Interpreting Key Trials

A new class of drugs for systolic heart failure: The PARADIGM-HF study

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ABSTRACTThe PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) found a combination drug containing sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II receptor blocker) superior to enalapril (an angiotensin-converting enzyme inhibitor) in patients with systolic heart failure. Recently approved by the US Food and Drug Administration, sacubitril-valsartan is the first new drug in over a decade to decrease death rates in patients with systolic heart failure.


  • Neprilysin is an endogenous enzyme that degrades vasoactive peptides such as bradykinin and natriuretic peptides. Inhibition of neprilysin raises the levels of these peptides, leading to less cardiac remodeling, less sodium retention, and less vasoconstriction.
  • Neprilysin inhibition must be combined with inhibition of the renin-angiotensin-aldosterone system, optimally with an angiotensin II receptor blocker.
  • PARADIGM-HF showed a 20% reduction in the primary outcome of death from cardiovascular causes or hospitalization for heart failure with sacubitril-valsartan 200 mg twice daily vs enalapril 10 mg twice daily at a median follow-up of 27 months.
  • The ultimate role of combined neprilysin and angiotensin receptor inhibitors remains to be determined.



In a large phase trial, a combination drug that contains the angiotensin II receptor blocker (ARB) valsartan and the neprilysin inhibitor sacubitril was found to be superior to the angiotensin-converting enzyme (ACE) inhibitor enalapril in terms of important end points, including death and hospitalization for heart failure, in patients with heart failure with reduced ejection fraction.1

See related editorial

Recently approved by the US Food and Drug Administration, this combination drug, marketed under the brand name Entresto, represents a new drug class, angiotensin receptor-neprilysin inhibitors, or ARNIs.

This article is an overview of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial1 and the implications it may have on the care of patients with chronic heart failure.


Heart failure is a major public health problem, and the care of patients with heart failure is challenging.

Almost 6 million US adults have heart failure, and the prevalence is projected to increase in the next few decades as the population continues to age.2 Furthermore, the total healthcare cost for heart failure patients was almost $31 billion in 2012 and is projected to rise to $70 billion by 2030.2

The care of patients with severely decompensated heart failure has changed dramatically in the last few decades with advances in heart transplantation and mechanical support devices. But day-to-day management of patients with chronic mildly to moderately symptomatic heart failure continues to pose a clinical challenge.

The drugs currently available for these patients include beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists, digoxin, diuretics, and vasodilators. But even with these drugs, the death and readmission rates of patients with heart failure with reduced ejection fraction remain high. More than 50% of patients with heart failure die within 5 years of diagnosis,3 and 25% of patients hospitalized with heart failure are readmitted within 30 days of discharge.2 Furthermore, death rates are higher in those patients who have a history of heart failure hospitalization.4

Although heart failure with preserved ejection fraction encompasses an important group of heart failure patients with high morbidity, the focus of this article will be on patients with heart failure with reduced ejection fraction.

Available drugs to date

The cornerstone drugs that lower the odds of death in patients with heart failure with reduced ejection fraction are ACE inhibitors, ARBs, beta-blockers, and mineralocorticoid antagonists.

ACE inhibitors were the first class of drugs shown to reduce the death rate in patients with heart failure with reduced ejection fraction. The landmark CONSENSUS trial,5 published in 1987, found that the death rate in patients who received enalapril was 27% lower than in those receiving placebo, an effect driven entirely by a reduction in progressive heart failure. Similarly, the SOLVD trial,6 published in 1991, showed a 26% reduction in heart failure hospitalization and a 16% lower rate of death with enalapril compared with placebo, an effect driven predominantly by a decrease in the progression of heart failure.

ARBs have also been shown to decrease the rate of death, although not by as much as ACE inhibitors. In the CHARM trial,7 compared with placebo, candesartan significantly decreased the risk of death from any cause, of death from cardiovascular causes, and of hospitalization related to heart failure.7

Beta-blockers. The MERIT-HF trial,8 published in 1999, was stopped early because fewer patients were dying in the group receiving metoprolol succinate than in the group receiving placebo (relative risk 0.66). Similarly, in 2001, the COPERNICUS trial9 reported a 34% reduction in deaths in patients receiving carvedilol in addition to an ACE inhibitor compared with those receiving an ACE inhibitor alone.

Mineralocorticoid receptor antagonists were found to be beneficial when added to standard therapy for chronic symptomatic heart failure in the RALES10 and EMPHASIS-HF11 trials.

Vasodilators (specifically, the combination of isosorbide dinitrate and hydralazine) were found to have benefit in terms of mortality when added to standard therapy in African American patients in the A-HeEFT trial.12


The renin-angiotensin-aldosterone system is a major focus in treating heart failure, as overactivity of this system plays a key role in the pathophysiology of this disease. Therefore, essential drugs for heart failure patients include those that inhibit overactivity of this system such as ACE inhibitors, ARBs, and aldosterone antagonists.

The natriuretic peptide system is another important pathway that can be targeted in patients with heart failure. Natriuretic peptides are key molecules that counteract heart failure, as they contribute to diuresis and vasodilation and protect against vascular remodeling.13 An increased understanding of the importance of this system in slowing the progression of heart failure has motivated evaluation of drugs such as nesiritide in patients with symptomatic heart failure. However, these drugs can cause hypotension and have limited bioavailability.14

Neprilysin is an endopeptidase—an endogenous enzyme that degrades vasoactive peptides such as bradykinin and natriuretic peptides.14 Drugs that inhibit neprilysin increase the levels of these peptides and thus counteract neurohormonal stimuli that lead to cardiac remodeling, sodium retention, and vasoconstriction.15

However, neprilysin also hydrolyzes angiotensin I to angiotensin (1–7), an inhibitor of angiotensin II. Thus, inhibition of neprilysin alone could lead to increased activity of angiotensin II and so have an overall neutral effect. To be beneficial, neprilysin inhibition needs to be combined with renin-angiotensin system inhibition. Furthermore, the benefit of renin-angiotensin-aldosterone system blockade may be amplified by up-regulation of the endogenous natriuretic peptide system.15

Omapatrilat, the most studied combination neprilysin inhibitor and ACE inhibitor, improved cardiac function and decreased cardiac mass in animal experiments.15 In addition, this drug showed promise in terms of blood pressure, heart failure readmissions, death, and preservation of renal function when compared with ACE inhibitors in patients with heart failure.15–17 But in clinical trials this drug posed a greater risk of hypotension, dizziness, and, its major shortcoming, an unacceptably high incidence of angioedema compared with ACE inhibitors.15,16,18 This higher risk of angioedema is thought to be from inhibition of three enzymes that break down bradykinin: ACE, neprilysin, and aminopeptidase P.19

Figure 1. The final effect of sacubitril-valsartan is lower blood pressure, increased diuresis, and decreasedcardiac fibrosis and hypertrophy.ACE = angiotensin-converting enzyme; BNP = B-type natriuretic peptide; GC-A = guanylyl cyclase A

ARNIs contain an angiotensin receptor blocker rather than an ACE inhibitor, and thus in theory they may be associated with a lower risk of angioedema.19 Sacubitril-valsartan, the first drug of this class, contains its two constitutive drugs in a one-to-one molecular ratio (Figure 1).

PARADIGM-HF investigated the benefit of this drug in patients with systolic heart failure.1

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