Sacubitril/Valsartan for the Prevention and Treatment of Postinfarction Heart Failure: Ready to Use?

Across the spectrum of patients with acute myocardial infarction (MI), early mortality has decreased over the past several years, concomitant with the widespread use of primary percutaneous coronary intervention and the adjunctive use of antiplatelet and antithrombotic drugs and neurohormonal blockers.1 Landmark randomized trials have established the improvement in 30-day mortality and heart failure (HF) after MI using either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) compared with placebo, with observed 30-day mortality rates of approximately 7% in those studies.2 With longer term follow-up, the clinical benefit is amplified. In the Acute Infarction Ramipril Efficacy trial (AIRE), with an average follow-up time of 15 months, ramipril was associated with a 6% absolute decrease in mortality (17% vs. 23% with placebo). The primary mechanism of benefit is thus suggested to be related in large part to a reduction in progressive HF, occurring in 46% of those who died.3,4 However, despite these advances, patients with MI—particularly those presenting with ST elevation MI—continue to experience a significant risk of HF-related events at follow-up. Indeed, 10% of such patients are hospitalized with HF within 1–2 years of the event in the modern era.5–8 The increasing number of MI survivors underscores the need to prevent and reduce HF burden in this patient population. A new class of drug combining sacubitril (a neprilysin inhibitor prodrug) and valsartan (an ARB) has been approved for patients with chronic HF and reduced ejection fraction with New York Heart Association functional class II to IV symptoms. This approval follows the positive results of the Prospective Comparison of angiotensin receptor–neprilysin inhibitor (ARNI) with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) trial, in which sacubitril–valsartan significantly reduced cardiovascular mortality or a first hospitalization for HF by 20% [95% confidence interval (CI), 0.73–0.87] compared with enalapril.9 The efficacy of sacubitril–valsartan in patients with acute HF was further explored in the comParIson Of sacubitril–valsartan versus Enalapril on Effect on NT-proB-type natriuretic peptide in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial,10 in which 881 patients hospitalized with acute HF were randomly assigned to sacubitril–valsartan (N = 440) or enalapril (N = 441) after hemodynamic stabilization. The primary outcome, a time-averaged reduction in NT-proB-type natriuretic peptide, was superior for sacubitril/valsartan compared with enalapril [−46.7% vs. −25.3%, hazard ratio (HR) 0.71, 95% CI, 0.63–0.81] and was apparent as early as 1 week after drug initiation. Prespecified secondary analyses of clinical outcomes found a significant reduction in rehospitalization for HF (8.0% with sacubitril–valsartan vs. 13.8% enalapril, HR 0.56; 95% CI, 0.37–0.84). Side effects, including worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema, did not differ significantly between the 2 groups, although there was a higher frequency of hypotension, defined as systolic blood pressure <100 mm Hg, at week 1 in the sacubitril–valsartan group.10 More recently, the Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial showed encouraging data for sacubitril–valsartan in reducing the primary composite endpoint of total (first and recurrent) HF hospitalizations and cardiovascular death in patients with HF with preserved ejection fraction compared with valsartan, narrowly missing statistical significance (95% CI, 0.75–1.01).11 Of note, a more favorable effect on the primary endpoint was seen in the prespecified subgroup of patients with HF and midrange ejection fraction (Rate ratio = 0.780; 95% CI, 0.641–0.949 in those with left ventricular ejection fraction 45%–57%).11–13 Following the positive results of the aforementioned studies in established HF populations, the Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing HF Events after Myocardial Infarction (PARADISE-MI) was designed to compare the efficacy and safety of sacubitril–valsartan with ramipril in patients with acute MI and left ventricular systolic dysfunction (ejection fraction < 40%) or pulmonary congestion.14 As recently presented at the 2021 American College of Cardiology Scientific Sessions,15 a total of 5661 patients (mean age 64 years, female sex 24%, White race 76%, and ST elevation MI presentation 76%) were randomized in a 1:1 fashion to either treatment arm. The primary outcome was a composite of cardiovascular death, first HF hospitalization, or development of outpatient HF. Baseline medical treatment and drug discontinuation were not different between groups. With a follow-up of 23 months, the combined primary endpoint had occurred in 11.9% of the sacubitril/valsartan group and 13.9% of the ramipril group (HR 0.90; 95% CI, 0.78–1.04). This translated to 6.7 events per 100 patient-years for sacubitril–valsartan and 7.4 events per 100 patient-years for ramipril. Although all the components of the primary outcome showed trends toward lower number of events with sacubitril–valsartan versus ramipril, they did not reach statistical significance. Nevertheless, there were several features of this trial that were encouraging for the experimental arm. First, for all components of the primary endpoint, the absolute numbers favored those randomized to sacubitril–valsartan. Second, the exploratory analysis looking at total (first and recurrent) HF events was statistically in favor of sacubitril–valsartan. Third, patients ≥65 years of age (who experienced twice as many HF-related events as younger patients) seemed to derive more benefit from sacubitril–valsartan on prespecified subgroup analysis. Fourth, the investigator-reported outcomes, which reported more HF-events than the central adjudication process in both arms, showed a reduction in events with sacubitril–valsartan that reached statistical significance. Of note, the lower event rates with centrally adjudication may have contributed to lower power in detecting differences between groups. All considered, this trial confirmed that sacubitril/valsartan is a safe drug, associated with a similar adverse event profile, and at least as effective as ramipril. The results of the PARADISE-MI trial allow the opportunity to make several additional observations. First, in the contemporary cohort of patients with MI treated with primary percutaneous coronary intervention, the early and long-term mortality seem to be significantly reduced when compared with the previous randomized control trials, likely because of the improved treatments including utilization of newer antithrombotic agents and early neurohormonal blockade. Second, HF-related events after MI remain unacceptably high, occurring in approximately 1 in every 10 patients at follow-up even with optimal medical therapy. Third, the lack of significant difference in the primary composite endpoint in the trial may be attributed to the PARADISE-MI study design, whereby the control arm was not randomized to placebo but rather to an active treatment with ramipril—already shown to reduce mortality and HF events in this cohort of patients.3 In an animal model of MI, both sacubitril–valsartan and valsartan alone reduced infarct size compared with placebo. However, sacubitril–valsartan was superior in preserving postinfarction LVEF compared with both placebo and valsartan. Furthermore, only sacubitril–valsartan was associated with smaller left ventricular scar compared with placebo.16 In the overall context of existing literature, the PARADISE-MI study adds valuable data to the best of our knowledge despite failing to meet statistical significance in key endpoints. Most importantly, the accumulation of evidence across multiple clinical trials now supports the safety of sacubitril–valsartan across a wide range of patients with [American Heart Association (AHA) stage C] or at risk for HF (AHA stage B). Moreover, positive findings among older patients suggests that the benefits of sacubitril–valsartan are most pronounced among patients at higher risk, further strengthening the biological plausibility of the benefit hypothesized in preclinical studies. Finally, the observation that benefits among investigator-reported outcomes outpaced centrally adjudicated outcomes suggests a high likelihood that the proposed clinical benefits will remain clinically significant outside of the rigid clinical trial environment (Fig. 1).FIGURE 1.: Clinical trials of sacubitril–valsartan in HFpEF, AMI, and acute and chronic HFrEF populations. In the PARAGON-HF trial in HFpEF patients, sacubitril–valsartan showed a trend toward reduction in the hospitalizations for HF, both first and recurrent ones. In the PARADISE-MI, in high-risk AMI, sacubitril–valsartan led to a reduction of 10% in cardiovascular death, hospitalization for HF, or outpatient HF. In the PARADIGM-HF trial, sacubitril–valsartan was more effective than enalapril in reducing both cardiovascular mortality and first HF hospitalizations in patients with HFrEF. In the PIONEER-HF, sacubitril–valsartan led to a 44% reduction of rehospitalization for HF versus enalapril in acute patients with HFrEF. HFpEF, HF with preserved ejection fraction; HFrEF, HF and reduced ejection fraction. AMI, acute myocardial infarction.