Angiotensin Receptor-Neprilysin Inhibitors Emerge as Potential Treatment for Acute Myocardial Infarction

Targeting the renin-angiotensin system (RAS) has been the gold standard for the treatment of heart failure (HF) for nearly 2 decades, and pharmacotherapies that inhibit angiotensin-converting enzyme inhibitors (ACEIs) and/or block the angiotensin II receptors (ARBs) have drastically changed outcomes for patients with cardiovascular disease (CVD) for >3 decades (1,2). Recently, the combination of an ARB with a prodrug that inhibits neprilysin activity (ARNi), sacubitril/valsartan (LCZ696), demonstrated superiority to the ACEI, enalapril, in the pivotal PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) clinical trial (3). LCZ696 treatment resulted in a 20% reduction in HF hospitalization and risk of cardiovascular death when compared with enalapril. Despite these positive outcomes, approval by the U.S. Food and Drug Administration and the European Medical Agency, and updated guidelines by the American College of Cardiology and the American Heart Association, there has been a significant lack of adoption of LCZ696 as the new primary pharmacotherapy for HF patients. The resistance to prescribing an ARNi versus ACEI/ARB comes from widespread skepticism that a single clinical trial should undermine >30 years of clinical data on ACEI/ARB therapeutic strategies combined with a lack of long-term safety data for this new heart failure therapeutic, especially in stable patients who are benefiting from standard therapy. Recently, Novartis has initiated a clinical trials program and several biomedical research studies to investigate the potential utility of LCZ696 when compared with an ACEI/ARB alone in a wide spectrum of CVDs. This includes trials investigating the efficacy of LCZ696 on N-terminal pro-B-type natriuretic peptide levels in stabilized patients after an acute decompensated heart failure episode (PIONEER-HF [comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode]) (4) and in patients who have experienced an acute myocardial infarction (PARADISE-MI [Prospective ARNI vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI]) (NCT02924727).

At present, there is a paucity of information regarding the precise mechanisms by which LCZ696 improves outcomes in patients with HF, and several laboratories have begun to tease out the beneficial effects in animal models of HF (5,6). While the PARADISE-MI trial is ongoing, an ability to answer fundamental questions regarding the efficacy and mechanisms of sacubitril/valsartan, in the setting of acute myocardial infarction (AMI) is important. In this issue of the Journal, Torrado et al. (7) report on a powerful new study in clinically relevant animal models of acute myocardial infarction and heart failure that provides important new insights into LCZ696 and cardioprotection.

The study published by Torrado et al. (7) is the first to investigate LCZ696 in a preclinical large animal model of AMI. This group sought to answer 3 very important fundamental questions: 1) is sacubitril/valsartan cardioprotective in the setting of AMI; 2) does early and sustained administration immediately post-AMI provide effective inhibition of pathological cardiac remodeling and HF prevention; and 3) does delayed chronic administration after the development of HF secondary to AMI provide efficacy? Convincing evidence in a preclinical large animal model would strengthen and substantiate the outcomes observed in the initial PARADIGM-HF study and provide evidence for an indication in patients following reperfusion therapy post-AMI. The group utilized a model of ischemia-reperfusion in conscious rabbits, which has been previously described (8). Employing a model of ischemia-reperfusion is vital to recapitulating the clinical events that AMI patients will undergo and is a true strength of the study. Torrado et al. (7) performed several studies: 1) dosing experiments; followed by 2) a single administration of LCZ696 (20 mg/kg) upon reperfusion to investigate cardioprotective effects; then 3) early treatment (10 mg/kg twice daily), upon reperfusion with a follow-up period of 10 weeks; and finally 4) delayed treatment study, which initiated therapy at 6 weeks post-AMI for another 4 weeks (10 weeks total).

In the acute cardioprotection study, Torrado et al. (7) administered a single oral dose of placebo, LCZ696 (20 mg/kg), or valsartan alone (9.1 mg/kg) upon reperfusion; acute hemodynamics and infarct size analysis were performed. The data clearly show a robust attenuation of infarct size and circulating cardiac troponin I in both treatment groups when compared with placebo at 72 h post-AMI. However, there was no difference between LCZ696 and valsartan alone, suggesting that both pharmacotherapies are comparable at attenuating initial infarct size.

In the early and delayed treatment studies post-AMI, there is no significant difference between LCZ696 and valsartan on scar size reduction, although the difference in scar size between LCZ696 and placebo, unlike valsartan, did reach statistical significance. Despite this, the echocardiographic data illustrate that LCZ696 early and delayed treatment is superior to valsartan alone and placebo. Simultaneously, there seems to be no statistical indication that valsartan alone has any efficacy when compared with placebo in the early and delayed chronic treatment studies on cardiac function. This observation is peculiar, considering that the effects of ARBs have been shown to be efficacious as standalone therapies in HF (9). Furthermore, previous work in animal models of HF has demonstrated that valsartan is efficacious at attenuating HF pathology (5). The authors, however, acknowledge that dosing of the valsartan-alone treatment used in this study was based on the concentration in the combined treatment arm, which is a limitation. While the authors briefly try to reconcile these quasi-negative findings, circulating troponin I levels in the HF models would solidify any concerns about initial injury size. Biomarker measurements (i.e., B-type natriuretic peptide) of HF and neprilysin inhibition pre- and post-LCZ696 administration would point to the efficacy of the drug in the context of HF development and/or rescue as observed in previous studies (5). With no molecular analysis, the paper hinges upon the echocardiography and cardiac fibrosis. Further functional analysis (i.e., echocardiographic 2-dimensional strain analysis, dobutamine stress response using invasive hemodynamics [to investigate cardiac reserve]) would strengthen their position as to the benefits of early and delayed treatment with LCZ696.

Another interesting observation by Torrado et al. (7) is that LV scar size at 6 weeks following AMI was not different from scar size at 10 weeks in the placebo group. The authors elude to the idea that the scar reduction with LCZ696 in the delayed-treatment group could involve scar resorption rather than preventative expansion. As the authors indicate, this finding is in agreement with previous studies in streptozotocin-induced diabetic mouse model of heart failure with reduced ejection fraction (HFrEF) (6) and in cardiac fibroblasts (10). Therefore, exploring the potential effect of LCZ696 on cardiac regeneration and repair would be intriguing.

With the manifestations of AMI-induced HFrEF, it is quite surprising that there was no apparent effect on renal function in any of the groups in this study, which may be a consequence of using healthy adult rabbits. Therefore, future studies in animal models of disease (i.e., hypertension, diabetes, and so on) may provide more information on the effects of LCZ696 in the context of AMI and subsequent HF in the presence of 1 or more risk factors for cardiovascular disease, which also impact renal function.

Based on the new findings from Torrado et al. (7), we are optimistic that LCZ696 might be utilized as a therapeutic to reduce infarct size and HF manifestation. More mechanistic studies are warranted to elucidate the pathways leading to such benefits with LCZ696 while awaiting the outcomes of the PARADISE-MI trial. Although treatment of HFrEF patients with New York Heart Association functional class II to IV was an excellent indication for ARNi therapy, the ability of this drug to treat AMI and prevent consequent ischemic HF, if proven, would be paramount.