Dual-Action Agent Shows Promise in Preserved-EF Heart Failure

August 26, 2012

August 26, 2012 (Updated August 27, 2012) (Munich, Germany) — If the results of a new phase 2 study are upheld in more definitive clinical-outcomes trials, an investigational drug that has shown some promise against hypertension could potentially become the mortality-cutting treatment long sought for patients with heart failure with preserved ejection fraction (HF-PEF) [1].

In a randomized comparison of the angiotensin-receptor/neprilysin inhibitor (ARNI) LCZ696 (Novartis) vs the angiotensin-receptor blocker (ARB) valsartan, levels of a heart-failure severity biomarker dropped significantly in HF-PEF patients who received the newer agent for 12 weeks, compared with those who received the ARB. Systolic blood pressure fell significantly more in patients receiving LCZ696. And the drug was associated with significant improvements in left atrial size and volume and in NYHA functional class at 36 weeks.

The two treatments were tolerated by patients to a similar degree, report investigators from the Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) trial, published online August 26, 2012 in the Lancet. Their report was published today online following the study's release here at the European Society of Cardiology (ESC) 2012 Congress [2].

Their findings support further exploration of LCZ696 in larger randomized clinical-outcomes trials in patients with HF-PEF, note the authors, led by Dr Scott D Solomon (Brigham and Women's Hospital, Boston, MA).

ACE inhibitors and ARBs, on their own, have failed to convincingly show they can improve survival and lower the risk of hospitalization in patients with HF-PEF, notably in the CHARM-Preserved, PEP-CHF, and I-PRESERVE trials. But LCZ696 is in effect two drugs, in that, once administered, it splits into two active compounds--valsartan as well as an inhibitor of neprilysin, a metalloprotease enzyme that breaks down endogenous natriuretic peptides and has antiangiotensin effects.

LCZ696 therefore both suppresses the renin-angiotensin system (RAS) and boosts circulating levels of brain-type natriuretic peptide (BNP) and other endogenous natriuretic peptides that can alleviate heart failure and some signs of cardiomyopathy.

PARAMOUNT randomized 149 patients to LCZ696 (up to 200 mg twice daily) and 152 to valsartan (up to 160 mg twice daily); 134 and 132 patients, respectively, were included in the primary 36-week analysis. Entry to the study called for NYHA class 2–3 heart failure with an LVEF of at least 45% and N-terminal-pro-BNP levels >400 pg/mL.

Levels of NT-proBNP dropped 23% (p=0.005) over 12 weeks but only by 15% (p=0.20) over 36 weeks among those receiving LCZ696 compared with valsartan. NT-proBNP isn't a neprilysin substrate, so reductions in concentration reflect beneficial changes in LV wall stress, the authors note.

"LCZ696 was effective for the primary [natriuretic-peptide] end point in every single one of the subgroups tested," Solomon pointed out for heartwire . The subgroup analysis broke patients out by age, normal vs elevated systolic blood pressure, low vs preserved left ventricular ejection fraction, with vs without atrial fibrillation or poor renal function, and with vs without a prior HF admission.

"But there was one subgroup in which [LCZ696] was more effective." There was a significant interaction in patients with diabetes, he said. "It appeared to be even more efficacious in that subgroup, even though it was effective in every subgroup."

NYHA class also improved significantly with LCZ696 (p<0.05) at 36 weeks, as did left atrial width (p=0.03), left atrial volume (p=0.003), and left atrial volume index (p=0.007).

In his formal presentation of the study, Solomon noted that the improvements in systolic blood pressure with LCZ696 "correlated poorly with the change in NT-proBNP. Even after adjustment for change in blood pressure, the reduction in NT-proBNP groups at 12 weeks remained statistically significant, suggesting that blood-pressure reduction alone could not account for the change in NT-proBNP."

In an editorial accompanying the PARAMOUNT paper [3], Drs John GF Cleland and Andrew L Clark (University of Hull, Kingston-upon-Hull, UK) observe that the results "will surely trigger a definitive trial. However, what will the comparator be? Valsartan, a drug not known to be effective for heart failure with preserved ejection fraction? This comparison would show whether there was an advantage to adding a neprilysin inhibitor but would not provide evidence that valsartan was useful in patients with heart failure with preserved ejection fraction." Or perhaps the comparator should be an ACE inhibitor?

A simple comparison with placebo "would be the easiest to interpret but could be confounded by the widespread use of renin-angiotensin-aldosterone system antagonists in patients with HF-PEF," they write.

Afterward, "if LCZ696 proves ineffective in heart failure with preserved ejection fraction, then more attention should be paid to targeting of comorbid disease, to the individual phenotypes, to the causes underlying disease with preserved ejection fraction, or to the aging process itself, which could be the ultimate determinant of prognosis in these patients."

Solomon reports receiving research support and consulting for Novartis. Disclosures for the coauthors are listed in the paper. Cleland reports receiving honoraria from Novartis related to heart-failure research and serving as chief investigator for the PEP-CHF study and as an investigator in I-PRESERVE and CHARM. Clark reports no conflicts of interest.