Sacubitril/valsartan reverses myocardial remodelling and improves outcomes in HFrEF
Chronic HF increases risk of death
HF, a chronic condition that affects 64 million people worldwide, is characterized by a progressive decline in heart function and quality of life. [Lancet 2017;390:1211-1259; Am J Cardiol 2005;96:11G-17G]
The HF trajectory is often unpredictable and sudden death can occur at any time, even in patients with mild symptoms. [Heart 2004;90:1137-1143] The risk of unexpected death in HF is 6–9 times higher compared with the normal population, and an estimated 50 percent of patients diagnosed with HF die within 4 years. [Medicographia 2015;37:125-134]
Adverse cardiac remodelling in HF
In response to cardiac injury, the heart undergoes cardiac remodelling – a process that involves molecular, cellular and interstitial changes that manifests clinically as changes in the size, shape and function of the heart. This is regarded as an adverse sign of HF progression. [J Am Coll Cardiol 2000;35:569-582] Remodelling can occur in untreated patients after myocardial infarction (MI) and in those with dilated cardiomyopathy. [JACC Cardiovasc Imaging 2011;4:98-108]
“Remodelling in HFrEF causes changes in left ventricular [LV] shape from elliptical to more spherical, along with increased LV volume and worsening systolic and diastolic functions,” said Gardner. These are accompanied by increases biomarker (eg, N-terminal pro-B-type natriuretic peptide [NT-proBNP], soluble suppression of tumorigenesis 2 [sST2], high-sensitivity troponin T [hsTnT]) concentrations. [J Am Coll Cardiol HF 2019;7:782-794]
“Adverse cardiac remodelling is associated with high morbidity and mortality. As cardiac function deteriorates, patients experience symptoms worsening followed by a decline in life expectancy,” noted Gardner.
Beneficial reverse remodelling significantly improves prognosis
Over the past three decades, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs), β-blockers and mineralocorticoid receptor antagonists (MRAs) have been the cornerstone of pharmacotherapy for HFrEF. Patients with HFrEF (LV ejection fraction [LVEF] ≤40 percent) treated with these agents who demonstrated reverse cardiac remodelling also experienced improved clinical outcomes in clinical trials. [Circulation 1994;89:68-75; Circulation 2004;109:201-206]
A meta-analysis of 30 HF therapy trials conducted in patients with HFrEF established a close relationship between functional changes in the heart, in terms of LVEF, LV end diastolic volume (LVEDV) and LV end systolic volume (LVESV), and mortality. [J Am Coll Cardiol 2010;56:392-406]
“Variables that conferred a higher likelihood of reverse remodelling were female sex, nonischaemic aetiology, shorter disease duration, lower LVEF, absence of scar/fibrosis, and lower/falling biomarker levels,” pointed out Gardner. [J Am Coll Cardiol HF 2019;7:782-794]
Reverse cardiac remodelling with sacubitril/valsartan and clinical outcomes
Sacubitril/valsartan is a first-in-class ARNI indicated for the treatment of patients with symptomatic HFrEF. [Entresto Hong Kong Prescribing Information, February 2016] It has become the European Society of Cardiology guideline-recommended first-line treatment for HFrEF, replacing ACEIs or ARBs. [Eur Heart J 2016;37:2129-2200]
“The complementary actions of sacubitril and valsartan achieve antifibrotic effects along with vasodilation, natriuresis and diuresis, which can potentially attenuate adverse LV remodelling in HFrEF,” said Gardner.
Several clinical studies have provided evidence for the positive impact of sacubitril/valsartan on cardiac remodelling. A double-blind study, PRIME, randomized 118 patients with HF and chronic functional mitral regurgitation (MR) to receive either sacubitril/valsartan or valsartan, in addition to standard medical therapy for HF. Patients on sacubitril/valsartan experienced greater reductions in MR, LVEDV index (LVEDVi), and left atrial volume index (LAVi) than those who received valsartan. [Circulation 2019;139:1354-1365] A meta-analysis of small observational studies of sacubitril/valsartan in HFrEF further confirmed its beneficial effects on LVEF, LV volume, LAV and LV mass over earlier HF therapies. [J Am Heart Assoc 2019;8:e012272]
Larger clinical trials, such as PARADIGM-HF, PIONEER-HF, PROVE-HF and EVALUATE-HF, which explored the effects of sacubitril/valsartan on HF reversal and associated improvements in outcomes, have confirmed these observations.
The randomized, double-blind PARADIGM-HF trial compared the efficacy and safety of sacubitril/valsartan vs enalapril in 8,442 patients with HFrEF (LVEF ≤40 percent). The primary endpoint was a composite of death from cardiovascular (CV) causes or a first hospitalization for HF. [N Engl J Med 2014;371:993-1004]
“After a median follow-up of 27 months, the trial was stopped prematurely because of the overwhelming benefit achieved with sacubitril/valsartan,” said Gardner.
Results showed a 20 percent relative risk reduction in the primary composite endpoint with sacubitril/valsartan vs enalapril (hazard ratio [HR], 0.80; 95 percent confidence interval [CI], 0.73 to 0.87; p<0.001). Comparable reductions were observed with sacubitril/valsartan for the individual components, namely, CV mortality (HR, 0.80; 95 percent CI, 0.71 to 0.89; p<0.001) and hospitalization for HF (HR, 0.79; 95 percent CI, 0.71 to 0.89; p<0.001).
Further analysis of PARADIGM-HF data showed that sacubitril/valsartan reduced the risk of hospitalization by 40 percent vs enalapril during the first 30 days after randomization (HR, 0.60; 95 percent CI, 0.38 to 0.94; p=0.027), and this benefit was sustained for recurrent HF hospitalizations in the following months. [Circulation 2015;131:54-61; Circulation 2016;134:A19644]
“Interestingly, the study also reported a 20 percent reduction in the risk of sudden death vs enalapril [HR, 0.80; 95 percent CI, 0.68 to 0.94; p=0.008],” highlighted Gardner. (Figure 1) [Eur Heart J 2015;36:1990-1997]
“Sacubitril/valsartan reduced NT-proBNP – the best surrogate marker of outcome – to a greater extent than enalapril, which reflects the much improved prognosis with this therapy,” remarked Gardner. [Circulation 2015;131:54-61]
PIONEER-HF was a randomized double-blind trial of sacubitril/valsartan vs enalapril in 881 patients hospitalized with decompensated HFrEF. Results showed a significantly greater reduction in NT-proBNP concentration with sacubitril/valsartan vs enalapril – a benefit that was evident as early as the first week of the 8-week trial period (ratio of change, 0.76; 95 percent CI, 0.69 to 0.85). There was also a 46 percent reduction in the composite outcome of serious clinical events (death, rehospitalization for HF, implantation of LV assist device, and listing for heart transplantation) associated with sacubitril/valsartan vs enalapril (HR, 0.54; 95 percent CI, 0.37 to 0.79). [N Engl J Med 2019;380:539-548]
An exploratory analysis of the PIONEER-HF data showed that the benefit on this composite outcome was driven by reductions in CV death or rehospitalization for HF (HR, 0.58; 95 percent CI, 0.39 to 0.87; p=0.007). [Circulation 2019;139:2285-2288]
“Initiation of sacubitril/valsartan significantly reduced the incidence of first rehospitalization for HF in a short period of time [8.5 percent vs 13.6 percent for enalapril by week 8; HR, 0.61; 95 percent CI, 0.40 to 0.93; p=0.021]. This was achieved without any significant increase in adverse events compared with enalapril,” noted Gardner. (Figure 2) [N Engl J Med 2019;380:539-548; Circulation 2019;139:2285-2288]
In the prospective, single-arm, open-label PROVE-HF study in 794 patients with HFrEF, researchers assessed the association between change in NT-proBNP level after starting sacubitril/valsartan and changes in markers of cardiac remodelling at 12 months. [JAMA 2019;322:1085-1095]
Treatment with sacubitril/valsartan led to a substantial reduction in median NT-proBNP level, from 816 pg/mL at baseline to 455 pg/mL at 12 months, with most of the reduction occurring within the first 2 weeks after treatment initiation. At 12 months, the change in NT-proBNP concentration significantly correlated with changes in LVEF, LVEDV index (LVEDVi), LVESVi, LAVi and mitral E/e′ ratio (p<0.0001 for all). Furthermore, significant improvements in LVEF were observed at 6 and 12 months, with corresponding decreases in LVEDVi and LVESVi.
“An important finding in this study was that patients who exhibited the largest reductions in NT-proBNP levels as well as LVESVi by 6 months experienced the lowest rates of subsequent death or HF hospitalization by 12 months,” noted Gardner. (Figure 3) [Circ Heart Fail 2020;13:e006946]
In addition, PROVE-HF demonstrated correlations between change in NT-proBNP and cardiac volume and function among three prespecified subgroups not represented in the PARADIGM-HF trial (namely: 1, new-onset HF patients [diagnosis <60 days from study enrollment] and/or not taking an ACEI or ARB at baseline; 2, patients with NTproBNP<600 pg/mL if not hospitalized or <400 pg/mL if hospitalized, BNP <150 pg/mL if not hospitalized or <100 pg/mL if hospitalized; and 3, patients not reaching target 97/103 mg BID doses of sacubitril/valsartan) that were similar to the group as a whole. The only exception was the lack of a significant change in E/e’ among patients not attaining the target dose of sacubitril/valsartan. [JAMA 2019;322:1085-1095]
In the 12-week, randomized, double-blind EVALUATE-HF trial, researchers assessed the effects of sacubitril/valsartan vs enalapril on central aortic stiffness and cardiac remodelling in 464 patients with HFrEF. [JAMA 2019;322:1-10]
“Although there was no difference in change in aortic stiffness between the two treatments, significantly greater reductions in several cardiac parameters and biomarkers, including LVEDVi [p=0.02], LVESVi [p=0.045], LAVi [p<0.001], NT-proBNP [p<0.001], sST2 [p=0.006], and hsTNT [p<0.001] were observed with sacubitril/valsartan,” commented Gardner. “The change in NT-proBNP was also correlated with improvements in quality of life, which is exceedingly important for patients.”
“Chronic HF presents a high risk of death even in patients with mild symptoms. Therefore, it is important to recognize HF early and ensure that patients receive optimal medical treatment for best clinical outcomes. Sacubitril/valsartan promotes reverse cardiac remodelling in patients with HFrEF, thereby reducing CV mortality and HF hospitalization and, given that shorter disease duration makes reverse remodelling more likely, sacubitril/valsartan should be used in the first line,” Gardner concluded.