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The Magic of Entresto (Sacubitril and Valsartan)

Entresto is the brand name of a drug that contains sacubitril and valsartan. It belongs to the group of drugs called ARNI or Angiotensin receptor Neprilysin inhibitor. Neprilysin is basically an enzyme that degrades the atrial and brain natriuretic peptides which are released as a result of cardiac stretch. Atrial and Brain Natriuretic peptides, in response to the cardiac stretch, cause the kidneys to excrete more water. Thus, by inhibiting the enzyme Neprilysin, Sacubitril allows the ANP and BNP to induce diuresis.

With this in mind, let's discuss the importance of Entresto first ...

Entresto (Sacubitril and valsartan) is the first of its kind to rival implantable cardioverter devices. The recent study “Paradigm-HF” in which enalapril was compared with sacubitril/valsartan, comprised more than 8000 patients, in a randomized manner. Patients with heart failure and a low ejection fraction participated in the trial. The experiment was terminated early because a significant benefit with ARNI had passed a line. Patients using Sacubitril/Valsartan experienced a 20% relative risk decrease in the primary outcomes of cardiovascular death or heart failure hospitalisation. Implantable cardioverter-defibrillators are recommended for individuals with a low ejection fraction, however, they do not reduce mortality. Therefore, entresto may be a good option for patients with heart failure and a low ejection fraction because it lowers mortality in these people.

Is Entresto FDA Approved?

Yes. In Europe, it is used to treat adult patients with symptomatic chronic heart failure and low ejection fraction. It is approved for the treatment of heart failure in individuals with systolic dysfunction (New York Heart Association class II-IV) in the United States.

What is new about Entresto (Sacubitril Valsartan)?

In patients with heart failure and a low ejection fraction, Entresto lowers mortality, hospitalisation, and death from cardiovascular causes, as demonstrated by the Paradigm-HF trial. The NT-ProBNP levels were said to have decreased and the ejection fraction to have improved in the new Prove-HF and Evaluate-HF studies.

Improvement in the Ejection Fraction?

This table from Medscape displays the findings of the study: Sacubitril/Valsartan-Induced Echocardiographic Changes and Correlation with Natriuretic Peptide Levels

Parameters	Change at 6 mo	Change at 12 mo	*Correlation (r) w/log2–NT-proBNP levels**
LVEF (%)	+5.2	+9.4	-0.381
LVEDVI (mL/m2)	-6.65	-12.25	0.320
LVESVI (mL/m2)	-8.67	-15.29	0.405
LAVI (mL/m2)	-4.36	-7.57	0.263
E/e′ ratio	-1.23	-1.30	0.269

*everything significant at P.001 Left ventricular ejection fraction (LVEF) Left ventricular end-diastolic volume index, or LVEDVI Left ventricular end-systolic volume index (LVESVI) Left Atrial Volume Index (LAVI) Early transmitral Doppler velocity to early diastolic annular velocity is measured as E/e′.

Where is the magic? A case scenario of my patient on Entresto ...

This 60 year of age patient is under my care for the last year.

He is on the following treatment:
- He has long-standing diabetes and on insulin with good control.
- He is also a case of End-Stage Chronic kidney disease and is on peritoneal dialysis.
- Six months back he was diagnosed as a case of hypothyroidism and on 50 mcg of Thyroxine with normal thyroid functions.
- For the past year, he is on treatment for dementia and on Rivastigmine 6 mg twice daily.
- For lumbar disc prolapse, he is taking lacosamide 100 mg at bedtime.
- Plus, he takes the pain and sleeping pills off and on.
- He is also a case of Ischemic heart disease with an ejection fraction of 25%.

[caption id="attachment_9097" align="aligncenter" width="1200"] patient with EF of 20% on entresto ECG shows RBBB and poor R waves progression[/caption] [caption id="attachment_9098" align="aligncenter" width="624"] patient with EF of 25% started on entresto Patient with an Ejection fraction of 25% at baseline[/caption] Three months back, I started him on Sacubitril + Valsartan 50mg for two weeks followed by 100 mg. The attendants were advised to monitor his potassium levels weekly along with blood pressure. The patient continued and tolerated Entresto (Uperio/ Sacvin) for three months after which his Echocardiography was repeated.

To our surprise, his Ejection Fraction was reported as 40%.

I didn't believe the report. After a day or two, the results of the two studies "Prove-HF" and "Evaluate-HF" trials were published that showed an increase in the ejection fraction of about 10%. I will post updates on the fresh Echocardiography report after a few weeks to confirm "the magic of entresto" as the attendants called it.

Sacubitril and valsartan: Drug Interaction

Risk Factor C (Monitor therapy)
Amphetamines	May lessen the effectiveness of antihypertensive agents.
Angiotensin II	The therapeutic benefit of angiotensin II may be reduced by receptor blockers.
Alfuzosin	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Antipsychotic Agents (Second Generation [Atypical])	Antipsychotic drugs' hypotensive effects may be enhanced by blood pressure-lowering medications (Second Generation [Atypical]).
Barbiturates	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Benperidol	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Blood Pressure Lowering Agents	May increase the hypotensive effects of agents associated with hypotension.
Brigatinib	May lessen the effectiveness of antihypertensive agents. Antihypertensive Agents' bradycardic action may be strengthened by Brigatinib.
Brimonidine (Topical)	The hypotensive effects of blood pressure-lowering medications may be strengthened.
CycloSPORINE (Systemic)	CycloSPORINE's hyperkalemic impact may be enhanced by angiotensin II receptor blockers (Systemic).
Dapoxetine	Angiotensin II Receptor Blockers' orthostatic hypotensive action might be improved.
Dexmethylphenidate	Can lessen an antihypertensive drug's therapeutic impact.
Diazoxide	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Drospirenone	Drospirenone's hyperkalemic impact may be enhanced by angiotensin II receptor blockers.
DULoxetine	The hypotensive impact of DULoxetine may be enhanced by blood pressure lowering medications.
Eltrombopag	May raise the level of OATP1B1/1B3 (SLCO1B1/1B3) Substrates in the serum.
Eplerenone	Angiotensin II Receptor Blockers' hyperkalemic impact might be strengthened.
Gemfibrozil	May raise the level of OATP1B1/1B3 (SLCO1B1/1B3) Substrates in the serum. Agents indicated as exceptions should be examined in separate drug interaction monographs.
Heparin	Angiotensin II Receptor Blockers' hyperkalemic impact might be strengthened.
Heparins (Low Molecular Weight)	Angiotensin II Receptor Blockers' hyperkalemic impact might be strengthened.
Herbs (Hypertensive Properties)	May lessen the effectiveness of antihypertensive agents.
Herbs (Hypotensive Properties)	The hypotensive effects of blood pressure-lowering medications may be strengthened.
HydroCHLOROthiazide	May intensify Valsartan's hypotensive effects. The serum concentration of HydroCHLOROthiazide may rise in response to Valsartan.
Hypotension-Associated Agents	The hypotensive action of hypotension-associated agents may be strengthened by blood pressure lowering medications.
Levodopa-Containing Products	Levodopa-Containing Products' hypotensive effects may be strengthened by blood pressure-lowering medications.
Lormetazepam	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Methylphenidate	May lessen the effectiveness of antihypertensive agents.
Molsidomine	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Naftopidil	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Nicergoline	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Nicorandil	Angiotensin II Receptor Blockers' hyperkalemic impact might be strengthened.
Nicorandil	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Nitroprusside	Nitroprusside's hypotensive impact may be strengthened by blood pressure-lowering medications.
Nonsteroidal Anti-Inflammatory Agents	Nonsteroidal Anti-Inflammatory Agents' negative/toxic effects may be amplified by angiotensin II receptor blockers. In particular, the combination may cause a marked decline in renal function. Angiotensin II Receptor Blockers' therapeutic impact may be lessened by non-steroidal anti-inflammatory drugs. Both glomerular filtration rate and renal function may be considerably reduced by the combination of these two drugs.
Pentoxifylline	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Pholcodine	Pholcodine's hypotensive impact may be strengthened by blood pressure lowering medications.
Phosphodiesterase 5 Inhibitors	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Potassium Salts	Angiotensin II Receptor Blockers' hyperkalemic impact might be strengthened.
Potassium-Sparing Diuretics	Potassium-Sparing Diuretics may have a stronger hyperkalemic impact when used with Angiotensin II Receptor Blockers.
Prostacyclin Analogues	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Quinagolide	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Ranolazine	Angiotensin II Receptor Blockers' hazardous or harmful effects might be exacerbated.
Tacrolimus (Systemic)	Tacrolimus's hyperkalemic impact may be enhanced by angiotensin II receptor blockers (Systemic).
Teriflunomide	May raise the level of OATP1B1/1B3 (SLCO1B1/1B3) Substrates in the serum.
Trimethoprim	Angiotensin II Receptor Blockers' hyperkalemic impact might be strengthened.
Yohimbine	May lessen the effectiveness of antihypertensive agents.
Risk Factor D (Consider therapy modification)
Aliskiren	Angiotensin II Receptor Blockers' hyperkalemic impact might be strengthened. The hypotensive effects of angiotensin II receptor blockers may be strengthened by aliskiren. Angiotensin II Receptor Blockers' nephrotoxic effects may be made worse by aliskiren. Treatment: It is not advised for diabetic patients to take aliskiren along with ACEIs or ARBs. Combination therapy should be avoided in other patients, especially when CrCl is less than 60 mL/min. If combined, keep a close eye on your blood pressure, potassium, and creatinine levels.
Amifostine	Amifostine's hypotensive impact may be strengthened by blood pressure lowering medications. Treatment: Blood pressure-lowering drugs need to be avoided for 24 hours before amifostine is administered when used at chemotherapeutic doses. Amifostine should not be given if blood pressure lowering treatment cannot be stopped.
Antihepaciviral Combination Products	Could raise the serum level of valsartan. Management: If these drugs are used in combination, take into account lowering the valsartan dose and monitoring for signs of hypotension and deteriorating renal function, according to the US prescribing instructions for antihepaciviral combination products.
Lithium	It's possible that angiotensin II receptor blockers will raise the level of lithium in the blood. Management: After adding an angiotensin II receptor antagonist, it will probably be necessary to lower the dosage of lithium.
Obinutuzumab	The hypotensive effects of blood pressure-lowering medications may be strengthened. Management: Take into account temporarily stopping blood pressure-lowering drugs 12 hours before the start of the obinutuzumab infusion and keeping them off until 1 hour after the infusion is finished.
Sodium Phosphates	Angiotensin II Receptor Blockers may make sodium phosphates more nephrotoxic. In particular, there may be an increased risk of acute phosphate nephropathy. Treatment: You might want to temporarily stop taking ARBs or look into alternatives to the oral sodium phosphate bowel preparation in order to prevent this combo. Maintaining appropriate hydration and properly monitoring renal function should be done if the combination cannot be avoided.
Tolvaptan	May raise the level of OATP1B1/1B3 (SLCO1B1/1B3) Substrates in the serum.
Risk Factor X (Avoid combination)
Angiotensin-Converting Enzyme Inhibitor	Sacubitril's harmful or poisonous effects can be amplified. In particular, this combination may raise the risk of angioedema.
Bromperidol	The hypotensive impact of bromperidol may be enhanced by blood pressure lowering medications. Blood Pressure Lowering Agents' hypotensive effects may be lessened by bromperidol.

Would you share your experience with Entresto (Uperio/ Sacvin)?

Do you think the increase in the ejection fraction is a subjective thing or is it really the magic of Entresto?

The Magic of Entresto (Sacubitril and Valsartan)

Risk Factor C (Monitor therapy)

Risk Factor D (Consider therapy modification)

Risk Factor X (Avoid combination)

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