Valsartan-Sacubitril: The Next “Best Thing” In Systolic Heart Failure?

“Realists do not fear the results of their study” Fyodor Dostoevsky
Heart failure is a problem. In fact, it is a massive problem1. Over five million adults in the United States live with heart failure2. Mozzafarian et al reported in their 2016 update on heart disease and stroke statistics that nearly half the patients diagnosed with heart failure (HF) will be deceased within five years1. That is a sobering fact. For today’s article, I will reference a novel agent which is becoming widely adopted for systolic HF. Although the past two decades saw a dramatic improvement in the understanding of HF mechanisms, there have been only a number of new pharmacologic “game changers.” Today, I will succinctly discuss the combination agent valsartan-sacubitril (VS) which is an “angiotensin receptor-neprilysin inhibitor” marketed as Entresto (Novartis).
Briefly, valsartan is an angiotensin II receptor blocker which counters vasoconstriction and aldosterone secretion; sacubitril is a pro-drug which is ultimately modified to an active component which inhibits neprilysin, a neutral endopeptidase responsible for the degradation of natriuretic peptides leading to their increased plasma levels. The end result of these cumulative effects is vasodilatation, prevention of sodium retention and accumulation of extracellular fluid3-5.
In September 2014, McMurray and colleagues published the result of the industry-sponsored PARADIGM-HF trial which compared VS (at that time known as LCZ696) to enalapril. Subjects with NYHA II-IV heart failure and originally a left ventricular ejection fraction of <40% (then amended to <35%) were randomly assigned to the study drug or the ACE-inhibitor. The study which enrolled over 8,000 patients, was terminated early due to a marked survival advantage of the VS arm with regards to the composite end point of death from cardiovascular causes or hospitalization for HF6.
Not only was there a survival advantage in patients assigned to the VS arm, but there was a 21% less risk of hospitalization for decompensated HF. Although the absolute risk reduction for cardiovascular death was only 3.2%, the data which was statistically significant, remained solidly in favor of ARB neprilysin inhibition superiority over ACE-inhibitor therapy6. From a clinician’s perspective, VS is being used increasingly to treat systolic HF patients with seemingly good results. Whether or not an indication will be given for a HF population with preserved left ventricular ejection fraction remains to be seen7.
There appears to be well-founded science supporting VS use in the vulnerable systolic HF population. Hopefully, insurance carriers and third-party payors will provide coverage for this novel agent.

  1. Mozzafarian D, Benjamin EJ, Go AS, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360
  2. https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm
  3. Hubers SJ, Brown NJ. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation. 2016;133(11):1115-24
  4. Ansara AJ, Kolanczyk DM, Koehler JM. Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. J Clin Pharm Ther. 2016;41:119-27 5.
  5. Jhund PS, McMurray JJ. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart. 2016;102:1342-7
  6. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 11;371:993-1004
  7. Solomon SD, Rizkala AR, Gong J, Wang W, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, Van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Shi VC, Lefkowitz MP, McMurray JJV. Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction: Rationale and Design of the PARAGON-HF Trial. JACC Heart Fail. 2017;5:471-482

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Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure. He reports no conflicts of interests.

Near Maggie Vallet, NC

Near Maggie Valley, NC 01/18 (CP)