Valsartan/sacubitril

Valsartan/sacubitril

Combination of
Valsartan	Angiotensin II receptor antagonist
Sacubitril	Neprilysin inhibitor
Clinical data
Trade names	Entresto
Synonyms	LCZ696
AHFS/Drugs.com	entresto
Routes of administration	By mouth
ATC code	C09DX04 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
CAS Number	936623-90-4
PubChem CID	24755604
KEGG	D10226

Valsartan/sacubitril (brand name Entresto) is a combination drug for use in heart failure developed by Novartis. It consists of the angiotensin receptor blocker valsartan and the neprilysin inhibitor sacubitril, in a 1:1 mixture by molecule count. It is recommended for use as a replacement for an ACE inhibitor or an angiotension receptor blocker in people with heart failure with reduced ejection fraction.^[1]

Side effects include angioedema, kidney problems, and low blood pressure.^[1] The risk of kidney problems and increased levels of serum potassium with valsartan/sacubitril is lower than that of an ACE inhibitor or angiotensin receptor blocker. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi).

It was approved under the FDA's priority review process on July 7, 2015.^[2] It is also approved in Europe.^[3] In the USA, the wholesale cost for a year of valsartan/sacubitril is $4,560 per person as of 2015.^[4] Similar class generic drugs without sacubitril, such as valsartan alone, cost approximately $48 a year.^[5] One analysis found a cost of $45,017 per QALY.^[6] The wholesale cost to the National Health Service in the UK is approximately £1,200 per person per year.^[7]

Medical uses

Valsartan/sacubitril is used instead of an ACE inhibitor or an angiotensin receptor blocker in people with heart failure and a reduced left ventricular ejection fraction (LVEF).^[1][2] It is not known whether valsartan/sacubitril is useful for the treatment of heart failure people with normal LVEF.^[8] The level of evidence to support its use is less than that for ACE inhibitors and ARBs.^[1] In those with class 2 or 3 failure who do well with an ACE inhibitor or ARB but still have symptoms, changing to valsartan/sacubitril decreases the risk of death.^[1] It has not been compared directly to ARBs as of 2016.^[1]

Changing 100 people from an ACE inhibitor or angiotensin II receptor antagonist to valsartan/sacubitril for 2.3 years would prevent 3 deaths, 5 hospitalizations for heart failure, and 11 hospitalizations overall.^[8]

Adverse effects

Common adverse effects the main study were cough, hyperkalemia (high potassium levels in the blood, which can be caused by valsartan), kidney dysfunction, and hypotension (low blood pressure, a common side effect of vasodilators and ECF volume reducers). 12% of the patients withdrew from the study during the run-in phase because of such events.^[9]

Valsartan/sacubitril is contraindicated in pregnancy because it contains valsartan, a known risk for birth defects.^[10]

Pharmacology

Valsartan blocks the angiotensin II receptor type 1 (AT₁). This receptor is found on both vascular smooth muscle cells, and on the zona glomerulosa cells of the adrenal gland which are responsible for aldosterone secretion. In the absence of AT₁ blockade, angiotensin causes both direct vasoconstriction and adrenal aldosterone secretion, the aldosterone then acting on the distal tubular cells of the kidney to promote sodium reabsorption which expands extracellular fluid (ECF) volume. Blockade of (AT₁) thus causes blood vessel dilation and reduction of ECF volume.^[11][12]

Sacubitril is a prodrug that is activated to sacubitrilat (LBQ657) by de-ethylation via esterases.^[13] Sacubitrilat inhibits the enzyme neprilysin,^[14] a neutral endopeptidase that degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Thus, sacubitril increases the levels of these peptides, causing blood vessel dilation and reduction of ECF volume via sodium excretion.^[15]

Chemistry

LCZ696 is co-crystallized valsartan and sacubitril, in a one-to-one molar ratio. One LCZ696 complex consists of six valsartan anions, six sacubitril anions, 18 sodium cations, and 15 molecules of water, resulting in the molecular formula C₂₈₈H₃₃₀N₃₆Na₁₈O₄₈·15H₂O and a molecular mass of 5748.03 g/mol.^[16][17]

The substance is a white powder consisting of thin hexagonal plates. It is stable in solid form as well as in aqueous (watery) solution with a pH of 5 to 7, and has a melting point of about 138 °C (280 °F).^[17]

History

It was approved under the FDA's priority review process on July 7, 2015.^[2] It was also approved in Europe in 2015.^[3]

Society and culture

Trial design

There was controversy over the PARADIGM-HF trial -- the Phase III trial on the basis of which the drug was approved by the FDA. For example, both Richard Lehman, a physician who writes a weekly review of key medical articles for the BMJ Blog and a December 2015 report from the Institute for Clinical and Economic Review (ICER) both found that the risk–benefit ratio was not adequately determined because the design of the clinical trial was too artificial and did not reflect people with heart failure that doctors usually encounter.^[4]:28[18] On the other hand, in December 2015 Steven Nissen and other thought leaders in cardiology said that the approval of valsartan/sacubitril had the greatest impact on clinical practice in cardiology in 2015, and Nissen called the drug "a truly a breakthrough approach."^[19]

One 2015 review stated that valsartan/sacubitril represents "an advancement in the chronic treatment of heart failure with reduced ejection fraction" but that widespread clinical success with the drug will require taking care to use it in appropriate patients, specifically those with characteristics similar to those in the clinical trial population.^[20] Another 2015 review called the reductions in mortality and hospitalization conferred by valsartan/sacubitril "striking", but noted that its effects in heart failure people with hypertension, diabetes, chronic kidney disease, and the elderly needed to be evaluated further.^[21]

Cost

The wholesale cost for a year of valsartan/sacubitril in the USA is $4,560 per person as of 2015,^[4] but the cost to the NHS in the UK is less than £1,200 per person per year.^[7] Similar class generic drugs without sacubitril, such as valsartan alone, cost approximately $48 a year.^[5] One analysis found a cost of $45,017 per QALY.^[6]

Research

The PARADIGM-HF trial compared treatment with valsartan/sacubitril to treatment with enalapril, Milton Packer was one of the two co-principal investigators.^[22] People with heart failure and reduced LVEF (10,513) were sequentially treated on a short term basis with enalapril and then with valsartan/sacubitril. Those that were able to tolerate both regimens (8442, 80%) were randomly assigned to long-term treatment with either enalapril or valsartan/sacubitril. Participants were mainly white (66%), male (78%), middle aged (median 63.8 +/- 11 years) with NYHA stage II (71.6%) or stage III (23.1%) heart failure.^[8]

The trial was stopped early after a prespecified interim analysis revealed a reduction in the primary endpoint of cardiovascular death or heart failure in the valsartan/sacubitril group relative to those treated with enalapril. Taken individually, the reductions in cardiovascular death and heart failure hospitalizations retained statistical significance.^[9] Relative to enalapril, valsartan-sacubitril provided reductions^[8] in

• the composite endpoint of cardiovascular death or hospitalization for heart failure (incidence 21.8% vs 26.5%)
• cardiovascular death (incidence 13.3% vs 16.5%)
• first hospitalization for worsening heart failure (incidence 12.8% vs 15.6%), and
• all cause mortality (incidence 17.0% vs 19.8%)

The favorable effect of valsartan/sacubitril was seen in all subgroups examined, including those based on age, sex, weight, race, NYHA class, presence or absence of reduced kidney function, diabetes mellitus, atrial fibrillation, hypertension, and prior hospitalization.^[10] Additional analyses of the trial demonstrated a meaningful representation of minority groups and well as a benefit in patients with an implantable cardiac device. Limitations of the trial include scarce experience with initiation of therapy in hospitalized patients and in those with NYHA heart failure class IV symptoms.^{[23] [24]}

References