The JACC: Heart Failure Position Paper, published in the Jan 2020 issue of JACC: Heart Failure is the result of a rich dialogue among experts related to the interpretation of the mandatory federal pay-for-performance Hospital Readmissions Reduction Program (HRRP) and its impact on heart failure. The expert panel make compelling arguments regarding the overall program effectiveness, hospital readmissions and on program impact on patient equity and on mortality. Their consensus recommendations include recommendations around the readmission measure, but also underscore the realities of socioeconomic and health disadvantage and its relationship to quality of care and readmissions. Without question, this medically complex population requires skilled management, both in hospital and in the outpatient setting.

Challenge your knowledge of this patient population with K2P and Dr. Biykem Bozkurt, MD, PhD’s series on evidence-based management of heart failure.

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Updates on Evidence-Based Management of Heart Failure: ARNI

Faculty: Biykem Bozkurt, MD, PhD

Learning Objectives

Explain the mechanism of action of angiotensin receptor and neprilysin inhibitors,

Ability to describe the scientific evidence supporting the pharmacological treatment with ARNI in stage C heart failure patients with a reduced ejection fraction, and

List the key recommendations for ARNI in the 2016 ACC/AHA/HFSA Focused Update of the 2013 Heart Failure Guidelines for Management of Heart Failure.

NEP Inhibition in CVD

Neprilysin inhibition has been envisioned as a beneficial strategy in cardiovascular disease by potentiation of beneficial peptides such as ANP, BNP, adrenomedullin, which are thought to counter the maladaptive mechanisms such as reduction in fibrosis or regression hypertrophy.

Mechanism of Action

Neprilysin is a neutral endopeptidase. It’s a zinc-dependent metalloprotease that cleaves and inactivates several of these vasoactive peptides that are important in the pathogenesis and progression of heart failure. And these enzymes can include natriuretic peptides, bradykinins, substance P. But it needs to be kept in mind that Neprilysin also breaks down other substrates such as angiotensin II. Thus, because angiotensin II is a substrate, neprilysin inhibitors will also elevate angiotensin levels, and this serves as the underlying rationale for co-administration of angiotensin receptor blockers along with neprilysin inhibition. NEP inhibitors are not combined with angiotensin-converting enzyme inhibitors due to increased risk of angioedema.

Consequently, when neprilysin inhibition was tried alone, was noted to result in hypertension and anecdotal increased death rate in cardiovascular small-scale studies. When combined with ACE inhibition, neprilysin inhibition resulted in increased incidences of angioedema with the recognition that both NEP inhibition and ACE inhibition result in increased bradykinin levels, which resulted in the concept of combining NEP inhibition with angiotensin receptor blockers.

With the ability to break down ANP and BNP with NEP inhibitor, sacubitril, and also block the AT1 receptor and provides RAAS antagonism without inhibiting ACE and risking further increase in bradykinin, angiotensin receptor blocker combined with neprilysin inhibition, which was initially called as LCZ696, now known as sacubitril/valsartan, was proposed as a safer and effective alternative.

Mechanisms of Action of ARNI

ARNIs represent a new class of drugs that simultaneously block ARBs and inhibit neprilysin.

Knowledge Check Question #1

NEP inhibition alone has little effect on blood pressure because the increased concentration of potential vasodilators such as ANP, BNP, adrenomedullin, and bradykinin is counteracted by increased concentrations of which of the following two circulating vasopressors.

ANP and BNP Angiotensin II and endothelin I Angiotensin II and LCZ696 None of the above

Answer A is incorrect because ANP and BNP, atrial natriuretic peptides and brain natriuretic peptides, are not vasopressors. They are vasodilators. And ANP, BNP, and C-type natriuretic peptides constitute a natriuretic peptide system and they both bind to activate membrane-bound natriuretic peptide receptors A. And these are coupled to activate guanylyl cyclase A, which in turn increases the intracellular concentrations of cyclic GNP leading to vasodilation, natriuresis, and diuresis.

Answer B is the best choice. While there was initial optimism that NEP inhibition would be beneficial in management of patients with hypertension, studies showed modest benefit and in certain cases, increases in hypertension. While NEP inhibition increased the concentration of circulating ANP, it also increased concentration of vasodilators such as adrenomedullin and bradykinin, as well as two circulating vasopressors, namely angiotensin II and endothelin I. Thus, the right answer is elevation in the levels of angiotensin II and endothelin I. These two opposing actions neutralize each other and NEP inhibition alone therefore had nil effect on the blood pressure lowering.

Answer C is incorrect. Although angiotensin II is a circulating vasopressor, LCZ696, which is included in answer C is not a neurohormone. It was actually the name of the prototype of the compound name of the agent which is the ARNI, now named as sacubitril/valsartan that was tested in the PARADIGM-HF trial. Thus, LCZ696 is the ARNI itself and it’s not a vasopressor, and it is the ARNI prototype that was tested in the trial and is a combination of angiotensin receptor blocker and NEP inhibition.

PARADIGM-HF: Angiotensin-Nepriysin Inhibition versus Enalapril in Heart Failure

The PARADIGM-HF was a study examining the effect of angiotensin and neprilysin inhibition versus enalapril in heart failure, and was published in New England Journal of Medicine in 2014. It included patients with NYHA Class II to IV heart failure. It should be noted that only less than 1% of the patients were in NYHA Class IV heart failure status. It included patients with ejection fraction less than 35% with elevated BNP, with a BNP cutoff of over 150 pg/ml. And patients had to be on guideline-recommended use of beta-blockers mineralocorticoid receptor antagonists as a background therapy. And background therapy also included ACE inhibition or ARB, with equivalence to enalapril 10 mg per day dose for at least four weeks. The blood pressure had to be over 95 mm Hg, eGFR over 30, serum potassium less than 5.4 at randomization.

PARADIGM-HF: Run-In Before Randomization

This study had an interesting run-in period which included a single-blind run-in with enalapril, and if the patients tolerated the enalapril, subsequently then had to go through a single-blind run-in period with LCZ696. If tolerated, then were randomized. It should be noted that approximately 10% of the patients dropped out at each level of the run-in period. With LCZ696, namely ARNI, there was a significant, approximately 20% risk reduction in the combined end-point of cardiovascular death or heart failure hospitalization in heart failure with reduced EF patients when compared against enalapril. The benefits of ARNI were seen throughout a variety of endpoints when compared against enalapril including reduction in heart failure hospitalizations, all-cause mortality, heart failure deaths, sudden deaths, with significance all across the endpoints.

If we examine the adverse events with ARNI compared against enalapril, ARNI resulted in a higher incidence of hypotension, symptomatic hypotension, but not resulting in a difference in discontinuation for hypotension. The rise in creatinine and rise in potassium was higher in the enalapril group compared to LCZ696 ARNI group. Interestingly, the angioedema incidences were not different between the enalapril and the ARNI groups.

Knowledge Check Question #2

In PARADIGM-HF trial, what percentage reduction was seen in the primary endpoint of cardiovascular death or heart failure hospitalization with sacubitril/valsartan versus enalapril?

10% 20% 30% 40%

Answer B is the correct answer. In PARADIGM-HF, there was a 20% reduction in the primary endpoint of cardiovascular death or heart failure hospitalization with sacubitril/valsartan versus enalapril.

PARADIGM-HF: Other Endpoints

The package insert recommendations for dosing include the following contraindications for ARNI: Patients with hypersensitivity to ARBs or neprilysin inhibition, patients with any history of angioedema, patients with concomitant use with ACE inhibition or within 36 hours of ACE inhibition, concomitant use of aliskiren in patients with diabetes, or pregnancy, are current contraindications to ARNI use. ARNI also is not recommended in patients with severe hepatic impairment.

PARADIGM-HF: Adverse Events

The recommended starting dosage per package insert is 49/51 mg twice daily dose, or the 24/26 mg twice daily dose for patients not currently taking an ACE inhibitor or an ARB, or are on the low doses of ACE inhibition or ARB. And those can be doubled after two to four weeks as tolerated to reach a target dose of 97/103 mg twice daily. It should be noted that ACE treatment should be stopped for 36 hours before starting the treatment with ARNI and never should be concomitantly administered with ARNI. And for patients with eGFR less than 30 or patients with moderate hepatic impairment, the starting dosage of ARNI is recommended to be 24/26 mg twice daily.

Knowledge Check Question #3

You want to initiate valsartan/sacubitril in a patient currently on lisinopril 5 mg twice a day. Which of the following is the amount of time you should wait after discontinuation of ACE inhibition before starting ARNI therapy?

12 hours 24 hours 36 hours 48 hours

The correct answer is C, 36 hours, is the best choice because all ARNIs used in combination with ACE concomitantly can lead to angioedema. Therefore, simultaneous use is contraindicated and should be avoided. In former studies of NEP inhibition with concomitant ACE inhibition, which was done with omapatrilat, when studied in patients with hypertension and heart failure resulted in significant incidences of angioedema, which was associated with significant morbidity and in certain cases, tracheostomy and ICU stay. This adverse effect that was thought to occur because of both ACE inhibition and neprilysin inhibition of bradykinin breakdown, results in increased incidences of angioedema.

Package Insert Recommendations for Dosing

For this reason, the 2016 ACC/AHA/HFSA guideline update gives a class III, harm, recommendation, meaning “should not be used,” stating that ARNIs should not be administered concomitantly with ACE inhibition within 36 hours of last ACE inhibition dose. The washout period of 36 hours corresponds to the duration of approximately three times the reported elimination half-life of most ACE inhibitors.

Case 1 Presentation

A 64-year-old woman with chronic heart failure with reduced EF due to dilated cardiomyopathy and NYHA Class II symptoms presents with progressive exertional dyspnea. She was hospitalized for an acute exacerbation of systolic heart failure approximately six months ago and now presents with dyspnea on moderate exertion after climbing two flights of stairs or walking her dog two blocks. She denies any orthopnea or PND. She has mild symmetric pedal edema which has been stable. She denies any chest discomfort, palpitations, lightheadedness, or syncope. She is treated with carvedilol 25 mg twice a day, spironolactone 25 mg daily, lisinopril 5 mg twice a day, and isosorbide dinitrate/hydralazine 40/75 mg three times a day.

Knowledge Check Question #4

On exam, blood pressure is 130/80. Heart rate is 72 beats per minute. She does not have JVD, S3, or edema. BNP is 151, AST is 19, ALT is 23, creatinine is 1.1. You believe this patient is a good candidate for ARNI, and after discussion of risks, benefits, and alternatives, you want to initiate sacubitril/valsartan. Which of the following represents the starting dose of sacubitril/valsartan in this patient?

97/103 mg twice a day 49/51 mg twice a day 24/26 mg twice a day None of the above

Correct answer is C, 24/26 mg. The reason for this is the patient is only on low dose ACE inhibition. When the patient is on low dose ACE inhibitors, the starting dose is recommended to be the lower range, 24/26 mg. And if we were to examine the dosage according to renal and hepatic function, for patients who are on optimum doses of ACE inhibitors with normal renal and hepatic function, as is in this case, or mild or moderate renal impairment with eGFR over 30, or mild hepatic impairment, and if the patient were to be on modest or higher dose of ACE inhibitors, the starting dose is 49/51 mg twice daily. After two to four weeks, the dose is doubled to the target maintenance dose of 97/103 mg twice daily as tolerated by the patient.

Answer A is incorrect because this is the target maintenance dose for patients with normal renal and hepatic function, or mild or moderate renal impairment, or mild hepatic impairment, but this is not the initial starting dose. We achieve this dose after uptitrating the dose over courses of weeks.

Answer B is incorrect because this patient is not on a good dose of ACE inhibitors as a background therapy and is only on modest doses of ACE inhibition with lisinopril of 5 mg.

Recommended Starting Dose of Sacubitril/Valsartan

Let’s review the recommended starting doses according to the background medical track therapies. For patients on moderate or high doses of ACE inhibition, the initial dose is recommended to be 49/51 mg twice daily. For patients who are on low-dose ACE inhibition, as was the case in our patient, the patient is only on 5 mg of lisinopril and the initial dose is recommended to be 24/26 mg twice daily.

Similarly, low-dose angiotensin receptor blockers are recommended with a similar low dose. And very similarly, elderly patients with severe renal impairment with eGFR less than 30, moderate liver impairment, are also recommended to be initiated on the low dose of 24/26 mg twice daily dose. Patients with severe liver impairment are not recommended to be treated with ARNI at all. And patients who are ACE inhibitor or ARB naive are also recommended to be initiated on the low dose.

Case 2 Presentation

A 61-year-old African-American man with ischemic cardiomyopathy presents to your clinic seven days after discharge from his second hospitalization for acute decompensated heart failure this year. He feels well currently and has returned to his dry weight of 80 kg. He reports good adherence to a low-salt diet and to his cardiac medication regimen at discharge, which includes furosemide 80 mg daily and metoprolol succinate 50 mg daily.

His blood pressure is 121/63 mm Hg. Heart rate is 60. He has a history of angioedema due to prior ACE inhibition exposure. He endorses NYHA Class III symptoms, reveals his most recent EKG shows that he is 85% biventricularly paced, and his transthoracic echocardiogram reveals an EF of 35. His sodium is 128, potassium 5.5, creatinine is 2.7.

Knowledge Check Question #5

Which of the following medications should be added to his regimen to reduce his risk of mortality and decrease his risk for hospitalizations?

Sacubitril/valsartan Spironolactone Isosorbide mononitrate/hydralazine None of the above.

Answer C is the best choice because the 2014 ACC/AHA heart failure guidelines provides a Class I recommendation with a level of evidence A, for use of isosorbide dinitrate and hydralazine to reduce morbidity and mortality for African-American patients with Class III-IV heart failure with reduced EF, who are receiving optimum medical therapy with ACE inhibition or beta-blockers unless contraindicated.

In the A-HeFT Trial, in approximately 1000 African-American patients with reduced EF, Class III or IV heart failure, the addition of hydralazine and isosorbide dinitrate through standard therapy reduced mortality, heart failure hospitalizations, significantly improved quality of life.

Answer A is incorrect because the 2016 ACC/AHA/HFSA guideline update gives a Class III, harm, contraindication to ARNI use for patients with history of angioedema. Again, this by package insert is a contraindication and by data that we know from NEP inhibition with ACE inhibition used in hypertension and heart failure trials, namely the OVERTURE Trial with omapatrilat, there was a significant increase in angioedema risk when ARNI, namely sacubitril/valsartan, is given in concomitant fashion with ACE inhibition. So ACE inhibition is never to be used with sacubitril/valsartan or neprilysin inhibition.

In the OCTAVE Trial, a large randomized clinical trial of hypertensive patients, omapatrilat was also associated with a threefold increase of angioedema than enalapril. And interestingly in that study, we also know that lifetime smokers were particularly at risk, which raises the possibility of us to show extra caution for elderly and also for African-Americans, and inquire about the history of angioedema in all patients but especially in patients that are potentially at risk. The high incidence of angioedema ultimately led to cessation of all clinical development of omapatrilat or ARNI use in combination with ACE inhibition. And thus at current level, ARNI therapy should not be administered in any patient with history of angioedema due to the concern that it will increase the risk of recurrent angioedema.

Answer B is incorrect because aldosterone antagonists are contraindicated in patients with hyperkalemia and renal insufficiency. According to the 2013 Heart Failure Guidelines, creatinine should be less than 2.5 for men, less than 2.0 for women, or eGFR should be greater than 30, and potassium levels should be less than 5. And if we were to examine the entry criteria for the RALES trial, it included patients with creatinine less than 2.5 and majority of the patients actually had even lower creatinine than the trial inclusion criteria. And with that safeguard, the trial demonstrated efficacy with 30% reduction in all-cause mortality with spironolactone in heart failure and reduced EF patients, and also resulted in significant improvement in all-cause deaths, cardiovascular deaths, heart failure hospitalizations, with patients with heart failure with reduced ejection fraction.

The 2016 ACC/AHA/HFSA Guideline Update provides a class I recommendation for aldosterone antagonists in selective patients with chronic heart failure with reduced EF to decrease morbidity and mortality.

In the 2016 ACA/AHA/HFSA Focused Update of the 2013 Guideline for the Management of Heart Failure, what class of recommendation was given to replacement by ARNI for patients who are NYHA Class II or III, who are currently tolerating ACE inhibition or ARBs and with heart failure with reduced EF? (a) Class I recommendation, which states, “ARNI is recommended to further reduce morbidity and mortality.” (b) Class IIa recommendation stating that, “ARNI can be useful to further reduce morbidity.” (c) Class IIb, which is a weaker recommendation, which states, “ARNI can be considered to further reduce morbidity.”

The answer is A stating that it’s a class I recommendation which is a strong recommendation and is stating that, “In patients with chronic symptomatic heart failure with a reduced EF, NYHA Class II or III, who tolerate an ACE inhibition or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality.

RAAS Inhibition

For patients who currently are not on ACE inhibition or ARB, we currently have one recommendation that combines the RAAS inhibition as a strategy together. So those patients who are not currently on ACE inhibitor or ARBs, the current guidelines state the following. “The clinical strategy of inhibition of the renal angiotensin system with ACE inhibitors, or ARBs, or ARNI in conjunction with beta-blockers, aldo antagonists, in select patients is recommended for patients with chronic heart failure with reduced EF to reduce morbidity and mortality.” In essence, this recommendation that’s currently in the guidelines provides an alternative to the clinician to either consider ACE inhibition or ARB if ACE intolerant, or ARNI as an initial strategy for RAAS inhibition. And the level of recommendation, class of recommendation is class I. And the level of evidence for ACE inhibition ARB is A and for ARNI is B.

Patient With Class II or III CHF

In patients with chronic symptomatic heart failure with reduced EF, NYHA Class II or III, who would tolerate an ACE inhibition or ARB, replacement by ARNI now is recommended to further reduce morbidity and mortality. So the clinician should be aware that even though the patient may be stable on ACE inhibition or ARBs, there is currently by guidelines a recommendation to switch patients to ARNI if the patient is Class II or III and is stable and symptomatic with chronic heart failure.

It should also be noted that the guidelines emphasize that ARNI should not be administered concomitantly with ACE inhibition or within 36 hours of the last dose of an ACE inhibition. That’s a class of recommendation III, implying harm, with a level of evidence C. An ARNI should not be administered to patients with any history of angioedema. Again, that’s a class of recommendation III, with harm, with level of evidence C. This recommendation actually definitely underlines the necessity for the clinicians to inquire about history of angioedema and to document it before proceeding with prescription of an ARNI for their patients.

The clinical pearls include the following:

Inhibition of renin-angiotensin system with ACE inhibition or ARBs or ARNI in conjunction with evidence-based beta-blockers, aldosterone antagonists in selected patients, is recommended for patients with chronic heart failure with reduced EF, to reduce morbidity and mortality.

In patients with chronic symptomatic heart failure with reduced EF and NYHA Class II or III, who tolerate ACE inhibition or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality.

ARNIs should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor, and

ARNIs should not be administered to patients with any history of angioedema.

Learning Objectives