The PARADIGM-HF trial: Valsartan-neprilysin inhibitor vs. enalapril in patients with heart failure [Classic Series]

1. LCZ696, a combination of valsartan with a neprilysin inhibitor, significantly reduced the risk of death from cardiovascular causes and hospitalization due to heart failure when compared to enalapril.

2. There were no significant differences between the two groups in the risk of angioedema, though patients treated with LCZ696 experienced significantly higher rates of symptomatic hypotension.

Original Date of Publication: September 2014

Study Rundown: Millions of North Americans suffer from heart failure. About half of these individuals have heart failure with reduced ejection fraction, and the current standard medication regimen includes an angiotensin converting enzyme (ACE) inhibitor, beta-blocker, and potentially an aldosterone antagonist. In patients who cannot tolerate ACE inhibitors, an angiotensin receptor blocker is used instead. Natriuretic peptides are produced by various tissues and lead to decreased vasoconstriction, sodium retention, and maladaptive remodelling. These peptides are degraded by neprilysin, a neutral endopeptidase, and inhibition of neprilysin had been previously shown to have beneficial hemodynamic effects. Moreover, combining ACE and neprilysin inhibition had been shown to be superior than either treatment alone, though with higher risk of severe angioedema. The risk of angioedema was lower with combination of neprilysin inhibitor and ARB.

The purpose of the Prospective Comparison of ARNI (Angiotensin Receptor-Neprilysin Inhibitor) with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was to compare the effects of LCZ696, a combination of a neprilysin inhibitor and valsartan, with enalapril in patients with heart failure. Treatment with LCZ696 significantly reduced the risk of death from cardiovascular causes and heart failure hospitalization when compared with enalapril in patients with NYHA class II-IV heart failure and left ventricular ejection fraction ≤35%. This trial demonstrates that treatment with LCZ696 will significantly reduce mortality in patients with heart failure with reduced ejection fraction, and is the first new intervention to do so in many years.

Click to read the study published in NEJM

In-Depth [randomized controlled trial]: This randomized, controlled, double-blind trial involved 8442 patients from 47 countries. Patients were eligible for enrolment if they were ≥18 years of age, NYHA class II-IV symptoms, and left ventricular ejection fraction ≤35%. Exclusion criteria included symptomatic hypotension, systolic blood pressure <100 mmHg at screening, and estimated glomerular filtration rate <30 mL/min/1.73m². The primary outcome was death from cardiovascular causes or a first hospitalization from heart failure. Secondary outcomes included time to death from any cause, the time to a new onset of atrial fibrillation, and the time to the first occurrence of a first decline in renal function.

Patients in the LCZ696 group experienced significantly lower rates of the primary outcome compared to those on enalapril (HR 0.80; 95%CI 0.73-0.87; p < 0.001). The LCZ696 group experienced significantly less death from cardiovascular causes (HR 0.80; 95%CI 0.71-0.89; p < 0.001) and hospitalization for heart failure (HR 0.79; 95%CI 0.71-0.89; p < 0.001) when compared to the enalapril group. Death from any cause was also significantly lower in the LCZ696 group (HR 0.84; 95%CI 0.76-0.93; p < 0.001). There were no significant differences between the two groups in the number of patients with new-onset atrial fibrillation (p = 0.83) or decline in renal function (p = 0.28). Moreover, there were no significant differences between the groups in the risk of angioedema, though patients on LCZ696 experienced significantly higher rates of symptomatic hypotension (p < 0.001).

Image: PD

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