Journal Logo


In-Hospital Initiation of Sacubitril/Valsartan

A New PARADIGM for Acute Decompensated Heart Failure?

Bonaventura, Aldo MD*,†; Wohlford, George F. PharmD; Vecchié, Alessandra MD*,†; Van Tassel, Benjamin W. PharmD; Abbate, Antonio MD, PhD*

Author Information
Journal of Cardiovascular Pharmacology: July 2019 - Volume 74 - Issue 1 - p 1-3
doi: 10.1097/FJC.0000000000000685
  • Free

The incidence and prevalence of heart failure (HF) is not decreasing, and its morbidity remains extremely high1,2 with future projections predicting further increases in incidence and costs over the next 20 years.1

Neurohormonal pathways [eg, renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system] have long been recognized as playing an important role in HF pathophysiology.3 More recently, the role of counter-regulatory systems that may work to delay disease progression has been recognized.4 The best characterized mediators of these systems are the natriuretic peptides, for example, atrial, brain, and C-type natriuretic peptide.5 Plasma levels of B-type natriuretic peptide (BNP) are increased in patients with left ventricular dysfunction. Therefore, BNP is a useful and established biomarker for aiding the diagnosis of HF. The increase in natriuretic peptides is likely a conserved compensatory mechanism to combat the overactivation of both RAAS and sympathetic nervous system, and the correlation between elevations of these peptides and disease progression is sometimes referred to as the “natriuretic peptide paradox.”6 Both the neurohormonal and natriuretic systems are notably activated in patients with acutely decompensated HF (ADHF).

Therapeutic strategies that mimic or manipulate natriuretic peptide concentrations have been developed and clinically tested. Inhibition of neprilysin, an enzyme that degrades natriuretic peptides, is increasingly being studied in expanded cardiac populations.7 When the inhibition of RAAS using an angiotensin II receptor blocker and neprilysin was combined, the effects were found to be superior to those of either approach alone in experimental studies.8,9 The first Food and Drug Administration (FDA)–approved combination of a neprilysin inhibitor and angiotensin II receptor blocker was sacubitril/valsartan following the results of the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial. PARADIGM-HF found a 20% reduction in major cardiac events (hazard ratio 0.80, 95% confidence interval 0.73–0.87, P < 0.001) for the treatment versus enalapril over 3.4 years of follow-up (Figure 1).10 The population studied in PARADIGM-HF, however, was patients with stable HF therefore leaving the benefit and safety in ADHF unknown (Figure 1).

Sacubitril/valsartan in HF. In 2014, sacubitril/valsartan was tested in the PARADIGM-HF in patients with HFrEF showing a great reduction in cardiovascular death and hospitalization for HF. Recently, the PIONEER-HF confirmed the efficacy and safety of sacubitril/valsartan also in patients with acute decompensated HF with a strong reduction in death, HF rehospitalization, left ventricular assist device, and transplant listing. HFrEF, HF with reduced ejection fraction. HR, hazard ratio; LVAD, left ventricular assist device; PARADIGM-HF, prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in HF; PIONEER-HF, comparison of sacubitril–valsartan versus enalapril on effect on NT-proBNP in patients stabilized from an acute HF episode.

Relative to the therapeutic strategies for chronic HF, few interventions have been tested in ADHF11 and many interventions have failed. The RELAX-AHF (RELAX in Acute Heart Failure) trial with serelaxin, a recombinant version of the vasodilatory human relaxin hormone that becomes elevated during pregnancy, failed to show a significant reduction in cardiovascular death or readmission for HF,12 despite encouraging results of the phase II pre–RELAX-AHF trial. Similarly, in the TRUE-AHF (Trial of Ularitide Efficacy and Safety in Acute Heart Failure) trial, ularitide, a hormone inducing natriuresis, did not reduce the long-term risk of cardiovascular death.13 Nesiritide, a recombinant BNP, was approved by FDA for ADHF in 2001 after showing benefit in surrogate hemodynamic endpoints of HF. However, in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial, nesiritide failed to show improvement for the composite endpoint of death and rehospitalization for HF (HHF) after a median of 41 hours of treatment.14 In all of these examples, short-term infusions of the aforementioned treatments in ADHF failed to translate into clinical outcome benefits, consistent with the historical futility of short-term ADHF interventions to influence long-term cardiovascular outcomes.

In contrast with this previous studies, the PIONEER-HF (Comparison of Sacubitril–Valsartan vs. Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute HF Episode) was a randomized (stratified by age at the time enrollment), double-blind, double-dummy, multicenter clinical trial that evaluated initiation—and outpatient continuation—of sacubitril/valsartan versus enalapril in 881 patients who were hospitalized for ADHF.15 The primary efficacy outcome of change in the N-terminal pro–B-type natriuretic peptide (NT-proBNP), a surrogate biomarker not elevated as a result of neprilysin inhibition, over the 8-week follow-up period was successfully reached (−46.7% vs. −25.3%, P < 0.001) (Figure 1). Key safety outcomes did not see any significant difference between groups. Prespecified exploratory analyses of clinical outcomes showed a 44% reduction in HHF for those treated with sacubitril/valsartan as compared to enalapril. For the studied population, this reduction is likely to be of importance given the natural history of the disease where a reduction in long-term survival is observed with each additional HHF.16

PIONEER-HF trial also found in-hospital initiation of sacubitril/valsartan in ADHF patients to be safe for patients once maintained on stable diuretic doses and not in the “hyperacute” phase (patients were enrolled no less than 24 hours after their initial presentation to the hospital). Although the early initiation of vasoactive drugs has been demonstrated to improve in-hospital mortality in patients hospitalized for ADHF,17 most of the oft-reported drugs tested for ADHF failed to show long-term benefits while initiated exactly during early recompensation differently from sacubitril/valsartan started following the stabilization of patients, as underlined by the inclusion criteria.

More than one-third of patients enrolled were black or African American, and no significant increase in the risk for angioedema was observed. The event rate of symptomatic hypotension was not different between treatment groups, which provides some reassurance against concerns for hypotension with in-patient initiation. The results may also confirm post hoc observations for associations of NT-proBNP levels and outcomes in PARADIGM-HF.18

Some limitations need to be acknowledged. First of all, because the PIONEER-HF trial pointed to evaluate the safety and efficacy of sacubitril/valsartan in patients with ADHF, it is quite surprising that the primary outcome was the change in the NT-proBNP concentrations, which, however, was significantly higher compared with enalapril but already seen in a subanalysis of the PARADIGM-HF.18 Second, key safety outcomes were reached showing that sacubitril/valsartan was safe, but most of these events showed wide confidence intervals, especially hyperkalemia (84%) and symptomatic hypotension (64%), suggesting, however, a strict surveillance for these patients.

In conclusion, sacubitril/valsartan initiated early in patients with ADHF was safe and effective in reducing HF outcomes within 8 weeks of follow-up. Whether this benefit is merely an extension of the benefits observed among patients with chronic HF with reduced ejection fraction (in the PARADIGM-HF study) or represents a distinct profile of benefits among ADHF patients remains unclear. In either case, however, the benefit of neprilysin inhibition presents a new paradigm for neurohormonal blockade in ADHF and defines a new standard of care. The pathophysiology and treatment of ADHF remains, however, complex, and additional studies are warranted to explore other mechanisms potentially involved in disease progression and acute decompensation of HF. Novel therapeutic targets may include the contractile function in the cardiomyocyte (myosin activators19), the vasculatures (adenosine20), the kidneys (sodium-dependent glucose cotransporter–2 inhibition21), the inflammatory response (interleukin-122), and others. Finally, considering that the prognosis of chronic HF is known to improve when other drugs, such as β-blockers23,24 and angiotensin-converting enzyme inhibitors,25 are not discontinued or early restarted during hospitalization in the need of withdrawal, it might be worth evaluating whether the discontinuation of sacubitril/valsartan is necessary or counterproductive in those ADHF patients already on the drug.


1. Benjamin EJ, Muntner P, Alonso A, et al; American Heart Association Council on E, Prevention Statistics C, Stroke Statistics S. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019;139:e56–e528.
2. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–2200.
3. Francis GS, Goldsmith SR, Levine TB, et al. The neurohumoral axis in congestive heart failure. Ann Intern Med. 1984;101:370–377.
4. Oatmen KE, Zile MR, Burnett JC Jr, et al. Bioactive signaling in next-generation pharmacotherapies for heart failure: a review. JAMA Cardiol. 2018. doi: [epub ahead of print].
5. Potter LR, Yoder AR, Flora DR, et al. Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol. 2009:341–366.
6. Goetze JP, Kastrup J, Rehfeld JF. The paradox of increased natriuretic hormones in congestive heart failure patients: does the endocrine heart also fail in heart failure? Eur Heart J. 2003;24:1471–1472.
7. Owens AT, Brozena S, Jessup M. Neprilysin inhibitors: emerging therapy for heart failure. Annu Rev Med. 2017;68:41–49.
8. Rademaker MT, Charles CJ, Espiner EA, et al. Combined neutral endopeptidase and angiotensin-converting enzyme inhibition in heart failure: role of natriuretic peptides and angiotensin II. J Cardiovasc Pharmacol. 1998;31:116–125.
9. Trippodo NC, Fox M, Monticello TM, et al. Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. J Cardiovasc Pharmacol. 1999;34:782–790.
10. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.
11. Cannon JA, McKean AR, Jhund PS, et al. What can we learn from RELAX-AHF compared to previous AHF trials and what does the future hold? Open Heart. 2015;2:e000283.
12. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381:29–39.
13. Packer M, O'Connor C, McMurray JJV, et al. Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med. 2017;376:1956–1964.
14. O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365:32–43.
15. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380:539–548.
16. Abbate A, Arena R, Abouzaki N, et al. Heart failure with preserved ejection fraction: refocusing on diastole. Int J Cardiol. 2015;179:430–440.
17. Peacock WF, Emerman C, Costanzo MR, et al. Early vasoactive drugs improve heart failure outcomes. Congest Heart Fail. 2009;15:256–264.
18. Zile MR, Claggett BL, Prescott MF, et al. Prognostic implications of changes in N-terminal pro-B-type natriuretic peptide in patients with heart failure. J Am Coll Cardiol. 2016;68:2425–2436.
19. Moin DS, Sackheim J, Hamo CE, et al. Cardiac myosin activators in systolic heart failure: more friend than foe? Curr Cardiol Rep. 2016;18:100.
20. Voors AA, Shah SJ, Bax JJ, et al. Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1-receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction. Eur J Heart Fail. 2018;20:1601–1610.
21. Bonaventura A, Carbone S, Dixon DL, et al. Pharmacologic strategies to reduce cardiovascular disease in type 2 diabetes mellitus: focus on SGLT-2 inhibitors and GLP-1 receptor agonists. J Intern Med. 2019. doi: [epub ahead of print].
22. Van Tassell BW, Canada J, Carbone S, et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (recently decompensated heart failure anakinra response trial). Circ Heart Fail. 2017;10:e004373.
23. Prins KW, Neill JM, Tyler JO, et al. Effects of beta-blocker withdrawal in acute decompensated heart failure: a systematic review and meta-analysis. JACC Heart Fail. 2015;3:647–653.
24. Jondeau G, Milleron O. Beta-blockers in acute heart failure: do they cause harm? JACC. Heart Fail. 2015;3:654–656.
25. Gilstrap LG, Fonarow GC, Desai AS, et al. Initiation, continuation, or withdrawal of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and outcomes in patients hospitalized with heart failure with reduced ejection fraction. J Am Heart Assoc. 2017;6:e004675.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.