Heart failure (HF) long ago reached epidemic proportions. There are 6.2 million people in the United States over the age of 20 with HF, and the prevalence is expected to increase to 46% by 2030. In 2016, HF was the underlying cause of death for 78,356 people. The total estimated cost of HF in 2012 was $30.7 billion (in 2010 dollars) and was projected to rise to $69.8 billion. In 2014 to2015, there were 900,000 hospital discharges for HF and 2.7 million outpatient office visits for HF.1 Clearly, HF is common, morbid, and expensive. It is also regularly encountered in the outpatient setting.

While these statistics are sobering, fortunately, significant progress has been made in treating HF over the last 30 years. Heart failure with reduced ejection fraction (HFrEF) accounts for approximately half of HF cases,2 and there are many therapies for HFrEF that are proven to improve survival and improve symptoms. These therapies arose from understanding the pathophysiology of HFrEF.

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Etiology and Pathophysiology

HFrEF has numerous causes; essentially anything that can damage the myocardium and prevent the heart from ejecting blood forward can lead to HF. Commonly, coronary artery disease, longstanding hypertension, severe valvular disease, myocarditis, and cardiomyopathy result in symptomatic HFrEF.3 These causes and the many other etiologies of HFrEF all share a decreased EF, resulting in a low stroke volume and low cardiac output. When this happens, there is activation of the renin-angiotensin-aldosterone system and neurohormonal system. Renin cleaves angiotensinogen to angiotensin I (AngI). AngI is then converted to angiotensin II (AngII) by angiotensin converting enzyme (ACE). AngII binds to the angiotensin receptor and stimulates aldosterone secretion, which causes the kidney to retain water and sodium. This results in increased preload, which is manifested as pulmonary edema, lower extremity edema, ascites, and jugular venous distension. In addition, AngII causes constriction of vascular smooth muscle cells, which increases afterload (systemic vascular resistance). This increase in afterload makes it even more difficult for a failing heart to eject blood, resulting in a vicious cycle of continued worsening of EF and cardiac performance. The initial decrease in cardiac output activates the sympathetic nervous system, leading to the release of epinephrine and norepinephrine. These catecholamines interact with alpha and beta receptors in the heart and blood vessels, causing an increase in vasoconstriction, contractility, and heart rate. These effects, while initially beneficial, are maladaptive and lead to progression of HF, worsening of EF, and ultimately death.4

To counteract the increase in preload and increase in afterload, the heart secretes hormones known as natriuretic peptides. One of the best characterized, pro B-type natriuretic peptide (BNP), is cleaved to the active form, BNP, and the inactive form, NT-proBNP: Both BNP and proBNP can be clinically measured in the blood and used as a diagnostic test in HF. BNP causes vasodilation, natiuresis, diuresis, a decrease in aldosterone level, and a decrease in sympathetic tone. All of these are salutary effects in patients with HF. Neprilysin, a neutral endopeptidase, breaks down vasoactive peptides such as BNP into inactive fragments.5


By understanding these renin-angiotensin-aldosterone systems and neurohormonal pathways, researchers have developed medications specifically for HFrEF. ACE inhibitors prevent the conversion of AngI to Ang II, while angiotensin receptor blockers (ARBs) prevent AngII from working at the level of the receptor. ACE inhibitors have been the cornerstone for HF treatment since the initial studies showing the benefits of enalapril compared with placebo.6 All ACE inhibitors have been shown to be therapeutic for HFrEF.7 If a patient has ACE inhibitor-induced cough, ARBs are useful alternatives.8 Mineralocorticoid receptor antagonists (spironolactone, eplerenone) lower blood pressure, cause diuresis, and block the deleterious effects of aldosterone. They improve survival on top of ACE inhibitors.9,10 Beta-blockers inhibit at the level of the beta receptor and similarly improve survival and symptoms of HFrEF.11 Important to note, while these medications are used in hospitalized patients, they were all studied and approved for the treatment of people with chronic HFrEF in the outpatient setting.

The angiotensin receptor-neprilysin inhibitor (ARNI) is the latest therapeutic agent that has been developed. As mentioned previously, neprilysin causes the breakdown of BNP and BNP has beneficial effects in HF. Increasing the BNP levels by inhibiting neprilysin leads to vasodilation, natiuresis, diuresis, a decrease in aldosterone level, and a decrease in sympathetic tone. However, neprilysin cannot be given in isolation, as in addition to inhibiting the breakdown of BNP, neprilysin inhibits the breakdown of multiple other molecules, chief among them AngII and bradykinin. An ACE inhibitor-neprilysin inhibitor drug was developed to simultaneously block the production of AngII and to increase BNP levels. Unfortunately, this drug caused unacceptably high rates of angioedema, as angioedema is mediated by bradykinin and ACE inhibitors, and neprilysin inhibitors both cause increase levels of bradykinin.5,12 This failure of the ACE inhibitor-neprilysin inhibitor led to the development of ARNIs. When the angiotensin receptor is blocked and neprilysin is inhibited simultaneously, the beneficial effects of increasing the BNP level are achieved, while the deleterious effects of high AngII levels are prevented.

Clinical Trial Results

The first-in-class ARNI, LCZ696, has been given the generic name sacubitril/valsartan. Sacubitril/valsartan was studied in the landmark PARADIGM-HF trial.13 This is the largest HF trial ever performed, and it compared the standard ACE inhibitor, enalapril vs sacubitril/valsartan: 8442 outpatients with symptomatic HFrEF (New York Heart Association [NYHA] Class II-IV) with an EF ≤40% were enrolled. Patients were grouped randomly to receive enalapril twice daily or sacubitril/valsartan twice daily. The primary endpoint was the composite of death from cardiovascular causes or hospitalization for HF. The trial was designed to have enough power to detect a difference in death from cardiovascular causes.

The average age of the patients in the trial was 63 years old and 21% of the participants were women. Average blood pressure was 122/72 mm Hg and average EF was 29%; 94% of patients had NYHA Class II-III HFrEF. Patients in the trial had excellent background medical therapy for HFrEF: 100% of patients were on an ACE inhibitor or ARB prior to enrollment, while 93% were on a beta-blocker, 80% were on a diuretic, and 54% were on a mineralocorticoid receptor antagonist. The trial was stopped early after a median follow-up of 27 months because sacubitril/valsartan met the prespecified stopping endpoint for an overwhelming benefit. The primary endpoint of death from cardiovascular causes or hospitalization for HF occurred in 21.8% of the patients who received sacubitril/valsartan compared with 26.5% of patients who received enalapril (hazard ratio [HR] 0.80; 95% CI, 0.73-0.87; P <0.001). Death from cardiovascular cause was 13.3% in the sacubitril/valsartan group vs 16.5% in the enalapril group (HR 0.80; 95% CI, 0.71-0.89; P <0.001). Hospitalization for HF improved substantially as well, with 12.8% for sacubitril/valsartan vs 15.6% for enalapril (HR 0.79; 95% CI, 0.71-0.89; P <0.001). All of these outcomes have a 20% lower event rate favoring sacubitril/valsartan. Death from any cause was 16% lower with sacubitril/valsartan compared with enalapril (95% CI, 0.76-0.93; P <0.001).

The overwhelming strength of the data from PARADIGM-HF in favor of sacubitril/valsartan is magnified when one considers the actual P value for the primary endpoint is .0000004. This means that there is a less than a 1 in 1 million chance that the findings of the trial are not reproducible and are instead just due to chance alone.14 Number-needed-to-treat was calculated and only 21 patients needed to be treated with sacubitril/valsartan instead of enalapril to prevent one death or one HF hospitalization.13 By switching an ACE inhibitor or ARB to an ARNI, it is estimated that >20,000 deaths could be prevented each year in the United States.15 Thirty-day readmission to the hospital for any cause was reduced by 26% for patients receiving sacubitril/valsartan as compared with enalapril. Rates of readmission for HF at 30 days was 38% lower for patients receiving sacubitril/valsartan compared with enalapril. This is a huge improvement in a readmission rate that any health care system would love to have.16 In addition to mortality and hospitalizations, health-related quality of life is also substantially improved with sacubitril/valsartan compared with enalapril.17 The American College of Cardiology/American Heart Association 2017 guideline update for the management of HF gives a Class I recommendation for the use of an ARNI to replace an ACE inhibitor or ARB to further reduce morbidity and mortality in patients who are in the NYHA Class II-III HFrEF.18

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Adverse Events

Sacubitril/valsartan had a similar adverse event profile compared with enalapril in terms of renal impairment and hyperkalemia. Hypotension was more common in patients who received sacubitril/valsartan, although the systolic blood pressure was only 3 mm Hg lower than in those patients who received enalapril. More patients who received enalapril had cough compared with those who received sacubitril/valsartan. Angioedema requiring steroids, catecholamines, or hospitalization only occurred in 14 patients in the entire trial with no difference between sacubitril/valsartan and enalapril.13 Thus, sacubitril/valsartan is safe and well tolerated.

Sacubitril/Valsartan Use in the Primary Care Setting

How does one identify a “good patient” and initiate sacubitril/valsartan in a busy primary care clinic? The first step is recognizing a patient has symptomatic HFrEF. Many people with HFrEF limit their activity to avoid dyspnea or fatigue and say they do not have symptoms. However, simple questions, such as how many blocks can a patient walk or if they can climb a flight of stairs or how much walking they do at the mall or supermarket, usually elicits a patient who is symptomatic and thus would qualify for sacubitril/valsartan. If they are already on an ACE inhibitor or ARB, the patient is likely to be a good candidate. If patients are not on an ACE inhibitor or ARB, if there is no contraindication to these medications (renal failure, hyperkalemia, hypotension, or history of angioedema), they would also be a good candidates.15 If patients have low or marginal blood pressure (systolic <100 mm Hg), they might not tolerate sacubitril/valsartan, so these patients would be best left for a cardiologist to initiate the medication if it is appropriate. For patients on an ACE inhibitor, they need to stop the ACE inhibitor for 36 hours to allow the medication to wash out of their system before starting sacubitril/valsartan. Practically speaking, to make it easier for patients, I instruct them to stop the ACE inhibitor for 2 days and then to start the ARNI. If patients are on an ARB, they can start the ARNI the next day and do not need a washout period. Patients on a low total daily dose of enalapril (≤10 mg), lisinopril (≤10 mg), ramipril (≤5 mg) or other low-dose ACE inhibitor should receive the low dosage of sacubitril/valsartan (24/26 mg twice daily). Patients receiving a total daily dose >10 mg enalapril, >10 mg lisinopril, >5 mg ramipril, or other medium-high dose of an ACE inhibitor, should receive the medium dose of sacubitril/valsartan (49/51 mg twice daily). The dose should be increased every 2 to 4 weeks as tolerated to reach the target dose of 97/103 mg twice daily.19

Just as with ACE inhibitors or ARBs,3 renal function and potassium should be checked every 1 to 2 weeks and periodically after initiation of or titration of the sacubitril/valsartan dose. If hypotension or orthostasis develops in a patient started on sacubitril/valsartan, this can often be handled by discontinuing any less than ideal antihypertensive medications for a person with HFrEF (calcium channel blockers) or lowering the dosage of the patient’s loop diuretic (eg, furosemide).15 Recall that sacubitril/valsartan, by increasing levels of BNP, causes diuresis. As a result, a lower dose of a loop diuretic may be appropriate if the patient has no evidence of volume overload. Usually, side effects of sacubitril/valsartan resolve within 14 days, especially if patients can take some of their medications at bedtime or stagger medications that are taken twice daily. If hypotension persists, a dose reduction of sacubitril/valsartan may be required. This is preferable to discontinuation of the medication as patients treated with a lower dose of sacubitril/valsartan had a 20% reduced risk for cardiovascular death or HF hospitalization compared with those taking lower-dose enalapril.20


ACE inhibitors and ARBs have been the initial drugs and standard of care for people with HFrEF for decades. There is a large amount of clinical trial data and real-world data showing their benefit. However, with the overwhelming results of the PARADIGM-HF trial and other data, the paradigm of using ACE inhibitors or ARBs should be shifted to using ARNIs for those with HFrEF. Use of sacubitril/valsartan further reduces all-cause mortality, cardiovascular mortality, and hospitalizations, and improves quality of life beyond the benefit of an ACE inhibitor. This happens by replacing an HF medication with another HF medication, not by adding on a new medication on top of the current regimen. Patients with symptomatic HFrEF even outpatients with clinically stable disease who appear to be doing well, have high morbidity and mortality. It behooves primary care physicians who practice guideline-driven, evidence-based medicine to familiarize themselves with sacubitril/valsartan and incorporate this life-saving medication into their practice.


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