Dr Rachel Bastiaenen, PhD, St George's Hospital, London, UK

Angiotensin-converting-enzyme inhibitors (ACE-I) have been the cornerstone of treatment for heart failure with reduced ejection fraction (HFREF) for nearly a quarter of a century and the heart failure treatment algorithm has remained essentially unchanged for a decade. The arrival of the angiotensin receptor-nephrilysin inhibitor (ARNI) drug LCZ696 (Valsartan-Sacubitril) looks set to change that.

In the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial published in the New England Journal of Medicine, 8442 patients with heart failure (majority NYHA class II) and LVEF ≤40% were randomised to receive LCZ696 200mg BD or Enalapril 10mg BD in addition to standard therapy.(1) The trial was stopped early (median follow-up of 27 months) after overwhelming benefit of LCZ696 was demonstrated. The primary endpoint of death from cardiovascular causes or hospitalisation for heart failure occurred in 21.8% of the LCZ696 group vs 26.5% of the Enalapril group (HR 0.8; 95%CI 0.73-0.87; p<0.001). Individual endpoints demonstrated similar patterns. There was reduced death from cardiovascular causes in the LCZ696 group 13.3% vs the Enalapril group 16.5% (HR 0.80; 95%CI 0.71-0.89; p<0.01) and, as compared with Enalpril, LCZ696 reduced the risk of hospitalisation for heart failure by 21% and decreased the symptoms and physical limitations from heart failure.

These benefits were seen in most of the subgroups except black patients, although this may reflect the small number of black patients included in the study. Following publication there were concerns raised that the results may not apply to patients with LVEF >35% and that the dose of Enalapril studied in the comparison group was lower than the recommended dose used in heart failure.  Data presented at the Heart Failure Society of America 2015 Scientific Meeting have shown that LCZ696 maintained its superiority over ACE inhibitor therapy irrespective of baseline LVEF (up to 40%) and whether the target dose was achieved.(2,3) LCZ696, now known as Entresto, was approved by the The US Food and Drug Administration (FDA) in 2015 and has already been included in the Canadian heart failure guidelines. The reduction in mortality demonstrated by Entresto suggests we should consider changing all our heart failure patients from ACE-I to ARNI, but this may not be feasible financially, and patients who are stable on their heart failure therapy may prefer not to change. Will international guideline recommendations change based on these results?


  1. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
  2. Vardeny O, Claggett B, McMurray JJV, et al. Efficacy of LCZ696 persists at lower than target doses in the PARADIGM-HF trial. J Card Fail 2015; 21:S9. Abstract 260.
  3. Solomon S, Packer M, Zile M, et al. The angiotensin receptor neprilysin inhibitor LCZ696 is effective across the spectrum of ejection fraction in heart failure with reduced ejection fraction. J Card Fail 2015; 21: S45. Abstract 088.
Cardio Debate Expert Comments

The results of the PARADIGM-HF study are without any doubt important and good news for the treatment of patients with chronic heart failure.  The study showed that in symptomatic patients with chronic heart failure despite treatment with beta-blockers and sub-optimal ACE-inhibitor dose, with a left ventricular function <35% and elevated BNP levels LCZ696 was superior to Enalapril 10 mg reducing the risk of death.

A superficial look at the study may suggest that the study sets the stage for a Copernican revolution in the treatment of heart failure.  However, despite the striking results of the PARADIGM-HF several questions remain to be answered before LCZ can definitively replace ACE-inhibitors in the treatment of patients with chronic heart failure.

The steering committee of the study must be congratulated for a clever design that using a ACE-inhibition run-in phase reduced the probability of angioedema during the study. Therefore, while this risk is low in patients who had been pre-treated with an ACE-inhibitor it is to be determined whether the use of LCZ696 is safe in ACE-inhibitor naïve patients.

The benefit seen in patients with elevated natriuretic peptides was relevant but it yet to be demonstrated that in patients with not elevated natriuretic peptides levels the same degree of benefit observed in PARADIGM-HF is maintained or whether the benefit tends to fade below a threshold of natriuretic peptide levels.

In addition, while ACE-inhibitors had been tested in all range of patients with heart failure ranging from acute to chronic the effect of LCZ in patients other than those tested in the PARADIGM-HF remains to be tested.

In conclusion, LCZ696 is an important medicinal product for the treatment of symptomatic chronic heart failure in patients with left ventricular function <35%, elevated natriuretic peptides and able to tolerate medium dose of ACE-inhibitors. It is too early to suggest its widespread use in patients other than those depicted above. An important endorsement of its place in therapy will be given in the next coming months by the guidelines of the Heart Failure Association of the European Society of Cardiology due to be released in May.

ARNIs, particularly sacubitril-valsartan -Entresto®-, have entered the heart failure (HF) field with the force of a tsunami, dramatically altering patient treatment. However, ARNI use is presently restricted to the subgroup of patients with HFrEF, LVEF<40%, and NYHA class II–III. To determine whether sacubitril-valsartan should be prescribed across the full spectrum of HF patients, we await the results of the ongoing PARAGON-HF trial, the pivotal trial for Entresto® in HFpEF.

The PARADIGM-HF trial has provided important data, but leaves several challenges unresolved. Among these, there are important drug tolerability issues related to symptomatic hypotension, hyperkalemia, and renal dysfunction, which may require adjustment of the doses of pharmacological agents that are used concomitantly and/or down-titration or discontinuation of sacubitril-valsartan. There are also additional issues that require clinical trial data to reassure clinicians as appropriate regarding safety issues that can affect day-to-day practice. Theoretically, neprilysin inhibition could also be associated with risks related to the accumulation of the neprilysin substrate, amyloid-β, in the brain. The PARADIGM-HF trial reported no increased incidence of cognition- or dementia-related adverse events; however, it is unlikely –given the relatively short term follow up- that any such effects would be detected.  Dementia may take longer to develop than the trial’s follow up/observation time elapsed to date. Moreover, subjects with mild dementia were not expected to participate in the trial, thus making the evaluation of potential effects of the drug on cognition, more difficult. To further investigate this issue, the PARAGON-HF trial includes among its objectives, the assessment of cognitive function. Also importantly, the cost of the treatment with this new agent is likely to represent a  barrier to its use in everyday real-life clinical practice, since the cost of effective agents such as the ACEI enalapril is very low (comparable to the cost of chewing gum in many countries). Conceivably, the implementation of a biomarker-driven strategy may be proposed to preferentially switch from ACEI treatment to Entresto® in the sickest patients. Along these lines, it is noteworthy that the use of natriuretic peptides was among the inclusion criteria in the PARADIGM-HF trial.

The PARADIGM-HF trial proves that Entresto is superior to enalapril for patients with heart failure and a reduced left ventricular ejection fraction (LVEF) even when the latter is given at doses higher than is usual in clinical practice. The study design required to prove this hypothesis had to be relatively complex; patients had to be stable and tolerate high doses of both agents before they could be enrolled. However, subsequently, more than 40% of patients required dose reductions, which occurred similarly often with each agent. This was not associated with loss of superiority of Entresto. Accordingly, it is reasonable to believe that Entresto is effective even in patients who cannot tolerate high doses of either agent. The effect compared to an imputed placebo is large; about double that scribed to an ACE inhibitor in a similar patient population.

So who should or should not get Entresto? Lack of evidence about safety or efficacy are two reasons not to prescribe Entresto to all patients with heart failure.

There is little or no experience of initiating Entresto in unstable patients, especially if they are ACE inhibitor naïve, or those with a systolic blood pressure <100mmHg. For safety reasons, Entresto should not be initiated in hospital during the recovery phase of a recent heart failure decompensation unless as part of an audit or research protocol. With more experience and information these safety contra-indications may be lifted.

Entresto has only been shown to be effective when LVEF is reduced but many patients with heart failure have a preserved LVEF; a large trial (PARAGON-HF) in such patients should complete enrolment in 2016 and will determine whether the indications for Entresto should be extended to this group of patients. In PARADIGM-HF, patients also had to have at least modestly elevated plasma concentrations of natriuretic peptides (eg:- NT-proBNP >400ng/L), which excluded many low-risk patients. Although the benefits of Entresto in relative terms might be as great for patients who have NT-proBNP <400ng/L, because they are at lower risk, the absolute benefits are likely to be smaller, reducing cost-effectiveness. When the PARADIGM-HF results were announced some joked that it was time to buy shares in Roche (which provides assays for NT-proBNP). Many a true word said in jest! For the cost of a few days treatment with Entresto, a measurement of NT-proBNP will convince you and your patient of the need, or lack thereof, to switch from an ACE inhibitor to Entresto. Routine measurement of NT-proBNP will stimulate people to switch and, at the same time, confirm that the switch is justified. Unfortunately, all the regulators have ignored this key inclusion criterion for fear that those who cannot afford to measure NT-proBNP will be precluded from prescribing a medicine that, though cost-effective when given to the right patients, is nonetheless costly. What folly!