First-in-Class Angiotensin Receptor Neprilysin Inhibitor Promising in Heart Failure with Preserved Ejection Fraction

Value-Based Care in Cardiometabolic Health Dec 2012, Vol 1, No 3 - Emerging Therapies

Munich, Germany—The first-in-class agent LCZ696, an angiotensin receptor neprilysin inhibitor, was associated with greater reductions of several measures that are associated with worse outcomes in patients who have heart failure with preserved ejection fraction (HFpEF) compared with the angiotensin receptor blocker (ARB) valsartan.

These results from the phase 2 PARAMOUNT study were presented by Scott D. Solomon, MD, Director of Noninvasive Cardiology at the Brigham and Women’s Hospital, Boston, and Professor of Medicine at Harvard Medical School, at the 2012 European Society of Cardiology Congress.

“LCZ696 in the PARAMOUNT study is the first compound to show both reductions in NT-proBNP and left-atrial size in HFpEF patients, each a powerful predictor of outcomes in heart failure,” said Dr Solomon. “The favorable effects of LCZ696 seen in patients with HFpEF in PARAMOUNT are encouraging, and further testing of this agent in this patient population is warranted.” LCZ696 is also being studied as an antihypertensive agent.

Approximately 50% of patients with heart failure have preserved ejection fraction compared with reduced ejection fraction, but no treatment has been shown to reduce morbidity and mortality in this population with HFpEF.

The PARAMOUNT study, which was conducted in 13 countries, randomized 308 patients (mean age, 70 years) to LCZ696 (50 mg twice daily for week 1, doubled to 100 mg twice daily) or to the ARB valsartan (40 mg twice daily for week 1, then doubled to 80 mg twice daily) to determine the effect on the natriuretic peptide NT-proBNP, a marker of cardiac wall stress that increases in patients with heart failure. Therapy with an angiotensin-converting enzyme inhibitor or an ARB was discontinued 1 day before randomization.

A 23% reduction in NT-proBNP, the primary end point, was found with LCZ696 compared with valsartan at 12 weeks (P = .005). This reduction was evident at week 4 and was sustained to week 36, but at 15% it was not a significant difference. The treatment effect was similar across all predefined subgroups and favored LCZ696, except in patients with diabetes, in whom there was a significantly greater effect with the novel agent.

LCZ696 reduced the left-atrial size, which indicates improvement in left-atrial remodeling. There were significant improvements in left-atrial width, left-atrial volume, and left-atrial volume index at 36 weeks.

After 36 weeks, the extended follow-up period, there was improvement in the New York Heart Association class in the patients taking LCZ696 compared with those taking valsartan.

The change in blood pressure at 12 weeks and at 36 weeks correlated poorly with the change in NT-proBNP, and the reduction in this marker remained significant between groups after adjustment for blood pressure.

“The favorable effects of LCZ696 seen in patients with HFpEF in PARAMOUNT are encouraging, and further testing of this agent in this patient population is warranted,” said Dr Solomon.

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