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).

packer-slide

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.”

Comments

  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”?

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