included some who were in cardiogenic shock from an acute myocardial infarction (MI) along with others with chronic HF who were hospitalized with a severe acute exacerbation.

Changes in hemodynamics in the 10 patients with chronic HF were followed during transition from IV to oral meds using a Swan-Ganz pulmonary artery (PA) catheter.  

Their average mean arterial pressure (MAP) dropped only about 9% from before to after initiation of sacubitril/valsartan, while other hemodynamic measures improved.

"Oral vasodilators are the goal for patients in cardiogenic shock on IV drugs," noted Dmitry M. Yaranov, MD, Cleveland Clinic, who presented hemodynamic data for the 10 patients in a separate report at the HFSA sessions.

Dr Dmitri Yaranov

The vasodilators of choice in the ICU are usually ACE inhibitors or angiotensin-receptor blockers (ARBs), hydralazine, or isosorbide dinitrate, Yaranov said in an interview. "This, to our knowledge, is the first reported experience with Entresto" and represents "a completely off-label use. It's not in the guidelines."

Sacubitril/valsartan, the lone approved member of the angiotensin receptor–neprilysin inhibitor (ARNI) drug class, is a conjoined complex of the two agents making up its name. It was approved as an alternative to ACE inhibitors or ARBs in patients with chronic HF based largely on mortality outcomes in the PARADIGM-HF comparison with enalapril.

Later, in the PIONEER-HF trial, the drug was successfully initiated predischarge in HF patients who had been stabilized after an acute decompensation. Levels of the biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) fell significantly over 8 weeks in those patients compared with others who had been started on the ACE inhibitor.

The 22 patients in the current analyses definitely had more severe disease than was permitted in the major sacubitril/valsartan randomized trials, Mark H. Drazner, MD, University of Texas Southwestern Medical Center, Dallas, told | Medscape Cardiology.

Dr Mark Drazner

"They extended the drug into a population that wasn't previously well studied," observed Drazner, who isn't connected with the two reports. The question was, where in the continuum of HF severity and acuity is the earliest time patients will tolerate sacubitril/valsartan?

The current study, he said, "moved it from the hospitalized patient in PIONEER-HF to the hospitalized patient who is on parenteral therapy in the ICU with a Swan. It's inching it further along to sicker and sicker patients."

Use of Swan-Ganz PA pressure readings in the ICU to guide a patient's transition from IV vasodilators and inotropic agents to oral vasodilators such as captopril, nitrates, or hydralazine — sometimes called tailored therapy — has been advocated for at least 20 years, Drazner noted.

The investigators here, he said, transitioned the patients to a novel vasodilator instead of a more traditional one. Their findings suggest that that sacubitril/valsartan is tolerated at that very early stage of acuity, with the caveats that it should be initiated in the ICU by highly experienced clinicians under PA-pressure guidance.

Importantly, these are early observations. "We clearly need more," Drazner said, but they are enough to make one pay attention. Still, "I think you need to do this prospectively. Then we'll really know."

An underlying rationale for the PIONEER-HF trial also applies to the current patients: in-hospital or even ICU initiation of sacubitril/valsartan makes it more likely that they will be discharged with a prescription for it rather than an ACE inhibitor or ARB; and PARADIGM-HF suggests that's preferable.

Typically, if a patient improves in the ICU on IV sodium nitroprusside, for example, "usually the practice at a lot of centers is to start them on oral medicines that replicate its effect, something like isosorbide dinitrate, hydralazine, captopril, or lisinopril," Martyn said.

"But if you start those drugs in the ICU, the chance that you're on sacubitril/valsartan by the time you leave the hospital, in our experience, is very low."

And, Drazner said, for patients who are discharged on the drug, "the odds of them being on it long-term are much higher than if they don't get started on it in the hospital."

Martyn's report looked at all heart failure with reduced ejection fraction (HFrEF) patients at his center who had been started for the first time on sacubitril/valsartan in the cardiac ICU, after insertion of a Swan-Ganz catheter. Their mean left ventricular ejection fraction was 18%, and 21 of the 22 patients met the CI-based definition for cardiogenic shock. The same proportion had been on IV sodium nitroprusside, milrinone, dobutamine, or a combination thereof in the ICU before the ARNI was started; about half had been on IV diuretics.

Sacubitril/valsartan was initiated in 15 of the 22 patients at the lowest standard twice-daily dose equivalent of 24 mg sacubitril and 26 mg valsartan (that is, "24/26" bid).

Seven patients were started on it at the mid-range dosage of 49/51 bid, and none at the highest dosage of 97/103 bid.

Five, 8, and 4 patients left the ICU on sacubitril at the lowest, mid, and highest dosages, respectively; and all 17 patients were discharged on the drug.

Of the 5 patients forced to withdraw from sacubitril/valsartan in the ICU, 4 stopped due to hypotension and the fifth to both hypotension and acute kidney injury.

Mean Hemodynamic Changes Before to After ICU Introduction of Sacubitril/Valsartan in 10 Patients With Advanced Decompensated HF




% Change

MAP (mmHg)




RA Pressure (mm Hg)




PA Pressure (mm Hg)




PCWP (mm Hg)




CI (L/min/m2)




Mixed Venous Saturation (%)




MAP = mean arterial pressure

RA = right atrial

PA = pulmonary artery

PCWP = pulmonary capillary wedge pressure

CI = cardiac index

In Yaranov's prospectively studied subset of 10 of the 22 patients, all had been hospitalized with decompensated chronic HF; three had ischemic and 7 had nonischemic cardiomyopathy. All of them were among those successfully transitioned from IV inotropes or vasodilators to sacubitril/valsartan.

Martyn, Yaranov, and Drazner have disclosed no relevant financial relationships.

Heart Failure Society of America (HFSA) 23rd Annual Scientific Meeting: Abstract 67. Presented September 13, 2019. Abstract 192. Presented September 14, 2019.

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