Review of the Chronic Heart Failure Combination Drug Sacubitril and Valsartan (ENTRESTO)

In the U.S., about 6.2 million adults suffer from heart failure, a serious condition most common in older adults that often requires hospitalization and can lead to death.[1],[2] Along with lifestyle changes (such as diet and exercise), physicians often treat heart failure by prescribing one or more medications, including angiotensin-converting enzyme (ACE) inhibitors, such as enalapril (EPANED, VASERETIC, VASOTEC); angiotensin receptor blockers (ARBs), such as valsartan (DIOVAN); beta-blockers, such as metoprolol (KAPSPARGO SPRINKLE, TOPROL-XL); diuretics (water pills); or digoxin (LANOXIN).[3]

ENTRESTO, one of the newest drugs for treating heart failure, has two components: sacubitril, a neprilysin inhibitor, which removes sodium (salt) from the blood; and the ARB valsartan, which helps the heart pump blood by relaxing blood vessels.[4] This combination is an alternative to treatment with ACE inhibitors or ARBs for certain heart failure patients.[5]

In 2015, Entresto was approved by the Food and Drug Administration (FDA) for adult patients who suffer from a type of heart failure that results in an abnormally reduced ejection fraction (a measure of the heart’s pumping function). The approval was expanded in 2021 to include adult heart failure with preserved (normal) ejection fraction. Although the drug is now approved for both types of heart failure, the FDA notes that Entresto is most beneficial for patients with heart failure with reduced ejection fraction.[6]

Given the risks associated with Entresto, Public Citizen’s Health Research Group has classified it as Limited Use, to be used only in adults with heart failure with reduced ejection fraction. Although this drug also has been approved for children with heart failure with reduced ejection fraction, we have not reviewed it for this patient group.

What is heart failure?

With each heartbeat, the lower heart chambers (ventricles) pump blood throughout the body when they contract and refill with blood once they relax. Heart failure occurs when the ability of the heart to pump or relax is compromised, resulting in decreased delivery of blood to the body.[7]

For about half of heart failure patients,[8] the proportion of blood the heart can pump from the filled left lower chamber (also called the “ejection fraction”[9]) is decreased. This is called “heart failure with reduced ejection fraction” (also “systolic heart failure”).[10]

For the other half of patients, the lower heart chambers are stiff and do not refill enough for the heart to pump out the necessary amount of blood. This is referred to as “heart failure with preserved ejection fraction” (or “diastolic heart failure”).[11]

Evidence on effectiveness

The FDA based its approval of Entresto for treating patients with reduced ejection fraction on a randomized, double-blind trial involving 8,442 subjects that compared Entresto to the ACE inhibitor enalapril. Patients taking Entresto were significantly less likely to die from cardiovascular causes (13%) than those taking the ACE inhibitor (17%), and fewer patients taking Entresto (13%) were hospitalized for heart failure than those in the other group (16%).[12]

For the additional approval for patients with heart failure with preserved ejection fraction, the FDA based its decision on a randomized, double-blind trial involving 4,822 subjects who were given either Entresto or only valsartan, one of its two components. For patients with this type of heart failure, Entresto did not significantly lower the rate of hospitalizations for heart failure and death from cardiovascular causes compared with valsartan alone.[13]

Important adverse effects

Entresto has several risks that also are seen frequently with ACE inhibitors and ARBs, discussed in more detail below. However, hypotension (low blood pressure) and a rare but potentially life-threatening allergic reaction called angioedema are of particular concern with this medication.[14],[15]

In the trial that evaluated Entresto in subjects with reduced ejection fraction, 78% of subjects were male and only 5% were Black.[16] The paucity of Black subjects is of particular concern, as angioedema due to ACE inhibitors and ARBs is more common in Black patients. In addition, about half of the subjects were 65 years of age or younger, and about three-fourths were not yet suffering from severe heart failure symptoms.[17] Several types of patient groups — most notably those who were suffering from low blood pressure or had a history of angioedema — were also excluded from the trial. Such factors together likely resulted in underestimates of the risk of adverse events due to Entresto.[18] The trial that assessed Entresto in subjects with heart failure with preserved ejection fraction had similar issues.[19]

Angioedema[20],[21],[22]

Both clinical trials showed that Entresto raises the risk of angioedema, a sudden swelling of the face, lips, tongue and throat that can make breathing difficult. It is more common in Black patients, as well as when Entresto is used in combination with an ACE inhibitor.

Hypotension[23],[24]

Entresto can cause low blood pressure, particularly for older patients or patients who are already taking high doses of diuretics.

Hyperkalemia[25],[26]

Like ACE inhibitors and ARBs, Entresto may cause dangerously high blood potassium levels, which can lead to abnormal heart rhythms. Patients with severe kidney failure or diabetes are particularly at risk.

Renal impairment[27],[28]

Patients taking heart failure drugs like Entresto are at a higher risk of kidney failure, especially when they are taking nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (ADVIL, MOTRIN), at the same time.

Pregnancy warnings[29]

The label for sacubitril/valsartan also includes an FDA-required black-box warning — the agency’s most prominent warning — that the drug can cause harm to fetuses during pregnancy. As soon as a pregnancy is detected, the drug should be discontinued.

What You Can Do

You should only consider taking Entresto if you have heart failure with reduced ejection fraction. Before taking Entresto for this approved indication, discuss with your doctor whether this drug is right for you. For example, if you are over 65 years of age or already have heart failure symptoms that limit your physical activity, this medication may not be as safe and effective for you.

Tell your doctor if you have kidney or liver problems and about all the medications and supplements you are taking. It is especially important for your doctor to know if you are taking NSAIDs, potassium supplements or a salt substitute.

Do not take Entresto if you have a history of angioedema; are already taking another ACE inhibitor, ARB or direct renin inhibitor (aliskiren); or are pregnant or breastfeeding. If you are planning to switch from an ACE inhibitor or ARB to Entresto, or vice versa, leave at least 36 hours between the last dose of the previous drug and the first dose of the new drug.

If you are taking Entresto and feel lightheaded, dizzy or very tired, call your doctor.
 

References

[1] Centers for Disease Control and Prevention. Heart failure. October 14, 2022. https://www.cdc.gov/heartdisease/heart_failure.htm. Accessed October 31, 2022.

[2] Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics—2020 update: A report from the American Heart Association. Circulation. 2020;141(9):e139-596.

[3] National Heart, Lung and Blood Institute. Heart failure treatment. March 24, 2022. https://www.nhlbi.nih.gov/health/heart-failure/treatment. Accessed October 31, 2022.

[4] Cleveland Clinic. ARNI. July 29, 2022. https://my.clevelandclinic.org/health/treatments/23939-angiotensin-receptor-neprilysin-inhibitor-arni. Accessed October 31, 2022.

[5] Belkin MN, Cifu AS, Pinney S. Management of heart failure. JAMA. 2022;328(13):1346-1347.

[6] Novartis. Label: sacubitril and valsartan (ENTRESTO). February 2021. Uhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2021/207620s018lbl.pdfRL. Accessed October 31, 2022.

[7] Mayo Clinic. Ejection fraction: What does it measure? February 26, 2021. https://www.mayoclinic.org/tests-procedures/ekg/expert-answers/ejection-fraction/faq-20058286. Accessed November 1, 2022.

[8] Food and Drug Administration. Medical Review 2015. Application number 207620Orig1s000. NDA 207620. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620orig1s000medr.pdf. Accessed November 7, 2022.

[9] Mayo Clinic. Ejection fraction: What does it measure? February 26, 2021. https://www.mayoclinic.org/tests-procedures/ekg/expert-answers/ejection-fraction/faq-20058286. Accessed November 1, 2022.

[10] Patient education: Heart failure with preserved ejection fraction (The basics). UpToDate. October 14, 2022.

[11] Ibid.

[12] McMurray JJ, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.

[13] Solomon SD, McMurray JJ, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609-1620.

[14] Food and Drug Administration. Center for Drug Evaluation and Research. Approval packager for application number 207620Orig1s018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/207620Orig1s018.pdf. Accessed November 2, 2022.

[15] Important Drug Interactions for Angiotensin-Converting Enzyme Inhibitors. Worst Pills, Best Pills Newsletter. January 2021. https://www.worstpills.org/newsletters/view/1376. Accessed November 1, 2022.

[16] McMurray JJ, Packer M, Desai A, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.

[17] Ibid.

[18] Sacubitril + valsartan in chronic heart failure. Favourable results in highly selected patients. Prescrire Int. February 2017;26(179):33-37. https://english.prescrire.org/en/81/168/52725/0/NewsDetails.aspx. Accessed November 2, 2022.

[19] Solomon SD, McMurray JJ, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609-1620.

[20] McMurray JJ, Packer M, Desai A, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.

[21] Solomon SD, McMurray JJ, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609-1620.

[22] Important Drug Interactions for Angiotensin-Converting Enzyme Inhibitors. Worst Pills, Best Pills Newsletter. January 2021. https://www.worstpills.org/newsletters/view/1376. Accessed November 2, 2022.

[23] Novartis. Label: sacubitril and valsartan (ENTRESTO). February 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/207620s018lbl.pdf. Accessed November 2, 2022.

[24] Food and Drug Administration. Drug Trials Snapshot: ENTRESTO. July 29, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-entresto. Accessed November 2, 2022.

[25] Important Drug Interactions for Angiotensin-Converting Enzyme Inhibitors. Worst Pills, Best Pills Newsletter. January 2021. https://www.worstpills.org/newsletters/view/1376. Accessed November 2, 2022.

[26] Novartis. Label: sacubitril and valsartan (ENTRESTO). February 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/207620s018lbl.pdf. Accessed November 2, 2022.

[27] Ibid.

[28] Sacubitril + valsartan in chronic heart failure. Favourable results in highly selected patients. Prescrire Int. February 2017;26(179):33-37. https://english.prescrire.org/en/81/168/52725/0/NewsDetails.aspx. Accessed November 2, 2022.

[29] Novartis. Label: sacubitril and valsartan (ENTRESTO). February 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/207620s018lbl.pdf. Accessed November 2, 2022.