Valsartan/sacubitril

Valsartan/sacubitril

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

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 may be used instead of 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 combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi).^[2][3]

It was approved under the FDA's priority review process on July 7, 2015.^[4] It is also approved in Europe.^[5] The wholesale cost for a year of Entresto is $4,560 per person as of 2015.^[6] Similar class generic drugs without sacubitril, such as valsartan alone, cost approximately $48 a year.^[7]

Medical uses

Valsartan/sacubitril may be 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][4] 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]

The Paradigm-HF trial compared treatment with valsartan/sacubitril to treatment with enalapril. 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]

Limitations of the trial include limited representation of important subgroups, such as blacks and those with implantable pacemakers, and lack of data regarding those with NYHA heart failure stages other than II or III.^[8]

Reviews

A 2015 review summarized one trial to state that 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, and recommended "broad use" of valsartan/sacubitril.^[8] A second 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.^[11] A third 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.^[12]

Adverse effects

Common 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]

Dementia risk

A December 2015 report from the Institute for Clinical and Economic Review (ICER) stated that "there is a theoretical risk that neprilysin inhibition might potentiate dementia from accumulation of amyloid plaques in the brain." The risks are unknown because of the limited experience of using drugs like sacubitril in the long term.^[6]:28

The FDA required Entresto's manufacturer to conduct a study comparing its effects on cognitive function to that of valsartan in patients with congestive heart failure. The FDA allowed Entresto to be approved before this trial, according to ICER, because the life expectancy of most heart failure patients is shorter than the time it usually takes dementia to develop.^[6]:28

Mechanism of action

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.^[13][14]

Sacubitril is a prodrug that is activated to sacubitrilat (LBQ657) by de-ethylation via esterases.^[15] Sacubitrilat inhibits the enzyme neprilysin,^[2] 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.^[16]

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.^[17][18]

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).^[18]

Controversy

The ICER report states,

"Criticisms of Entresto center on the PARADIGM-HF trial having compared the combination neprilysin inhibitor and ARB valsartan to the ACE inhibitor enalapril rather than to valsartan alone. Another critique relates to the fact that the pivotal trial was conducted only among patients who tolerated a “run-in” phase of treatment with enalapril followed by treatment with Entresto. There is also concern that neprilysin inhibition itself can potentiate angioedema. In fact, more patients in the treatment arm developed angioedema than did in the enalapril arm of the PARADIGM-HF trial (0.5% versus 0.2%). Further, investigators in the PARADIGM-HF trial gave patients in the control arm 10mg twice daily dosing of enalapril rather than 20mg twice daily dosing, which is the maximum (and goal) dose."^[6]

Overall, the report concluded,

"We judge there to be moderate certainty of an incremental to substantial net benefit for Entresto compared to standard of care with ACE inhibitor treatment in patients with Class II-IV CHF and reduced ejection fraction. There is moderate certainty because the PARADIGM-HF trial was a large, good quality study in which Entresto produced significant reductions in cardiovascular and all-cause mortality as well as in heart failure specific hospitalization and ED visits in comparison to an agent that itself has demonstrated clinical benefits in these domains. Some uncertainties remain, however, including the relative contribution of sacubitril versus valsartan to these results, the expected tolerability of Entresto, its clinical performance in real-world practice, and its potential for harm in certain patient subgroups."^[6]

The criticisms echoed those of Richard Lehman, a physician who writes a weekly review of key medical articles for the BMJ Blog. He sharply criticized the trial design and data analysis, stating, "this trial is a perfect example of everything that is wrong with heart failure trials." Lehman's stated that the trial results were likely biased by the use of inappropriate doses of enalapril and valsartan; that the patient population was not typical of those seen in clinical practice, that the use of a run-in period and early termination of the trial may have biased the results, and that the inavailability of patient level data to outside researchers makes the trial results uninterpretable.^[19]

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."^[20]

References