Sacubitril; Valsartan

What it is

Sacubitril/valsartan is a single tablet containing two different medicines in fixed proportions. Sacubitril is a prodrug whose active metabolite, LBQ657, blocks the enzyme neprilysin; valsartan blocks the angiotensin II type-1 receptor. It is a prescription-only medicine, sold as Entresto, and appears in the pivotal trials under the development code LCZ696. It is not a nutrient or a supplement and is not present in food.

What the research says

The evidence is strong for one specific situation and weak or absent for the others. In chronic heart failure with a reduced ejection fraction, a single large trial of 8,442 people (PARADIGM-HF) found fewer cardiovascular deaths and heart-failure hospitalisations than with enalapril, with an absolute difference of about 4.7 percentage points over a median 27 months. In heart failure with an ejection fraction of 45% or higher (PARAGON-HF) the primary outcome did not reach statistical significance, and after a heart attack (PARADISE-MI) it was no better than ramipril. The price is more low blood pressure and a small excess of angioedema.

Evidence grade: Well established.

How it works

Drug class: Angiotensin receptor-neprilysin inhibitor (ARNI): a fixed-dose combination of the neprilysin inhibitor prodrug sacubitril and the angiotensin II receptor blocker valsartan

The tablet does two things at once. Valsartan blocks the receptor that angiotensin II acts on, so blood vessels relax and the body retains less salt and water. Sacubitril's active metabolite blocks neprilysin, the enzyme that breaks down natriuretic peptides, so those peptides last longer and promote salt and water loss and vessel relaxation. The combination is used because blocking neprilysin alone also raises angiotensin II. (Source 1)

Boxed warning

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue ENTRESTO as soon as possible (5.1) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1)

(Source 2)

What it is used for

• In the 8,442-patient PARADIGM-HF trial, sacubitril/valsartan beat enalapril on cardiovascular death or heart-failure hospitalisation (21.8% vs 26.5%) and on death from any cause (17.0% vs 19.8%). This is the one use supported by a positive mortality outcome trial. Evidence: established. (Source 3)
• PARAGON-HF randomised 4,822 such patients against valsartan and missed its primary outcome (rate ratio 0.87, 95% CI 0.75 to 1.01, P = 0.06). The US label nonetheless covers chronic heart failure broadly while saying benefit is clearest when ejection fraction is below normal. Evidence: disputed. (Source 4)
• PIONEER-HF (881 patients) showed a larger fall in NT-proBNP than enalapril with no difference in worsening renal function, hyperkalaemia, symptomatic hypotension or angioedema. NT-proBNP is a blood marker, not an outcome such as death or readmission. Evidence: limited. (Source 5)
• The US label states the paediatric approval rests on a reduction in NT-proBNP and an expectation of improved cardiovascular outcomes, not on a completed paediatric outcome trial. We did not retrieve the paediatric trial itself. Evidence: limited. (Source 6)
• PARADISE-MI randomised 5,661 patients against ramipril. The primary outcome occurred in 11.9% versus 13.2% (hazard ratio 0.90, 95% CI 0.78 to 1.04, P = 0.17), so the trial did not show a benefit. Evidence: not-supported. (Source 7)
• A 114-patient, 52-week randomised comparison against olmesartan found a greater fall in left ventricular mass index but no difference in local aortic distensibility. Left ventricular mass is a surrogate; no hypertension outcome trial of sacubitril/valsartan was found. Evidence: limited. (Source 8)

Interactions

• ACE inhibitors (for example enalapril, ramipril, lisinopril) (label): Taking both together is contraindicated because the risk of angioedema - swelling of the lips, tongue or airway - rises. The label requires a 36-hour gap when switching from an ACE inhibitor. (Source 9)
• Potassium supplements and potassium-containing salt substitutes (and potassium-sparing diuretics such as spironolactone, triamterene, amiloride) (label): Blood potassium can rise. Hyperkalaemia was reported in 12% of people on sacubitril/valsartan in PARADIGM-HF even without these additions, so added potassium compounds the effect. (Source 9)
• Potassium-rich low-sodium salt substitutes used in cooking (label): The same potassium problem arises from food-grade salt substitutes, which are often potassium chloride. The label names them explicitly alongside potassium supplements. (Source 9)
• Non-steroidal anti-inflammatory drugs including ibuprofen, naproxen and COX-2 inhibitors (label): Kidney function can worsen, particularly in older people, those who are volume-depleted or on a diuretic, or whose kidney function is already reduced. (Source 9)
• Lithium (label): Lithium levels can rise, with a risk of lithium toxicity. The label flags this as a monitoring issue. (Source 9)
• Aliskiren (label): Combining two drugs that block the renin-angiotensin system is contraindicated in people with diabetes and is to be avoided when kidney function is reduced. (Source 9)

Stopping it

• The label requires a 36-hour washout when switching from an ACE inhibitor to sacubitril/valsartan, because overlapping the two raises the risk of angioedema. (Source 10)
• The boxed warning directs that the drug be stopped as soon as pregnancy is detected, because drugs acting on the renin-angiotensin system can injure or kill the developing fetus. (Source 2)
• The only randomised evidence on deliberately withdrawing heart-failure drug treatment, in 51 people whose dilated cardiomyopathy had apparently recovered, found relapse in 11 of 25 (44%) within six months against none of those who continued; the authors concluded treatment should continue indefinitely until predictors of relapse are known. This trial withdrew heart-failure therapy as a whole, not sacubitril/valsartan specifically. (Source 11)
• There is no withdrawal syndrome or dependence described for sacubitril/valsartan in the sources we read; the risk of stopping is the return of the underlying heart failure, not drug withdrawal. (Source 11)

What goes wrong

In PARADIGM-HF more people on sacubitril/valsartan had low blood pressure and non-serious angioedema, while fewer had kidney impairment, raised potassium and cough than on enalapril. (Source 3)

• Randomized trial, High certainty.
• Size: 8,442 participants.
• Who: Adults with HFrEF.
• How long: Median 27 months.
• Result: Label tabulation of the same trial: hypotension 18% vs 12%, hyperkalaemia 12% vs 14%, cough 9% vs 13%, dizziness 6% vs 5%; angioedema 0.5% vs 0.2% overall and 2.4% vs 0.5% in Black participants.
• Funding: industry-funded (Novartis)

The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.

Angioedema was about twice as common on sacubitril/valsartan as on enalapril in PARADIGM-HF, and markedly more common in Black participants. (Source 12)

• Official position, Moderate certainty.
• Size: 4,203 treated with sacubitril/valsartan vs 4,229 on enalapril.
• Who: PARADIGM-HF double-blind period.
• How long: Median exposure 24 months.
• Result: Angioedema 0.5% vs 0.2%; in Black patients 2.4% vs 0.5%. Orthostasis 2.1% vs 1.1%, falls 1.9% vs 1.3%.
• Funding: not stated (manufacturer label text)

In the double-blind period, the incidence of angioedema was higher in patients treated with ENTRESTO than enalapril (0.5% and 0.2%, respectively). The incidence of angioedema in Black patients was 2.4% with ENTRESTO and 0.5% with enalapril

When heart-failure drug treatment was deliberately withdrawn in people whose dilated cardiomyopathy appeared to have recovered, almost half relapsed within six months. (Source 11)

• Randomized trial, Low certainty.
• Size: 51 participants.
• Who: Adults with previous dilated cardiomyopathy, now asymptomatic, ejection fraction recovered to 50% or more, normalised left ventricular volume and NT-proBNP below 250 ng/L.
• How long: 6 months, then crossover withdrawal in the control group.
• Result: 11 of 25 (44%) relapsed on withdrawal versus none of 26 who continued (Kaplan-Meier event rate 45.7%, 95% CI 28.5 to 67.2; P=0.0001); nine further relapses after the control group also withdrew.
• Funding: independent (British Heart Foundation and charitable/academic funders)

11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001)

What the evidence supports

In chronic heart failure with reduced ejection fraction, sacubitril/valsartan reduced cardiovascular death or heart-failure hospitalisation compared with enalapril, an absolute difference of about 4.7 percentage points. (Source 3)

• Randomized trial, High certainty.
• Size: 8,442 participants.
• Who: Adults with NYHA class II-IV heart failure and an ejection fraction of 40% or less, on recommended background therapy, who tolerated sequential enalapril and LCZ696 run-ins.
• How long: Median follow-up 27 months; trial stopped early for benefit.
• Result: Primary composite 914/4,187 (21.8%) vs 1,117/4,212 (26.5%); hazard ratio 0.80 (95% CI 0.73 to 0.87), P<0.001. Absolute risk reduction about 4.7 percentage points, roughly 21 people treated for 27 months to avoid one event.
• Funding: industry-funded (Novartis)

the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001)

In the same trial, all-cause death was lower with sacubitril/valsartan than enalapril, 17.0% versus 19.8%. (Source 3)

• Randomized trial, High certainty.
• Size: 8,442 participants.
• Who: As above.
• How long: Median 27 months.
• Result: 711 (17.0%) vs 835 (19.8%) deaths; hazard ratio 0.84 (95% CI 0.76 to 0.93), P<0.001. Absolute difference about 2.8 percentage points.
• Funding: industry-funded (Novartis)

A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001)

Starting sacubitril/valsartan in hospital after acute decompensated heart failure lowered NT-proBNP more than enalapril, with no measured safety penalty, but the trial measured a blood marker and not clinical outcomes. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 881 participants.
• Who: Adults hospitalised with acute decompensated heart failure and reduced ejection fraction, after haemodynamic stabilisation, at 129 US sites.
• How long: 8 weeks.
• Result: Time-averaged NT-proBNP change -46.7% vs -25.3%; ratio of change 0.71 (95% CI 0.63 to 0.81), P<0.001.
• Funding: industry-funded (Novartis)

the ratio of the geometric mean of values obtained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril-valsartan group as compared with 0.75 in the enalapril group (percent change, -46.7% vs. -25.3%; ratio of change with sacubitril-valsartan vs. enalapril, 0.71; 95% confidence interval [CI], 0.63 to 0.81; P<0.001)

What the evidence does not support

In heart failure with an ejection fraction of 45% or higher, sacubitril/valsartan did not significantly reduce total heart-failure hospitalisations and cardiovascular death compared with valsartan. (Source 4)

• Randomized trial, High certainty.
• Size: 4,822 participants.
• Who: Adults with NYHA class II-IV heart failure, ejection fraction 45% or higher, raised natriuretic peptides and structural heart disease.
• How long: Median follow-up about 35 months.
• Result: 894 primary events in 526 patients vs 1,009 in 557; rate ratio 0.87 (95% CI 0.75 to 1.01), P = 0.06. Cardiovascular death 8.5% vs 8.9% (hazard ratio 0.95, 95% CI 0.79 to 1.16). Mean KCCQ clinical summary score 1.0 point higher (95% CI 0.0 to 2.1).
• Funding: industry-funded (Novartis)

Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher.

After acute myocardial infarction, sacubitril/valsartan was not better than ramipril for cardiovascular death or new heart failure. (Source 7)

• Randomized trial, High certainty.
• Size: 5,661 participants.
• Who: Adults with myocardial infarction complicated by reduced ejection fraction, pulmonary congestion, or both.
• How long: Median 22 months.
• Result: 338 (11.9%) vs 373 (13.2%) primary events; hazard ratio 0.90 (95% CI 0.78 to 1.04), P = 0.17. Death from any cause 7.5% vs 8.5% (hazard ratio 0.88, 95% CI 0.73 to 1.05).
• Funding: industry-funded (Novartis)

a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17)

Where the evidence is mixed

Pooling five randomised trials, angioedema was uncommon and the difference from control did not reach statistical significance. (Source 13)

• Meta-analysis, Low certainty.
• Size: 14,841 patients across 5 randomised controlled trials.
• Who: Heart failure trial populations.
• How long: Follow-up 2 to 27 months.
• Result: 0.5% vs 0.3%; pooled odds ratio 1.35 (95% confidence interval 0.45 to 4.1), P = .59, with moderate heterogeneity (I2 55.2%). The paper also reports 426 angioedema cases among 40,559 adverse-event reports in the US FAERS database over five years.
• Funding: not stated.

Limit of this finding: The quote reproduces two printing faults in the published paper. The confidence interval appears as "95% confidence interval - 0.45 to 4.1": the dash there is a separator between the two bounds, not a minus sign, so the interval runs from 0.45 to 4.1. A negative lower bound would be impossible for an odds ratio. The heterogeneity figure is printed as "I2 55.2.%" with a stray extra full stop; the value is 55.2%. Read as published: the pooled odds ratio of 1.35 has a confidence interval that spans 1, so this analysis does not show that sacubitril/valsartan raises angioedema risk, and it is too imprecise to rule a difference out either.

The collective rate of angioedema in RCTs was 0.5% in sacubitril/valsartan arms vs. 0.3% in control arms (pooled odds ratio of 1.35; 95% confidence interval - 0.45 to 4.1; P = .59) with moderate heterogeneity (I2 55.2.%).

In hypertension, sacubitril/valsartan reduced left ventricular mass index more than olmesartan over a year, but did not change local aortic distensibility. (Source 8)

• Randomized trial, Low certainty.
• Size: 114 participants (57 per group)
• Who: Adults with hypertension and elevated pulse pressure, mean age 59.8 years, 67.5% male.
• How long: 52 weeks.
• Result: Left ventricular mass index -6.36 vs -2.32 g/m2 at 12 weeks (P = 0.039) and -6.83 vs -3.55 g/m2 at 52 weeks (P = 0.029); no significant difference in local distensibility; larger reduction in central pulse pressure (P = 0.010)
• Funding: not stated.

Left ventricular mass index decreased to a greater extent in the sacubitril/valsartan group compared to the olmesartan group from baseline to 12 weeks (-6.36 vs. -2.32 g/m2; P = 0.039) and from baseline to 52 weeks (-6.83 vs. -3.55 g/m2; P = 0.029).

Where the research disagrees

Whether sacubitril/valsartan should be used in heart failure with a preserved ejection fraction

• PARAGON-HF investigators (2019), A 4,822-patient randomised double-blind trial whose primary outcome narrowly missed significance (P = 0.06): "Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher." (Source 4)
• US labelling for ENTRESTO (Novartis, revised April 2024), A regulatory position that widens the indication beyond reduced ejection fraction while hedging on where benefit is clearest: "ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal." (Source 6)

How much

• Reference intake: There is no reference intake for a prescription medicine; the dose is set by the prescriber. As a position, the US label states a starting dose for adults of 49/51 mg twice daily, doubled after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily as tolerated (DailyMed label for ENTRESTO, Novartis, revised April 2024). (Source 10)
• Upper limit: No upper limit is set by a nutrition body. The label's highest adult dose is the target maintenance dose of 97/103 mg twice daily (DailyMed label for ENTRESTO, Novartis, revised April 2024). (Source 10)
• Studied: PARADIGM-HF gave LCZ696 200 mg twice daily (equivalent to 97/103 mg) against enalapril 10 mg twice daily, after run-in periods on both drugs. (Source 3)
• Studied: PARAGON-HF targeted 97 mg sacubitril with 103 mg valsartan twice daily against valsartan 160 mg twice daily. (Source 4)
• Studied: PIONEER-HF targeted 97 mg sacubitril with 103 mg valsartan twice daily against enalapril 10 mg twice daily, started in hospital. (Source 5)
• Studied: PARADISE-MI gave 97 mg sacubitril and 103 mg valsartan twice daily against ramipril 5 mg twice daily. (Source 7)

A common belief, and what the research shows

The belief: Entresto is a better drug for heart failure, full stop - so it should help whatever kind of heart failure you have.

What the research shows: The benefit is specific to reduced ejection fraction. PARADIGM-HF reported that "LCZ696 was superior to enalapril" in that population, with the primary outcome in 21.8% versus 26.5%. In preserved ejection fraction PARAGON-HF concluded that "Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher." After a heart attack, PARADISE-MI concluded it "was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril". Three trials, one clear win.

Questions and answers

What is it?

Sacubitril/valsartan is one tablet holding two medicines: sacubitril, which blocks an enzyme called neprilysin, and valsartan, an angiotensin receptor blocker. It is sold as Entresto and appears in trials as LCZ696. It is a prescription heart-failure medicine, not a nutrient, and nothing you eat contains it. (Source 1)

What does it do in the body?

Valsartan blocks the receptor angiotensin II acts on, which relaxes blood vessels and reduces salt and water retention. Sacubitril's active metabolite blocks neprilysin, the enzyme that destroys natriuretic peptides, so those peptides persist and help the body shed salt and water and keep vessels relaxed. Working on both pathways at once is the point of combining them. (Source 1)

Is it good or bad for you?

It depends entirely on which heart failure. In reduced ejection fraction it is one of the few drugs with a mortality benefit in a large trial: 21.8% of people had a cardiovascular death or heart-failure hospitalisation versus 26.5% on enalapril. In preserved ejection fraction and after a heart attack the trials did not show a benefit. In every setting it causes more low blood pressure than the comparator and a small excess of angioedema, which is higher in Black patients. (Source 3)

How do you get more of it?

It is available only on prescription. The label's adult schedule starts at 49/51 mg twice daily and doubles after two to four weeks to a target of 97/103 mg twice daily if tolerated; lower starting doses apply to some people. There is no food, drink or over-the-counter product that provides it, and this is not a recommendation about dose. (Source 10)

If it is harmful, what reduces it?

It is removed by stopping it, which is a decision for the prescriber. The one circumstance where the label demands immediate discontinuation is pregnancy. Stopping it does not cause a withdrawal syndrome, but withdrawing heart-failure medication can let the heart failure return, so it is not a drug to stop on your own. (Source 2)

Why might someone be low in it or missing it?

Someone may not be on it, or may be on a lower dose than the trials used, because of its side effects. In the PARADIGM-HF run-in period, before randomisation even started, 10.4% of people stopped the drug, 5.9% because of an adverse event - most often kidney dysfunction, low blood pressure and raised potassium. It is also contraindicated with an ACE inhibitor, in a history of angioedema and in pregnancy. (Source 14)

Which whole foods contain it or feed it?

Does not apply. No whole food contains sacubitril or valsartan, and nothing in the diet produces them. The dietary issue runs the other way: potassium-containing salt substitutes - the low-sodium salts sold for cooking - are named in the label as something that can push blood potassium up when combined with this drug. (Source 9)

What happens if you do not have it?

Nothing happens from lacking the drug itself, because it is not something the body needs. What matters is the untreated or less-treated heart failure. In PARADIGM-HF 26.5% of people on enalapril, the active comparator, had a cardiovascular death or heart-failure hospitalisation over a median 27 months. And when heart-failure drugs were deliberately withdrawn from people who appeared recovered, 44% relapsed within six months against none of those who kept taking them. (Source 11)

How can you test for it?

There is no blood test of sacubitril or valsartan levels used in practice, and none is needed. What gets measured instead is blood pressure, serum potassium and kidney function for safety, and in trials the blood marker NT-proBNP, which the drug lowers - the paediatric approval rests on that marker. One practical catch: sacubitril raises BNP itself, so NT-proBNP rather than BNP is the marker used while on this drug. (Source 6)

References

1. Novartis Pharmaceuticals Corporation, via DailyMed (US FDA structured product label). ENTRESTO (sacubitril and valsartan) tablet, film coated - Clinical Pharmacology, Mechanism of Action. 2024. Read the source
2. Novartis Pharmaceuticals Corporation, via DailyMed (US FDA structured product label). ENTRESTO (sacubitril and valsartan) tablet, film coated - boxed warning. 2024. Read the source
3. New England Journal of Medicine. Angiotensin-neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). 2014. PMID 25176015, DOI 10.1056/NEJMoa1409077. Read the source
4. New England Journal of Medicine. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction (PARAGON-HF). 2019. PMID 31475794, DOI 10.1056/NEJMoa1908655. Read the source
5. New England Journal of Medicine. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure (PIONEER-HF). 2019. PMID 30415601, DOI 10.1056/NEJMoa1812851. Read the source
6. Novartis Pharmaceuticals Corporation, via DailyMed (US FDA structured product label). ENTRESTO (sacubitril and valsartan) tablet, film coated - Indications and Usage. 2024. Read the source
7. New England Journal of Medicine. Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction (PARADISE-MI). 2021. PMID 34758252, DOI 10.1056/NEJMoa2104508. Read the source
8. European Heart Journal. The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension. 2017. PMID 29029087, DOI 10.1093/eurheartj/ehx525. Read the source
9. Novartis Pharmaceuticals Corporation, via DailyMed (US FDA structured product label). ENTRESTO (sacubitril and valsartan) tablet, film coated - Drug Interactions. 2024. Read the source
10. Novartis Pharmaceuticals Corporation, via DailyMed (US FDA structured product label). ENTRESTO (sacubitril and valsartan) tablet, film coated - Dosage and Administration. 2024. Read the source
11. The Lancet. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF). 2019. PMID 30429050, DOI 10.1016/S0140-6736(18)32484-X. Read the source
12. Novartis Pharmaceuticals Corporation, via DailyMed (US FDA structured product label). ENTRESTO (sacubitril and valsartan) tablet, film coated - Adverse Reactions. 2024. Read the source
13. International Journal of Cardiology. Angioedema with sacubitril/valsartan: Trial-level meta-analysis of over 14,000 patients and real-world evidence to date. 2021. PMID 32841619, DOI 10.1016/j.ijcard.2020.08.067. Read the source
14. Novartis Pharmaceuticals Corporation, via DailyMed (US FDA structured product label). ENTRESTO (sacubitril and valsartan) tablet, film coated - Adverse Reactions, run-in period discontinuations. 2024. Read the source