The combination of a neprilysin inhibitor and an ARB rescued neprilysin inhibition from obscurity.
Heart failure has been with us for a long time. It was described in ancient Egypt, Greece, and India. The Romans figured out that it could be treated with foxglove, the source of digoxin. Some notable developments over the last several hundred years that helped with the understanding include William Harvey’s description of the relation of heart failure to the circulatory system in 1628, the invention of the stethoscope by René Laënnec in 1819, and the invention of the X-ray by Wilhelm Röntgen in 1895 and electrocardiogram technology shortly thereafter.
But most of our knowledge about treating heart failure has come in the past half century. Although early—and quite toxic—forms of diuretics were in use in the ’20s, modern diuretics were not discovered until the ’50s. We’ve seen a parade of other new therapy classes added since the diuretics, including loop diuretics, beta blockers, ACE inhibitors, and ARBs.
But, remarkably, despite all of the research over the past half century, we are still learning more about this ancient disease. Now a new medicine that combines one of the most commonly prescribed ARBs, valsartan, with an enzyme, neprilysin, is set to change how heart failure is treated in this country.
Giving some of neprilysin’s back story might be helpful in appreciating the excitement about this new medication, because it wasn’t that long ago that it seemed like it would end up on the dust heap rather than in the medicine cabinet. (If you want the full history, I recommend a review written by Eugene Braunwald, the prominent Harvard cardiologist, published in the March 2015 issue of the Journal of the American College of Cardiology.) Congestive heart failure is typically treated with compounds like ACE inhibitors and ARBs that stymie the renin–angiotensin–aldosterone system. In the ’70s, a second path to treating heart failure started to open up when scientists discovered an enzyme that degrades endogenous vasoactive peptides. It went by various names but in cardiology the name neprilysin won out. Researchers first tried compounds that inhibited just neprilysin, but they had little effect on blood pressure or heart failure because they affected both vasoconstrictive and vasodilatory peptides, according to Braunwald’s account. Then researchers tried combining neprilysin inhibition with ACE inhibition—omapatrilat was the name of the leading compound—but angioedema was a serious side effect. The quest to take advantage of the understanding of neprilysin seemed to have hit a dead end.
The breakthrough came when researchers tried combining a neprilysin inhibitor, called sacubitril, with an ARB, valsartan, because ARBs stifle the breakdown of bradykinin—and that was expected to reduce the risk of angioedema. The pivotal trial of the new compound—experimental name, LCZ696; brand name, Entresto—was stopped early after a median follow-up of 27 months because it compared so favorably against the control medication, enalapril (Vasotec), an ACE inhibitor. The primary endpoints of the industry-sponsored trial, called PARADIGM-HF, were cardiovascular death or hospitalization for heart failure. The results were persuasive: Cardiovascular death was 20% lower in the treatment group; heart failure hospitalizations were lower by about the same amount, and all-cause mortality was 16% lower than the control group taking enalapril.
Importantly, the adverse event rate was low, with angioedema occurring in just 0.1% of patients. Another good sign is that more people discontinued therapy in the control arm than in the treatment arm.
The FDA approved Entresto with the indication “to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA II-IV) and reduced ejection fraction. Entresto is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.”
The combination tablet is available in three dosages: 24 mg sacubitril/26 mg valsartan; 49 mg sacubitril/51 mg valsartan; and 97 mg sacubitril/103 mg valsartan. In the pivotal study, these dosages were referred to as 50 mg, 100 mg, and 200 mg, respectively—but this nomenclature was not carried into the package insert, so it is important to clarify the exact dosage when prescribing.
The recommended starting dose for Entresto is 49/51 mg (sacubitril/valsartan) twice daily. The dose is doubled after two to four weeks to the target maintenance dose of 93/103 mg (sacubitril/valsartan) twice daily, as tolerated by the patient.
Lower doses are suggested for several groups of patients, including those with severe renal impairment, those not currently taking an ACE inhibitor or ARB, those previously only taking a low dose of an ACE inhibitor or an ARB, and finally, for those with moderate liver impairment. (Note that Entresto is not recommended for those with serious cases of liver impairment.)
Entresto is contraindicated in patients with a history of angioedema related to ACE inhibitors or ARB therapy. It also is contraindicated for concomitant use of ACE inhibitor and patients with diabetes who are taking aliskiren, a direct renin inhibitor. Entresto also comes with a list of drug interactions that include potassium-sparing diuretics, NSAIDs, and lithium. It also is contraindicated during pregnancy as it can cause fetal harm.
An issue that needs to be clarified in future studies is that neprilysin is one of multiple enzymes involved in the clearance of beta amyloid from the brain and spinal fluid. Beta amyloid has been implicated as a cause of Alzheimer’s disease so, in theory, prolonged use of a drug like Entresto that inhibits beta amyloid clearance may increase the risk of Alzheimer’s. During the PARADIGM-HF trial, cerebrospinal fluid levels of beta amyloid were higher in the treatment group than in the control group, but the cognition changes were not mentioned in the package insert. The clinical relevance of this finding is unknown at the present time and will be subject to future study.
According to a Forbes article, Entresto will cost about $12.50 per day less discounts, adding about $4,500 to the cost of treating a patient with heart failure. Executives at Novartis, the drug’s maker, have stated that they are interested in working closely with payers. CEO Joe Jimenez told the Wall Street Journal that the company was “looking hard” at going to insurers with add-on services intended to improve outcomes for patients taking Entresto. The article went on to discuss the potential use of remote monitoring devices and other e-health measures to improve overall patient care.
Entresto, focusing on a treatment strategy that was decades in the making, is likely to become an important new medication for heart failure patients, again adding to the hope of Tomorrow’s Medicine.
Entresto will cost about $12.50 per day less discounts adding about $4,500 to the cost of treating a patient with heart failure.