Sacubitril and valsartan in fixed combination (sacubitril/valsartan) is used to reduce the risk of cardiovascular death and hospitalization for patients with chronic heart failure (New York Heart Association [NYHA] class II-IV) and reduced ejection fraction. Sacubitril/valsartan is usually administered in conjunction with other heart failure therapies (e.g., β-adrenergic blocking agent [β-blocker], aldosterone antagonist, diuretic) as a substitute for therapy with an angiotensin-converting enzyme (ACE) inhibitor or other angiotensin II receptor antagonist. Current evidence indicates that sacubitril/valsartan results in improved outcomes compared with enalapril based on reductions in cardiovascular death and heart failure hospitalization in patients with chronic heart failure and reduced ejection fraction receiving optimal heart failure therapy.
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Sacubitril/valsartan achieves dual neurohormonal modulation of the renin-angiotensin-aldosterone (RAA) system and neprilysin enzyme; the beneficial effects of RAA inhibition by valsartan are augmented by enhanced natriuretic peptide activity due to sacubitril. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations.
Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (i.e., American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality. In patients with prior or current symptoms of chronic heart failure with reduced LVEF (ACCF/AHA stage C), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the RAA system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with an ARNI (sacubitril/valsartan) may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization and that such ARNI therapy is cost-effective. ACCF, AHA, and HFSA recommend that patients with NYHA class II or III chronic symptomatic heart failure with reduced LVEF who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality. However, in patients in whom an ARNI is not appropriate, ACCF, AHA, and HFSA strongly advise continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction. In patients in whom therapy with an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used. For additional information on the use of angiotensin II receptor antagonists in the management of heart failure,
Efficacy and safety of sacubitril/valsartan in the management of heart failure have been established principally by the results of a randomized, double-blind trial (PARADIGM-HF) comparing the long-term efficacy and safety of sacubitril/valsartan with that of enalapril in addition to standard-of-care therapy in 8442 patients with symptomatic (NYHA class II-IV) chronic heart failure and reduced ejection fraction (LVEF of 40% or less). In this trial, sacubitril/valsartan was superior to enalapril in reducing the risk of death and hospitalization for heart failure in patients who were receiving these drugs in addition to the best available medical therapy; the benefit of sacubitril/valsartan was similar for both death and hospitalization and was consistent across subgroups. Benefits of sacubitril/valsartan were observed in comparison with optimal therapy with enalapril; the mean dosage of enalapril was similar to the well-established target dosages shown to reduce mortality in patients with chronic heart failure and reduced ejection fraction.
Patients enrolled in the PARADIGM-HF trial were receiving an ACE inhibitor or angiotensin II receptor antagonist at a dosage equivalent to at least 10 mg of enalapril daily for at least 4 weeks prior to trial screening in addition to maximally tolerated dosages of β-blockers. Most patients also received diuretics and mineralocorticoid receptor antagonists and had mild to moderate heart failure symptoms. Patients with a systolic blood pressure of less than 100 mm Hg at the time of screening were excluded from the trial. All enrolled patients discontinued their existing ACE inhibitor or angiotensin II receptor antagonist therapy and entered sequential single-blind run-in periods during which they received enalapril 10 mg twice daily (a dosage that has previously been shown to reduce mortality), followed by sacubitril 49 mg/valsartan 51 mg twice daily, increasing to a target maintenance dosage of sacubitril 97 mg/valsartan 103 mg twice daily. To minimize the potential for angioedema caused by overlapping ACE and neprilysin inhibition, enalapril was withheld a day before initiating sacubitril/valsartan, and sacubitril/valsartan was withheld a day before initiating randomized therapy. The most common reason for patients failing to successfully complete the enalapril and sacubitril/valsartan run-in period was an adverse event, often related to renal dysfunction, hyperkalemia, or hypotension. Patients who successfully completed the sequential run-in periods were randomized to receive either sacubitril 97 mg/valsartan 103 mg twice daily or enalapril 10 mg twice daily in addition to standard-of-care therapy. The primary end point was a composite of death from cardiovascular causes or first hospitalization for heart failure.
The PARADIGM-HF trial was terminated prematurely following the revelation of a substantially lower rate of the primary composite outcome of cardiovascular death or heart failure hospitalization in the sacubitril/valsartan treatment group at a prespecified interim analysis. After a median follow-up duration of 27 months, sacubitril/valsartan reduced the primary end point by approximately 20% compared with enalapril. The treatment effect of sacubitril/valsartan compared with that of enalapril reflected a reduction in both cardiovascular death (20% reduction; event rate 13.3 or 16.5%, respectively) and first hospitalization for worsening heart failure (21% reduction; event rate 12.8 or 15.6%, respectively). Therapy with sacubitril/valsartan reduced the likelihood of a first hospitalization as well as of multiple hospitalizations. Sacubitril/valsartan therapy also improved measures of nonfatal clinical deterioration, including the need for intensification of outpatient treatment, frequency of emergency department visits for worsening heart failure, the requirement for intensive care or IV inotropic support during hospitalization, and the incidence of progression to heart failure mechanical device implantation or cardiac transplantation. Sacubitril/valsartan also substantially improved overall survival evidenced by a 16% reduction in all-cause mortality, which was attributable principally to a lower incidence of cardiovascular mortality. Symptomatic hypotension occurred more frequently with sacubitril/valsartan therapy than with enalapril (14 or 9.2%, respectively) but was not associated with an increased rate of discontinuance of therapy due to hypotension-related adverse effects. There were numerically more cases of angioedema with sacubitril/valsartan than with enalapril therapy but the difference was not statistically significant. While it has been stated that the final adverse event rate for sacubitril/valsartan may not reflect clinical practice because of exclusion of patients with intolerance to the drug during the initial run-in period, the overall number of patients who were excluded during this period was small and was higher in the enalapril treatment group; therefore, it is considered unlikely that the implementation of a run-in period in this trial substantially affected the observed safety profile of sacubitril/valsartan.