Results were released today from the first two clinical studies designed specifically to examine the effects of the heart drug sacubitril/valsartan on the structure and function of the failing heart.
Treatment with sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor (ARNI), substantially lowers rates of death and hospitalization in certain types of heart failure patients.
However, the mechanisms by which the drug actually affects the heart are poorly understood.
These two new studies suggest a key effect of ARNI is to reverse cardiac remodeling – a finding that could lead to better management of this condition.
One of the studies, called PROVE-HF, was led by James L. Januzzi, MD, a physician in the Division of Cardiology at Massachusetts General Hospital (MGH).
The other study, called EVALUATE-HF, was led by Akshay S. Desai, MD, director of Cardiomyopathy and Heart Failure in the Cardiovascular Division at Brigham and Women’s Hospital.
Both studies were published online this morning in the Journal of the American Medical Association and presented today at the European Society of Cardiology Scientific Sessions in Paris, France. Scott Solomon, MD, director of Noninvasive Cardiology and senior physician at Brigham and Women’s Hospital, helped to lead both studies, and is a co-author on both reports.
In heart failure, progressive cardiac remodeling leads to changes in the shape and size of the heart, contributing to weakened heart function and progressive symptoms such as shortness of breath, reduced exercise capacity, and fluid retention.
The researchers found that treatment with ARNI was associated with significant improvements in cardiac structure and function and that these changes were strongly associated with reductions in blood levels of the biomarker amino-terminal-pro-B-type natriuretic peptide (NT-proBNP).
Levels of NT-proBNP levels are tightly linked to the risk of death and heart failure hospitalization.
“In remodeling, the heart gets larger and stiffer, making it more difficult for it to pump,” says Januzzi.
“Reversing remodeling can reduce those effects and lead to better function.”
The PROVE-HF trial was a prospective, single arm study of nearly 800 patients with heart failure and reduced ejection fraction who were over the age of 65 and had just started on ARNI.
Patients were followed for one year and monitored serially with blood tests to measure cardiac biomarkers and echocardiography to assess cardiac structure and function.
Treatment with ARNI rapidly and significantly lowered levels of NT-proBNP at one year, and this reduction in levels of the biomarker was strongly associated with improvements in cardiac structure and function at both six months and one year.
Ejection fraction is an important measure of the heart’s ability to pump blood.
When the study started, the mean ejection fraction among the participants was just 28%:
In healthy individuals that number is usually above 50%.
After patients started the drug their ejection fraction levels rose by an average of 9.5% per quarter, with 25% patients seeing dramatic increases of 13% or more.
“An overwhelming number of patients showed improvement, and some people were all the way back to a normal ejection fraction level by the end of study,” says Januzzi.
An important observation of the PROVE-HF study was that ARNI appeared to benefit patients that had not been studied in previous trials of the drug, including those with relatively new-onset heart failure, those with lower concentrations of NT-proBNP, and those who could not tolerate higher doses of the medication.
Safety and tolerability of ARNI at one year were also consistent with the findings of the PARADIGM-HF trial, which led to initial FDA approval of the drug. “Our results suggest that ARNI therapy would be expected to benefit a wide range of patients suffering from heart failure with reduced ejection fraction,” Januzzi says.
Changes in cardiac structure and function may also be closely related to progressive stiffening of the aorta, which increases the load on the failing heart and may stimulate further cardiac remodeling.
The second study, EVALUATE-HF, was designed as a prospective, randomized comparison of the effects of ARNI versus enalapril (a cornerstone of heart failure treatment) on aortic stiffness and cardiac structure and function in patients with heart failure and reduced ejection fraction.
This study randomly allocated 464 patients with chronic heart failure, reduced ejection fraction, and history of high blood pressure to treatment with ARNI or enalapril and followed them for a period of 12 weeks with periodic assessment of arterial stiffness, cardiac structure and function, cardiac biomarkers, and quality of life.
At 12 weeks, no difference was noted between the two treatments with regard to change in aortic impedance – a measure of aortic stiffness.
However, consistent with PROVE-HF’s findings, significant reductions were seen with ARNI in secondary measures of cardiac structure and function. In this study, improvements in remodeling were also correlated to reductions in NT-proBNP and improvements in quality of life.
Overall, the EVALUATE-HF data suggest that the clinical benefits of ARNI are likely unrelated to changes in central aortic stiffness, but might be related to favorable early effects of neprilysin inhibition (one of the primary effects of ARNI) on myocardial remodeling.
“Significant improvements in cardiac structure and function, biomarkers of cardiac wall stress and injury, and overall quality of life in the patients treated with sacubitril/valsartan, compared to those treated with enalapril after just 12 weeks underscores the potent effect of sacubitril/valsartan on cardiac remodeling in heart failure,” said Desai.
“Together, the PROVE-HF and EVALUATE-HF studies present compelling evidence that the established clinical benefits of sacubitril/valsartan in patients with heart failure and reduced ejection fraction may be related to improvements in cardiac structure and function,” said Desai.
“These trials suggest that sacubitril/valsartan may actually reverse the cardiac remodeling that drives heart failure progression and worsening of clinical outcomes.”
Journal information: Journal of the American Medical Association
Provided by Massachusetts General Hospital
Clinical Applications of ARNi
Heart Failure with Reduced Ejection Fraction
The prospective comparison of angiotensin receptor–neprilysin inhibitor with ACEi to determine impact on global mortality and morbidity in heart failure (PARADIGM-HF) trial first tested sacubitril/valsartan in HFrEF .
In PARADIGM-HF, sacubitril/valsartan was compared to enalapril in a cohort of patients affected by symptomatic HFrEF with left ventricular ejection fraction (LVEF) ≤ 35% and elevated B-type NP levels or hospitalization for HF within the previous year.
Sacubitril/valsartan proved to be more effective than enalapril in reducing the primary outcome, a composite of death from CV causes or first hospitalization for HF (Table 1).
Although there were more events of symptomatic hypotension in the case of using sacubitril/valsartan, more participants assigned to enalapril discontinued their study medication due to adverse effects.
In clinical practice, this would mean a higher proportion of patients achieving optimal RAAS inhibition (as well as the additional benefits associated with concomitant neprilysin inhibition) with an ARNi rather than with enalapril. 
Main clinical trials about the effects of LCZ696 on cardiovascular outcomes.
|Study; Aim||Study Population||Design||Outcomes|
|PARADIGM-HF (and post hoc analysis)|
Comparison of efficacy of LCZ696 versus enalapril in patients with HFrEF (LVEF ≤35%) [5,47]
|Patients with symptomatic HFrEF (NYHA functional classes II to IV), and elevated B-type natriuretic peptide levels or hospitalization for HF within the previous 12 months;|
n = 8442
|Multicenter, randomized, double-blind study||LCZ696 reduced the composite primary of CV death or HF hospitalization more than enalapril;|
LCZ696 reduced secondary endpoint more than enalapril:
• any CV death;
• first worsening HF hospitalization;
• all-cause mortality
Moreover, LCZ696 group had fewer hospitalizations for worsening HF, less necessity to receive intensive care, intravenous positive inotropic agents, and to have implantation of a HF device or cardiac transplantation.
To assess the safety and tolerability of starting a therapy with LCZ696 while still in the hospital or after discharge 
|HFrEF patients hospitalized|
for ADHF, after stabilization
n = 1002
|Multicenter, randomized, open-label, parallel-group study||The percentage of patients taking target dose of sacubitril/valsartan 200 mg BID at 10 weeks post randomization was the same among patients who started taking LCZ696 during hospitalization or after discharge|
To assess the percentage change from baseline in NTproBNP levels with LCZ696 
|HFrEF patients hospitalized for ADHF after stabilization|
n = 736
|Multicenter, randomized, double-blind study||LCZ696 led to a reduction in the NTproBNP concentration than a therapy with enalapril at 4 and 8 weeks;|
LCZ696 led to a reduction in the level of high-sensitivity cardiac troponin T;
LCZ696 led to lower rate of rehospitalization for HF
To assess the tolerability of initiating/uptitrating LCZ696 from 50 to 200 mg BID over 3 and 6 weeks 
|Patients with symptomatic HFrEF (NYHA functional classes II to IV) + one or more of the following additional eligibility requirements: for outpatients currently treated with ACEi/ARB, the dose must have been stable for at least 2 weeks; to be classified as ACEi/ARB-naïve, the patient must not have taken ACEi/ARB for at least 4weeks; hospitalized patients had to be either ACEi/ARB-naïve, or on a tolerated dose of an ACEi/ARB at screening|
n = 429
|Multicenter, randomized, double bind, parallel study||Initiation/uptitration of LCZ696 from 50 to 200 mg BID had a tolerability profile in line with other HF treatments.|
To assess the efficacy of LCZ96 versus valsartan to change NTproBNP levels from baseline 
|Patients with signs and symptoms of HF, ≥40 years, with NTproBNP ≥400 pg/mL and a LVEF ≥45%, while on active diuretic therapy|
n = 301
|Multicenter, randomized, double-blind study||The decline in NTproBNP at 12 weeks after initiation of the treatment was greater in the LCZ696 group. LCZ969 was also able to ameliorate LA size and NHYA class (secondary endpoints)|
To assess the efficacy of LCZ696 versus olmesartan in reducing arterial stiffness 
|Elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mmHg|
n = 454
|Multicenter, randomized, double-blind study||LCZ696 reduced central aortic SBP more than olmesartan and reduced mean 24-hour ambulatory brachial and central aortic SBP|
ACEi: angiotensin converting enzyme inhibitors; ARB: angiotensin II receptor I blockers; CV: cardiovascular; ADHF: acute decompensated heart failure; BID: bis in die; LVEF: left ventricular ejection fraction; HFrEF: heart failure with reduced ejection fraction; HFrpEF: heart failure with preserved ejection fraction; NTproBNP: amino-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association; SBP: systolic blood pressure.
Improvement in the prognosis of patients assigned to sacubitril/valsartan also remained consistent in the subgroup of prediabetic, undiagnosed diabetic, and diagnosed diabetic patients, who are at a higher risk of adverse CV outcomes .
A subsequent analysis of the PARADIGM trial reported that sacubitril/valsartan use was associated with further evidence of clinical benefit in comparison with enalapril, including fewer visits to an emergency department for HF, a reduced need for intensification of the treatment for HF, and a lower requirement for intensive care, HF devices, or cardiac transplantation .
Moreover, another subsequent analysis of PARADIGM trial, which has enrolled almost half of the patients with a high CV risk, showed fewer coronary events in those treated with sacubitril/valsartan .
A recent experimental study in rats provided insight into the differential effects of sacubitril and valsartan in a model of HF.
In particular, it has been shown that sacubitril in association with valsartan significantly improves load-dependent left ventricle contractility and relaxation with a reduction of myocardial collagen content, while the improvement in load-independent left ventricular contractility is due to valsartan .
Following the evidence for chronic HF, the PIONEER-HF study, a multicenter trial, has been designed to investigate the role of sacubitril/valsartan in patients affected by HFrEF hospitalized for an episode of acute HF (AHF), after hemodynamic stabilization, regardless of the duration of diagnosis or background HF therapy, and without a preceding run-in period.
Thus, this trial has been performed in treatment-naïve hospitalized patients.
The primary endpoint of PIONEER-HF was the proportional change in amino-terminal pro-brain natriuretic peptide (NTproBNP) level from baseline through one month and then two months.
The main result was that sacubitril/valsartan led to a greater reduction in the NTproBNP concentration than enalapril from the first week of treatment, as well as to a decrease of markers of myocardial injury.
Furthermore, in-hospital initiation of sacubitril/valsartan therapy was associated with a subsequent lower rate of rehospitalizations for HF. The rates of experienced side effects did not differ significantly between the sacubitril/valsartan group and the enalapril group .
More insights about the management of patients hospitalized for HF have been retrieved by the TRANSITION trial.
This is a randomized, phase IV, multicenter, open-label study which assessed the safety and tolerability of introducing a therapy with sacubitril/valsartan in 1002 patients hospitalized for decompensated acute HFrEF still in the hospital or once discharged.
Almost one-third of patients were newly diagnosed with HFrEF, and one-quarter were naïve to ACEi or ARB.
The primary endpoint of achieving the target dose of sacubitril/valsartan 200 mg BID at 10 weeks after randomization has been achieved in 45% of patients that started taking sacubitril/valsartan in hospital, and in 50.4% of the post-discharge group, without any significant difference in adverse effects between the two groups .
Recently, subsequent analyses of previous trials have given more insightful data about a specific subset of patients.
Indeed, a post hoc analysis of the PARADIGM trial investigated the effects of sacubitril/valsartan in diabetic patients, showing that this treatment leads to a better glycemic profile (reduction of Hb1Ac and less need to undertake insulin therapy or oral hypoglycemic agents) in the long term, independent of the reduction in body weight . Similar beneficial effects of sacubitril/valsartan on lipid and glucose metabolism have also been reported in hypertensive obese patients as .
Preclinical models of diabetes seem to indicate that this beneficial effect of sacubitril/valsartan depends on the rise in NP levels, bradykinin, glucagon-like peptide 1, and on the reduction in angiotensin II levels that would result in subsequently improved insulin sensitivity [62,63].
These data may have great clinical relevance since diabetes is not only a comorbidity widely present among HF patients, but its evolution can substantially modify the patient prognosis.
Moreover, recent interesting preclinical data seem to confirm the beneficial effects of sacubitril/valsartan on vascular and neural complications in type 2 diabetes, giving room for hypotheses about possible wider future applications of ARNi in diabetic patients .
Heart Failure with Preserved Ejection Fraction
Up to now, sacubitril/valsartan does not have an official indication in patients with HFpEF. However, it has also been supposed to play a beneficial effect in HFpEF by blocking a profibrotic/prohypertrophic mechanism (valsartan) while stimulating an antifibrotic/antihypertrophic mechanism (sacubitril) .
Indeed, the RAAS may play a pivotal role in enhancing the inflammation, endothelial dysfunction, and remodeling implicated in the progression of HFpEF. Despite this, RAAS inhibitors have failed to demonstrate mortality benefits in this setting.
Beyond the single RAAS inhibition, the sacubitril/valsartan might ameliorate several key pathways in the development of HFpEF, namely cardiac remodeling, such as left ventricular hypertrophy and stiffness, microvascular dysfunction, and oxidative stress by increasing NPs levels . Sacubitril/valsartan has been tested in a phase II trial in patients affected by HFpEF, the PARAMOUNT (prospective comparison of ARNi with ARB on management of heart failure with preserved ejection fraction) trial . In this trial, sacubitril/valsartan 200 mg BID was compared with valsartan 160 mg BID in patients symptomatic for HFpEF, aged ≥40 years, with NTproBNP ≥400 pg/mL, while on diuretic therapy. The primary endpoint, the decline in NTproBNP at 12 weeks, was greater in the sacubitril/valsartan group.
Furthermore, after 9 months, the left atrial dimension, which may indicate diastolic function , declined more in the sacubitril/valsartan arm as well as markers of fibrosis . Subsequent analyses have shown that these sacubitril/valsartan effects were independent of the BP-lowering effect . In addition, patients in the sacubitril/valsartan arm had greater improvements in New York Heart Association (NYHA) class and preserved better renal function compared to the valsartan group .
Given these favorable results, the current phase III PARAGON (prospective comparison of sacubitril/valsartan with ARB global outcome in HF with preserved ejection fraction) trial has been designed to determine whether sacubitril/valsartan can reduce CV death or total HF hospitalizations in patients with HFpEF. This trial has enrolled symptomatic patients with LVEF ≥45% and elevated NP, or history of HF hospitalization within 9 months and evidence of structural heart disease. The results of this trial are expected in 2019 .
Finally, the randomized, 24-week, double-blind multicenter controlled study comparing sacubitril/valsartan with medical therapy for comorbidities in HFpEF patients (PARALLAX) is currently recruiting participants to test the superiority of LCZ696 in reducing NTproBNP levels and improving HF symptoms and exercise function in HFpEF patients .
Preclinical studies have given insights on how may ARNi favorably exert antihypertensive and cardioprotective effects in animal models of hypertension . In fact, a significant reduction of BP and proteinuria levels and a full prevention from stroke was observed over long-term treatment with sacubitril/valsartan, as compared to valsartan, in the high-salt-fed, stroke-prone, spontaneously hypertensive rat . Furthermore, in a model of spontaneous hypertensive rat, sacubitril/valsartan proved to be as effective as valsartan in improving endothelium-dependent and -independent vasorelaxation . Moreover, sacubitril/valsartan has shown an improved ability to reduce BP levels compared to valsartan, regardless of the amount of salt intake. This effect was associated with a significant increase of urinary sodium excretion and suppression of sympathetic activity. In addition, it reduced myocardial inflammation, remodeling, and endothelial dysfunction, also ameliorating coronary circulation .
In hypertensive patients, a proof-of-concept trial enrolling mostly white, mild-to-moderate hypertensive patients demonstrated that compared with valsartan or AHU377 alone, sacubitril/valsartan treatment for 2 months provided additional reduction of BP, systolic, diastolic, and pulse pressures, both sitting and ambulatory, without any excess in serious adverse effects . In the PARAMETER (prospective comparison of angiotensin receptor–neprilysin inhibitor with angiotensin receptor blocker measuring arterial stiffness in the elderly) study, sacubitril/valsartan demonstrated efficacy in reducing arterial stiffness in the elderly with systolic hypertension and pulse pressure >60 mmHg . At 3 months, sacubitril/valsartan reduced central aortic systolic BP more than olmesartan and reduced mean 24-hour ambulatory brachial and central aortic systolic BP, therefore, fewer patients in the sacubitril/valsartan group required add-on antihypertensives . Similarly, a recent study in a cohort of elderly Asiatic patients affected by isolated systolic hypertension showed that sacubitril/valsartan was more effective than olmesartan in reducing mean systolic BP and pulse pressure . Tolerability of sacubitril/valsartan and olmesartan was the same.
Furthermore, Ruilope and colleagues demonstrated that LCZ696 monotherapy was dose-dependently superior to valsartan monotherapy by clinical and ambulatory BP measurements for all tested doses . Therefore, available evidence seems to support an application of ARNi as an antihypertensive compound with adequate tolerability and effectiveness throughout 24 hours.