(3rd September, 2014); The new agent, an angiotensin receptor-neprilysin inhibitor (ARNI) known as LCZ696, has already been granted Fast Track status by the United States Food and Drug Administration (FDA) – a designation which can expedite the review of new medicines intended to treat serious or life-threatening conditions. And surprisingly, LCZ696 was superior to ACE-inhibitor, enalapril, on key endpoints in the largest heart failure study ever done.
PARADIGM-HF is a randomized, double-blind, phase III study evaluating the efficacy and safety profile of LCZ696 versus enalapril (a widely studied ACE inhibitor) in 8,442 patients with HF-REF. The baseline characteristics showed the patients enrolled were typical HF-REF patients with NYHA Class II-IV heart failure. PARADIGM-HF was specifically designed to see if LCZ696 could decrease CV mortality by at least 15% vs. enalapril.
Analysis of the safety data from PARADIGM-HF showed side effects were manageable in the study. Fewer patients on LCZ696 discontinued study medication for any adverse event compared to those on enalapril (10.7% vs 12.3%, respectively, p=0.03). The LCZ696 group had more hypotension and non-serious angioedema but less renal impairment, hyperkalemia and cough than the enalapril group.
The magnitude of benefit with LCZ696 against enalapril in heart failure with reduced ejection fraction (HF-REF) patients was highly statistically significant and clinically important. In the study, the benefit of LCZ696 was seen early, was sustained and was consistent across subgroups. LCZ696:
- reduced the risk of death from cardiovascular causes by 20% (p=0.00004)
- reduced heart failure hospitalizations by 21% (p=0.00004)
- reduced the risk of all-cause mortality by 16% (p=0.0005)
Overall there was a 20% risk reduction on the primary endpoint, a composite measure of CV death or heart failure hospitalization (p=0.0000002).
LCZ696 is an ARNI (Angiotensin Receptor Neprilysin Inhibitor) and has a unique mode of action which is thought to reduce the strain on the failing heart. It harnesses the body's natural defences against heart failure, simultaneously acting to enhance the levels of natriuretic and other endogenous vasoactive peptides, while also inhibiting the renin-angiotensin-aldosterone system (RAAS).
Heart failure is a debilitating and potentially life-threatening disease in which the heart cannot pump enough blood around the body. Symptoms such as breathlessness, fatigue and fluid retention can appear slowly and worsen over time, significantly impacting quality of life.
It is a significant and growing public health concern with a high unmet need for new treatments. Every year, HF costs the world economy $108 billion, and hospitalizations comprise 60-70% of treatment costs.
“This really is an astonishing result and a real breakthrough for patients with heart failure,” added John McMurray, MD, the co-primary author, from the University of Glasgow, UK.
Findings from the PARADIGM-HF trial, published simultaneously in the New England Journal of Medicine, “are extraordinarily powerful and compelling; they are destined to change the management of patients with chronic heart failure for years to come,” said Milton Packer, MD, co-primary author of the study from University of Texas Southwestern Medical Center, in Dallas, Texas USA.
