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).
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.
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