Debate: Switching From Standard HF Therapy To Entresto

–A debate at the HFSA in Orlando over whether all patients tolerating standard therapy should be switched to Entresto.

Editor’s Note: Heart failure specialist Eiran Z. Gorodeski (Cleveland Clinic) wrote this account of an important debate on Monday at the Heart Failure Society of America meeting in Orlando. (This account has been updated by Gorodeski with additional information about the debate.)

Should every ambulatory patient tolerating moderate-dose ACEI/ARB be switched from ACEI/ARB to ARNI?

In a spirited session at the HFSA meeting Milton Packer (Dallas, TX) and Nancy Sweitzer (Tucson, AZ) debated whether every ambulatory patient with chronic heart failure with reduced ejection fraction (HFrEF) tolerating moderate dose of an ACE inhibitor (ACEI) or angiotensin-receptor blocker (ARB) should, or should not, be switched to the angiotensin-receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (Entresto, Novartis Pharmaceuticals).

Packer, one of the PARADIGM-HF authors, stated provocatively that “no reasonable person who has been awake during the past 2 years should think that this proposition… is ethically open for debate.”

Packer first reminded the audience of HFSA’s latest Class I Recommendation that “in patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACEI or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality.”

Packer then proceeded to explore the question, “why do the latest 2016 updated ACC/AHA/HFSA guidelines recommend switching to ARNI at any dose rather than target dose?” He explained that a majority (approximately 5,500) of patients in PARADIGM-HF were taking medium doses of ACEI or ARB before the trial. Of this subset of the total trial participants, those randomized to ARNI benefited significantly more in terms of reductions in CVD death (see slide provided by Dr. Packer).


Based on this he continued to argue that the question is not “should” patients taking medium doses of ACEI or ARB be switched, but rather “how.” He explained that “forcing” patients to up titrate to highest dose of ACEI first (enalapril 10mg twice daily) before switching to the ARNI, may have risks, and is not preferable. Specifically, he highlighted risks of cough, renal impairment, and hyperkalemia. In PARADIGM-HF, there were lower rates of these side-effects in those patients randomized to the ARNI. Additionally, he showed a Kaplan-Meier plot showing early splitting of the curves in favor of ARNI over the ACEI, arguing that “withholding” the medication until the patient reaches target dose of ACEI is “time wasted.”

But what if switching from medium dose ACEI to ARNI results in dose reduction? He mentioned results that were also noted in a recently published PARADIGM sub-study that there were mortality and hospitalization benefits in favor of ARNI over ACEI even for patients who couldn’t maintain the target dose.

Packer concluded by saying that based on population estimates (Fonarow et al, JAMA Cardiol 2016) the failure to switch from ACEI to ARNI could result in one avoidable death every 18 minutes. He emphasized this by putting his phone up to the microphone and playing a sound effect of a clock ticking down. Point made.

Sweitzer, Packer’s opponent, came out swinging and landed a punch when she pointed out that “‘everybody’ is a very potent word.” She reminded Packer, and the audience, of Packer’s own words from 2014 describing the types of patients enrolled in PARADIGM-HF, and for whom the findings are generalizable.

Sweitzer then described the case of an 88 year old (1.44% of PARADIGM patients were ≥85) African American (5% of PARADIGM-HF patients) woman (22% of PARADIGM-HF patients), with non-ischemic cardiomyopathy (40% of PARADIGM-HF) and ejection fraction of 20% (29% of PARADIGM-HF). The patient was on a complex regimen of HF medications including isosorbide mononitrate and hydralazine. She pointed out that managing these medications in the setting of ARNI introduction is unknown. The patient further had colon cancer as a comorbidity, and hospice was being considered. When Dr. Sweitzer asked the hypothetical question, “would you switch this patient to Sacubitril-valsartan?”, the audience burst out laughing.

The debate was accompanied by discussion on social media. Ryan Daly (@DrRyanPDaly), a cardiologist from Indianapolis, noted another barrier to transitioning everyone from ACEI to ARNI: “in the real world [it] takes weeks for precertification and approval [by insurance companies].” Another factor that should be mentioned is that a a sizable number of patients won’t be able to afford the co-pays, even after their prescription is approved by insurance.

The debate ended on a positive note with moderator Dr. Marc Pfeffer (Boston, MA), thanking Dr. Packer for his enthusiasm, “Dr. Packer argued in favor of beta-blocker use 20 years, and he still hasn’t lost his passion.”


  1. Why do people insist on making absurdly ambiguous proclamations, such as “no reasonable person who has been awake during the past 2 years should think that this proposition… is ethically open for debate”?

  2. As a heart failure patient due to a wrong size stent placement, I am trying to learn as much as I can on Entresto vs ACE/ARB’s. I feel the study was lacking. I also feel 20% salvation was not high enough for hearty salvation. I also feel men vs women in Entresto trials was lacking. One size shoe does not fit all. Normally, women will weigh less than a male..did they take into account women taking Birth Control and HRT into trial results.

    I personally feel Entresto needs to be fine tuned. There are three strengths offered. Must one have to take all three strengths to maximize the 20% salvation?

    In my humble opinion, I feel this med recipe needs to be adjusted. I feel prescribing physicians need to be attentive to patient’s metabolism, kidney/liver functions, fairly often. BNP’s and Echocardiograms, also. Chest x-rays, also. Watching closely the patient’s EF numbers is critical. This is not being done to everyone taking this medication.

    Could it be that some can be well maintained on the lower dose of this medication or using a low dose with a middle dose, daily? Doctors need to tweek each patient, I feel. I would be one happy patient if I could maintain an EF of 45-50. I am getting there going from an EF of 25 now to 41, mainly on the lowest of doses and my others meds, I take daily. I try to stay on top of everything. I feel there is more to maintaining better heart function than Entresto even though at this time, Entresto is part of my daily regime.

    Signed: 75 year old female not on HRT. Medicare Patient. Yes, Entresto is expensive. Very expensive.

    • Joanna Claterson says

      If patients feel their physician does not take into consideration their kidney/liver function, metabolism, NTproBNP levels, EF, etc. like you claim, that’s on them, not the drug. I’ve treated enough patients with this drug to see the difference. We have a duty to utilized evidence based medicine. Entresto has gone up against the best in class ACEi, and won. To say a 20% reduction isn’t that much is absolutely outrageous. This is 20% above the BEST WE COULD DO as a medical community. It is not 20% against placebo.

      To salvage as much cardiac function as we are able, patients need to be a maximally tolerated doses. There is no evidence that we are doing any good by providing sub-optimal doses to patients who could tolerate more. People’s lives are at risk. Also to say that a woman will weight less, this is a conversation that I am not willing to even engage on as I think it highlights the lack of understanding of this poster.

  3. Paul Bruins says

    I am a 71 year old male. 8 years since stemi. Well compensated heart failure with excellent excercise tolerance. (32 mile bike rides. 3 mile fast paced walks are well tolerated. ). EF at 35% , BNP levels at 60. Recently 3 weeks, switched to Ernesto from standard ace, beta blocker, spironolactone, and digoxin. Only ace was dropped. My excercise tolerance has been reduced. Several severe bouts of persistent hypotension post excercise or physical exertion leaves me doubtful that I can even tolerate the lowest dosage of Entresto. I would love to get better EF but looks like I am not a good candidate. Any Hope here for me?

  4. Lilli Mapes says

    Admitted for v tach two weeks ago. Hx of paroxysmal atrial flutter short term and high bp with bradycardia for many years. (Cardiologist waiting to see if CPAP would help.prior to vtach episode) Seriously. Switch from valsartan hctz which was conttolling my bp for a long time to enestro lowest dose twice a day after an icd placement. Then sent home. My bp has gone higher and higher in the last two weeks. How can this be better for me? I almost put myself back on the valsartan. I have appt tomorrow.

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