ARNIs: Shifting the PARADIGM in Heart Failure?

Written By

Peter Koval, PharmD, CPP, BCPS
Stacey Karl, PharmD

Reviewed By

Matthew Pitlick, Pharm.D., BCPS
William D. Linn, Pharm.D.


McMurray JV, Parker M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014; 371: 993-1004.

Heart failure not only causes disability and death but also millions of hospitalizations each year.1  The standard of care for patients with heart failure with reduced ejection fraction (HFrEF) includes a cocktail of drugs comprising an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) plus a beta-blocker and, in many cases, an aldosterone antagonist.1  The angiotensin receptor-neprilysin inhibitors (ARNIs) are a new class of drugs that could change the standard.2

The current model used to describe the pathophysiology of heart failure is the neurohormonal model. Myocardial injury leads to sympathetic nervous system and renin-angiotensin-aldosterone system activation. The activation of these systems leads to ventricular hypertrophy and cardiac remodeling. Neprilysin is an endopeptidase that degrades natriuretic peptides, bradykinin, and adrenomedullin. Thus, neprilysin inhibition would increase the levels of these peptides increase and counteract the neurohormonal activation seen in heart failure.  But would such approach when combined with our current standards of treatments actually work?  The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) was designed to answer this question by comparing treatment with an ACE-inhibitor to a combination neprilysin inhibitor – ARB combination product.2

This double-blind, multi-center trial evaluated LCZ696, a combination of valsartan (160mg equivalent dose) and the NRNI sacubitril (n = 4187) given twice daily, versus enalapril 10mg twice daily (n = 4212) in patients with symptomatic heart failure and a low ejection fraction (EF). All patients in the study received other evidenced-based HFrEF therapies as indicated and tolerated. Inclusion criteria were age >18 years, NYHA class II, III, or IV symptoms, an EF of less than 35%, and a BNP level of 150 pg/mL or NT-proBNP level of 600 pg/mL or greater, or if hospitalized for heart failure in the past 12 months, a BNP of 100 pg/mL or NT-proBNT of 400 pg/mL or greater. Major exclusion criteria were symptomatic hypotension, systolic blood pressure less than 95 mm Hg at randomization, an estimated glomerular filtration rate (eGFR) less than 30 ml/min/1.73m2 at screening or more than a 35% decrease in eGFR between screening and randomization, a serum potassium level of greater than 5.2 mmol/L at screening or greater than 5.4 mmol/L at randomization, or a history of angioedema. The primary outcome was a composite of death from cardiovascular causes or first heart failure hospitalization. Secondary outcomes included time to death from any causes, the change from baseline to 8 months in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score, the time to a new onset of atrial fibrillation, and the time to the first occurrence of a decline in renal function (end stage renal disease, 50% decrease in eGFR, or a decrease of 30 ml/min/1.73m2 to less than 60 ml/min/1.73m2). Baseline characteristics were similar in both groups. The “average” patient in PARADIGM-HF was a 64 year old Caucasian male with NYHA II heart failure, an EF of 30% due to ischemic cardiomyopathy, and taking standard heart failure therapy. The mean systolic blood pressure was 121.5 mm Hg and average serum creatinine 1.13 mg/dL. Although PARADIGM-HF included patients from all NYHA classes of heart failure, nearly 70% had NYHA class II heart failure.  Approximately 24% or patients had NYHA class III.  Class I (5%) and class IV (<1%) heart failure patients were under-represented in this study.2

PARADIGM-HF was halted early after a median follow up of 27 months (planned duration = 34 months) due to the overwhelming benefit seen with valsartan-sacubitril (See Table 1).

Table 1. PARADIGM –HF Results2

Primary Endpoints




P value


Composite of CV deaths and HF hospitalization






Death from CV causes






First hospitalization for worsening heart failure






Secondary Endpoints






Death from any cause






Change in KCCQ score



Diff 1.64



New-onset AFib






Decline in renal function







Valsartan-sacubitril was generally well tolerated by patients. Enalapril was significantly more likely to increased serum creatinine to greater than 2.5 mg/dL and potassium greater than 6.0 mmol/L when compared to valsartan-sacubitril.  Enalapril-treated patients were more likely to experience a cough (14.3 vs. 11.3%; p < 0.001).  Conversely, valsartan-sacuitril patients were significantly more like to experience symptomatic hypotension (14.0 vs. 9.2%; p<0.001). There was no significant difference between the groups with respect to the incidence of angioedema (less than 0.5% in both groups).2

ACEIs and ARBs are associated with hyperkalemia and elevated serum creatinine and these parameters need to be routinely monitored in patients taking ACEIs and ARBs. A general rule of thumb is that serum creatinine may increase up to 30% before the ACEI or ARB is discontinued. In order to minimize adverse effects, doses are usually started low and titrated up as tolerated. In the SOLVD trial, which used a mean daily dose of enalapril of 11.2 mg, 6.4% of patients had a potassium >5.5 mmol/L compared to 2.5% of patients on placebo.3  In PARADIGM-HF both valsartan-sacubitril and enalapril treated patients experienced increased potassium and serum creatinine.  If the valsartan-sacubitril combination product is approved, similar to ACE-inhibitors and ARBs. potassium and renal function should be routinely monitored.

Both valsartan-sacubitril and enalapril decreased blood pressure. According to the supplementary material, hypotension (systolic blood pressure < 90 mmHg) occurred in 17.6% of patients in the valsartan-sacubitril group and in 12.0% of the enalapril group. After 8 months of treatment, systolic blood pressure was 3.2 mm Hg lower in the valsartan-sacubitril group than in the enalapril group. Therefore valsartan-sacubitril may be useful in those with elevated blood pressure but may not be the best choice in patients who are at high risk for hypotension. It should be remembered that valsartan was used at the maximum dose while enalapril was not. Similar rates of hypotension may be seen when enalapril is titrated to 20 mg twice a day.

One potential limitation of PARADIGM-HF study was the use of the maximal dose of valsartan in the valsartan-sacubitril combination but not the maximum dose of enalapril.2   The mean daily dose for valsartan-sacubitril was 375 mg and 18.9 mg for enalapril.  It is possible the lower dose of enalapril impacted the results.  ATLAS compared the effects of low and high doses of lisinopril on morbidity and mortality in heart failure patients.4 The average dose was 4.5 mg daily in the low-dose group and was 33.2 mg in the high dose group. While the study found no statistically significant difference in all-cause mortality, high dose lisinopril significantly reduced the composite endpoint of all-cause mortality and hospitalization for heart failure (55.1% vs. 60.4%; p<0.001).  How much of the differences obversed in PARADIGM-HF can be explain by the doses used?  Who knows?

A likely barrier to using valsartan-sacubitril will be cost. Many ACE-inhibitors are on drug discount lists at a cost of less than $4 per month. A pharmacoeconomic analysis, including hospitalization and monitoring costs, will be needed to justify the routine use of valsartan-sacubitril when pricing information becomes available. 

PARADIGM-HF challenges ACEI’s place in therapy.  Valsartan-sacubitril demonstrated clear superiority when compared to enalapril for the treatment of HFrEF.2 Valsartan-sacubitril reduced all cause mortality (NNT = 36) and decreased heart failure hospitalizations (NNT = 36) when compared enalapril.  Moreover, the deleterious effects of serum potassium and renal function often seen with ACEIs were less with valsartan-sacubitril. Will PARADIGM-HF change the standard of care for HFrEF?  What do you think?



This is an industry-funded study: enough said about the limitations thereof. The randomized groups did not receive - in my opinion - treatments that truly tested the new ARNI independently. Why was the ANRI not added to the (suboptimally-dosed) enalapril? Because of the industry interest. I'm very interested in this new class of drugs, make no mistake about that, but I will NOT preach and teach the 'overwhelming significance' of the differences found in this trial, for the reasons just stated. We've all lived long enough to recognize the threats to the integrity of this supposed 'comparison'. Time and patience will give us better data.