Congestive heart failure (CHF) remains a leading cause of death and expenditure in the United States, affecting approximately 6.5 million people and costing more than $30 billion annually.1,2 Despite advances in medical therapy, the 5-year survival for patients with CHF is still approximately 50%.3 The prevalence of heart failure in the United States is expected to rise 25% by 2030.2 In this review, we will discuss sacubitril/valsartan, which is showing great promise in reducing mortality and morbidity from CHF.
CHF is stratified into 2 classes based on left ventricular ejection fraction (EF). According to the American College of Cardiology (ACC) and American Heart Association (AHA), CHF with EF <40% is considered heart failure with reduced ejection fraction (HFrEF); CHF with EF >50% is considered heart failure with preserved ejection fraction (HFpEF); CHF with EF between 40% and 50% is considered borderline HFpEF.3 Some clinicians call this latter group heart failure with midrange ejection fraction (HFmrEF), adopting the terminology coined by the European Society of Cardiology (ESC).4
Irrespective of EF, there are 4 heart failure phenotypes or stages described by the AHA.3 Stage A describes those at risk for heart failure without structural heart disease seen on imaging; an example would be a patient with hypertension who has a completely normal echocardiogram.3 Stage B describes those with structural heart disease without clinical symptoms; an example would be the prior patient who now has concentric hypertrophy or reduced EF seen on echocardiogram.3 Stage C describes those with current or prior symptomatic structural heart disease that can be controlled by current therapies. Patients in this stage start having the clinical syndrome of CHF; an example would be the prior patient who now develops signs and symptoms of volume overload.3 Stage D describes those with end-stage symptomatic structural heart disease that cannot be controlled by current therapies; an example would be the prior patient who no longer responds to therapies to control CHF.3
It is important to remember that CHF is a clinical syndrome characterized by the presence of specific symptoms and signs of volume overload. Thus, only patients with Stages C or D heart failure have present or prior history of CHF. This terminology can sometimes be confusing to patients and clinicians as Stage A and B heart failure are “at-risk” phenotypes. In other words, patients with Stage A and B heart failure do not have any symptoms or signs of CHF but are at risk of developing it. Furthermore, the stages are only progressive; once a patient has Stage C heart failure, the patient’s heart failure stage does not reverse to Stage B even if the patient becomes asymptomatic. Lastly, it is only when a patient has Stage C heart failure that he or she is diagnosed with either HFrEF or HFpEF depending on the patient’s EF at the time of CHF diagnosis.
Patients with Stage C or D heart failure are further stratified into functional classes using the New York Heart Association (NYHA) classification.5 Class I is characterized by a lack of symptoms during ordinary physical activity; this means the patient has no symptoms of palpitations, fatigue, dyspnea, or chest pain at rest or with any exertion. Class II is characterized by symptoms during ordinary physical activity; this generally means the patient does have exertional symptoms but can still walk 2 blocks or up 2 flights of stairs at a normal pace without symptoms. Class III is characterized by a marked limitation of activity and symptoms that occur during less than ordinary physical activity; this generally means exertional symptoms occur with less than 2 blocks of walking or with less than 2 flights of stairs. Class IV is characterized by symptoms at rest or with any physical activity.3 NYHA functional class is determined by the clinician at each assessment of the patient and can improve or deteriorate depending upon patient symptoms.
What is the pathophysiology of heart failure and how do current medical therapies work?
Currently, it remains unclear what etiologies lead to HFpEF, which has limited the development of medical therapies to treat it.6 Much more is understood about HFrEF. The etiologies of HFrEF fall into 3 groups: those causing diseased myocardium, those causing abnormal loading conditions, and arrhythmias.7 After the initial insult to the heart, neurohumoral mechanisms govern the onset of CHF. Decreased perfusion by the heart due to reduced EF leads to activation of the renin-angiotensin-aldosterone system (RAAS) and subsequent sympathetic activation. Over time, this leads to excess fluid and sodium retention, vasoconstriction, oxidative stress, and adverse cardiac remodeling.8 Angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), β-blockers (BB), and mineralocorticoid receptor antagonists (MRA) all target different elements of the RAAS pathway to combat neurohumoral activation and have remained the mainstay of guideline-directed medical therapy for HFrEF.3
In recent years, however, it has been increasingly appreciated that RAAS is also physiologically counter-regulated by the natriuretic peptide system. Sympathetic overactivation by RAAS leads to increased atrial and ventricular wall stress, causing the release of natriuretic peptides.9 Natriuretic peptides promote vasodilation and natriuresis and are downregulated in part by neprilysin, the enzyme that degrades natriuretic peptides.9 Because neprilysin inhibitors alone have been shown to increase activation of RAAS, angiotensin receptor/neprilysin inhibitors (ARNi), which target both neprilysin and RAAS, were developed.9,10 The only ARNi currently on the market in the United States is sacubitril/valsartan.11 Sacubitril is a prodrug of the neprilysin inhibitor sacubitrilat; it is combined with the ARB valsartan to provide synergistic upregulation of the natriuretic peptide pathway and inhibition of the RAAS pathway, a dual-pronged approach to limit sympathetic activation in HFrEF.9
When do we start medications for heart failure and which ones are appropriate?
The mainstay for treating chronic HFrEF centers on treating the underlying etiology of HR, treating CHF symptoms, preventing or ameliorating ventricular remodeling with medical therapy, and controlling comorbidities.12 Certain ACEi, ARB, BB, and MRA have long been components of guideline-directed medical therapy (GDMT) for HFrEF. However, the initiation of medical therapies is recommended even earlier, once patients reach Stage B heart failure. These patients should be initiated on ACEi and BB.3 For Stage C heart failure, guidelines recommend certain BB, ACEi or ARB, and diuretics as needed.11 However, in 2017 the guidelines were updated to include the addition of ARNi as an alternative to ACEi or ARB based on a key clinical trial that showed a significant benefit in improving survival.13
Additional class I therapies depend on the patient context: for patients with NYHA Class > II meeting renal criteria, MRA are recommended; for African American patients with NYHA Class > III already on an ACEi or ARB, isosorbide dinitrate and hydralazine are recommended.11 Notably, data strongly suggest that GDMT is prescribed at much lower than the target dosages used in clinical trials; these lower dosages have been studied and shown to be less effective or ineffective in preventing cardiovascular mortality or HF hospitalizations.14,15 Thus, guidelines recommend that medications should be initiated at low doses and uptitrated every 2 weeks with monitoring of symptoms and laboratory studies until the target dosage (the dosage used in clinical trials) or maximally tolerated dosage is reached. The goal blood pressure is minimally <130/80 mm Hg and the goal heart rate is 60 to 70 bpm, but we recommend that clinicians continue to uptitrate medication doses to achieve target doses as long as the patient remains normotensive and asymptomatic.
Why consider ARNi medical therapy?
The US Food and Drug Administration approved the use of sacubitril/valsartan for HFrEF in 2015 after the publication of a key clinical trial.9,13,16 PARADIGM-HF (ClinicalTrials.gov Identifier: NCT01035255) was a double-blind, randomized, multicenter trial that included more than 8000 patients with HFrEF in nearly 50 countries and compared sacubitril/valsartan to enalapril. Patients had predominantly NYHA Class II > III symptoms, were clinically without signs of CHF, and were on stable doses of BB, ACEi, or ARB.13 Thus, the patients included in the trial were what we would consider “stable outpatients.” Furthermore, before randomization, patients had to show they could tolerate either drug through defined “run-in” time periods. This study concluded that sacubitril/valsartan significantly reduced the risk of cardiovascular death or CHF hospitalization when compared with enalapril.13
Despite the promising results of PARADIGM-HF, clinicians were slow to incorporate the drug into practice, primarily due to concerns over trial design and the comparative cost of the drug to patients relative to ACEi or ARB.17 However, with the publication of another key clinical trial in 2018 (PIONEER-HF, ClinicalTrials.gov Identifier: NCT02554890), more clinicians are now making a concerted effort to treat patients with HFrEF with sacubitril/valsartan in anticipation of continued positive results. PIONEER-HF was a double-blind, randomized, multicenter trial that included more than 800 patients with HFrEF who were hospitalized in the United States with acute decompensated CHF and had predominantly NYHA Class III > II symptoms. Thus, the patients in this study were sicker than those in PARADIGM-HF.13,18 Patients were randomly assigned to receive sacubitril/valsartan vs enalapril.18 This study found that sacubitril/valsartan significantly reduced N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels compared with enalapril.18 The safety component of the study found adverse effects were comparable among both treatment groups.18 An exploratory clinical analysis suggested a significantly lower rate of heart failure rehospitalizations in the sacubitril/valsartan group, even while initiating therapy during an acutely decompensated state.18 These data further bolstered the benefits of ARNi therapy in HFrEF and changed the perception of ARNi from a “drug viewed with a cautious eye” to the “drug of choice” relative to ACEi and, by extension, ARB.
Which patients are candidates for ARNi medical therapy?
Sacubitril/valsartan can be initiated in any patient with HFrEF with NYHA Class II or III symptoms as an alternative to an ACEi or ARB if there are no contraindications.11 Both sacubitril and valsartan are highly protein bound16; thus, both renal and hepatic impairment affect elimination time of sacubitril/valsartan and require dosage adjustment or avoidance.16 Major drug interactions occur with ACEi due to the additive effects of increasing bradykinin when both ACE and neprilysin are inhibited.16 Lastly, patients with a prior history of angioedema to ACEi or hypersensitivity to ARB may be at higher risk of developing angioedema with sacubitril/valsartan.11,19 Thus, absolute contraindications to sacubitril/valsartan use are: (a) use within 36 hours of an ACEi; (b) prior angioedema with ACEi or ARB; (c) prior hypersensitivity to ARB; (d) severe hepatic impairment; (e) pregnancy (due to potential risks to the fetus with ARB therapy); and (f) active diabetes being treated with aliskiren, due to drug interaction with ARB.12
Common adverse effects can be easily remembered as those seen with ACEi or ARB plus bradykinin-mediated effects. These include renal impairment, hyperkalemia, hypotension, angioedema, and cough.16 Notably, angioedema risk is higher in African American patients,12,16 and both PARADIGM-HF and PIONEER-HF excluded patients who had a history of ACEi-associated cough.13,18 Thus, we recommend shared decision-making in these patient populations and close monitoring if ARNi is initiated. Lastly, we also advise that patients have a robust systolic blood pressure of >100 mm Hg prior to ARNi initiation given that patients with lower blood pressures were excluded from the 2 key clinical trials.13
My patient seems to be a good candidate for ARNi therapy. How do I start therapy?
Our practice has been to initiate ARNi therapy in stable outpatients with HFrEF, an approach we adopted and modified based on the study design of PARADIGM-HF. Prior to ARNi initiation, patients should be on a stable dosage of an ACEi or ARB.12 If the patient is on an ACEi, the ACEi should be held for at least 36 hours prior to ARNi initiation.11 In real-world practice, we find it less confusing for our patients if we advise them to initiate ARNi therapy 48 hours after stopping the ACEi, and we remind them that sacubitril/valsartan is a drug that is taken twice daily. When prescribing ARNi to a patient on an ACEi, we also strongly advocate for patients to discard, hide, or seal their ACEi prescription bottle to limit potential for accidental ACEi-ARNi interactions and educate them about signs of angioedema.9,16 Once the ARB has been stopped, for patients already on an ARB, ARNi therapy can be initiated. The ACC/AHA guidelines do not recommend ARNi initiation for patients with HFrEF who have not been on an ACEi or ARB but leave it to clinicians to consider it in some patients with shared decision-making.
Though guidelines suggest ARNi should be initiated at the 49/51-mg dose, in our practice we find it more practical to advise clinicians to initiate ARNi at the 24/26-mg dose as most patients we treat have other comorbidities requiring this dose adjustment.11,12 After initiation, ARNi should be uptitrated every 2 weeks to achieve a target dose of 97/103 mg or the maximum tolerated dose that does not cause symptomatic hypotension.12 Prior to each uptitration, blood pressure, renal function, and potassium level should be checked and dosing of potentiating drugs such as loop diuretics or other antihypertensive agents should be considered.12 We find that due to the blood-pressure lowering and natriuretic effects of ARNi therapy, doses of loop diuretics can often be reduced. If it is anticipated that a patient may have uncontrolled hypertension, we advocate weekly checks and uptitration.
With the results of PIONEER-HF, in-hospital initiation of ARNi may become increasingly common. If this occurs, we advise clinicians to obtain hospital records and assess whether an ARNi was appropriately started in the inpatient setting and whether the patient continued to take it appropriately upon hospital discharge. We have discovered that some patients do not fill the prescription at their outpatient pharmacy due to an inability to afford the medication, leaving them vulnerable to rehospitalization for CHF because they are now not taking medications that target ventricular afterload.
When should I consult with a cardiologist or advanced heart failure specialist regarding ARNi therapy?
For most patients, ARNi can be safely started by internists with close monitoring. However, for patients with systolic blood pressure <110 mm Hg, moderate hepatic or renal impairment, advanced age, history of ACEi-associated cough, or NYHA Class III or IV symptoms, we would advise clinicians to consider consultation with a cardiologist or advanced heart failure specialist before initiating ARNi therapy.12 Symptomatic hypotension, worsening kidney function, hyperkalemia, or cough after initiation of ARNi therapy would be additional considerations for referral.
Otherwise, the ACC/AHA recommends that all patients with new-onset CHF be referred to a cardiologist or advanced heart failure specialist for evaluation of etiology and assistance with disease and medical management.12 Specific high-risk characteristics of CHF that clinicians should be attuned to are: greater than one CHF hospitalization in 12 months, the need to reduce doses of previously tolerated doses of GDMT, development of arrhythmias, persistent HRs > 90 bpm, persistent EF < 35%, renal disease (creatinine >1.8 mg/dL), or progression of heart failure.12 Upon referral to an advanced heart failure specialist, these patients may be considered for additional medication therapy, specific device therapies (defibrillator or resynchronization therapy), advanced therapies for heart failure (heart transplant, mechanical circulatory support/ventricular assist devices), or prognostication.12
I think my patient should be on an ARNi but my patient cannot afford it. What do I do?
The ACC/AHA have offered a framework for ways clinicians can help patients manage costs associated with treatment for CHF.12 With respect to ARNi, 2 critical pieces of this framework are considering limitations of medication coverage and a multidisciplinary approach to working with patient assistance programs.12 The ACC/AHA also have tips for prior authorization form completion and recommend price matching to help limit costs.12 They also recommend splitting tablets to limit costs when appropriate; we agree with this practice in select patients who are adherent with their treatment regimens.
In our practice, we have developed an ARNi initiation protocol and have trained our staff to assist patients who are ARNi candidates to help transition them onto ARNi therapy. First, the clinician discusses the possibility of starting ARNi therapy with a potential candidate in the outpatient clinic. During this appointment, the clinician reviews absolute contraindications, informs the patient of potential costs associated with ARNi therapy, gives specific instructions on how a transition from ACEi or ARB to ARNi would be made, and describes potential side effects of ARNi therapy. If the patient is agreeable, the clinician initiates an informal inquiry with regard to the specific cost to the patient. Staff then utilize an online open-access website, www.covermymeds.com, which reports the cost of the patient’s co-pay for sacubitril/valsartan based on the patient’s insurance information. Staff then contact the patient via phone to confirm affordability of the co-pay. If the patient considers the treatment affordable, the clinician orders the medication and the prior authorization paperwork is sent to the pharmacy. The clinician must remember to discontinue the ACEi or ARB. In the meantime, the patient is again given specific instructions over the phone about how to transition to sacubitril/valsartan once they have picked up the prescription. If the patient owns a blood pressure cuff and it is anticipated that blood pressure monitoring will be required for early titration, the patient is asked to measure his/her blood pressure for 7 days and report the measurements to our staff so that dosage adjustments can be made. Otherwise, we arrange follow-up in 2 weeks for blood pressure, renal function, and potassium checks and consideration for further uptitration by a clinician.
In cases where medication costs have been unaffordable for patients, we make a formal inquiry into our hospital’s financial assistance program and enlist the resources identified by our case manager to work with patient assistance programs that can help lower costs for patients.
CHF is a clinical syndrome with extensive morbidity and mortality requiring a dedicated multidisciplinary team consisting of an internist, a cardiologist or advanced heart failure specialist, and often trained staff to help facilitate patients getting access to optimal medications. Sacubitril/valsartan is an important new addition to GDMT for HFrEF management. Through simultaneous RAAS and neprilysin inhibition, sacubitril/valsartan has shown the ability to reduce CHF hospitalizations and cardiovascular death with a favorable safety profile.
ARNi therapy should be considered when patients are stable and tolerating an ACEi or ARB but transitioned after a minimal 36-hour washout period of any ACEi use. Titration should occur every 2 weeks to achieve target dosages, with monitoring of patients’ blood pressure, renal function, electrolytes, and symptoms of angioedema. We recommend discussion with or referral to a cardiologist when initiating ARNi in certain patients. Internists have a critical role in the lives of patients with HFrEF, including initiation and titration of GDMT to target dosing, adverse effect monitoring, coordinating multidisciplinary care including cardiology referral, and helping patients with HF navigate the costs of therapy.
1. Benjamin EJ, Muntner P, Alonso A, et al; on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56-e528.
2. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States. Circulation. 2011;123(8):933-944.
3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure. Circulation. 2013;128:e24-e327.
4. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016;18:891-975.
5. Russell SD, Saval MA, Robbins JL, et al; for the HF-ACTION Investigators. New York Heart Association functional class predicts exercise parameters in the current era. Am Heart J. 2009;158:S24-S30.
6. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2014;11:507-515.
7. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016;18:891-975.
8. Orsborne C, Chaggar PS, Shaw SM, Williams SG. The renin-angiotensin-aldosterone system in heart failure for the non-specialist: the past, the present and the future. Postgrad Med J. 2017;93:29-37.
9. Jhund PS, McMurray JJ V. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart. 2016;102:1342-1347.
10. Corti R, Burnett Jr JC, Rouleau JL, Ruschitzka F, Lüscher TF. Vasopeptidase inhibitors. Circulation. 2001;104:1856-1862.
11. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136:e137-e161.
12. Yancy CW, Januzzi JL, Allen LA, et al. 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018;71:201-230.
13. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
14. Maggioni AP, Anker SD, Dahlström U, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12 440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2013;15:1173-1184.
15. Atherton JJ, Hickey A. Expert comment: is medication titration in heart failure too complex? Card Fail Rev. 2017;3:25-32.
16. Anon. Sacubitril-valsartan: summary review.; 2015. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000SumR.pdf. Accessed July 20, 2019.
17. Sangaralingham LR, Sangaralingham SJ, Shah ND, Yao X, Dunlay SM. Adoption of sacubitril/valsartan for the management of patients with heart failure. Circ Heart Fail. 2018;11:e004302.
18. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380:539-548.
19. Brown PC. Tertiary pharmacology review. Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000PharmR.pdf. Accessed July 30, 2019.