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Landmark Study Shows Novartis Experimental Drug Far Superior to ACE Inhibitor Enalapril in Reducing Risk of Death Associated with Heart Failure

According to a Novartis press release, on August 30, 2014, at the European Society of Cardiology congress in Barcelona, and published simultaneously in the New England Journal of Medicine, the company revealed that its investigational heart failure medicine, LCZ696, was superior to ACE inhibitor enalapril on key endpoints in the largest heart failure study ever done. In PARADIGM-HF patients with heart failure with reduced ejection fraction (HF-REF) who were given LCZ696 were more likely to be alive and less likely to have been hospitalized for sudden deterioration of their heart failure than those given the ACE inhibitor enalapril. Patients received LCZ696 or enalapril on top of the current best treatment. The magnitude of benefit with LCZ696 against enalapril in 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 (CV) 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). "By demonstrating a very significant reduction in cardiovascular deaths while improving quality of life, Novartis's new heart failure medicine, LCZ696, represents one of the most important cardiology advances of the last decade," said Dr. David Epstein, Division Head, Novartis Pharmaceuticals. "We want to thank leading cardiologists from around the world for their collaboration with us and their determination in advancing this important new life saving therapy for heart failure patients." LCZ696, a twice-a-day tablet being investigated for heart failure, has a unique mode of action which is thought to reduce the strain on the failing heart. It acts to enhance the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful system (the RAAS). Currently available medicines for HF-REF work only to block the detrimental effects. Despite existing therapies, the mortality rate remains very high with up to 50% of patients dying within 5 years of a diagnosis of heart failure. Approximately half of the patients with heart failure have HF-REF. 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. Novartis plans to file the application for marketing authorization with the US FDA by the end of 2014 and in the EU in early 2015. 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 that 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. Patients received LCZ696 or enalapril in addition to the current best treatment regimen. The primary endpoint is a composite of time to first occurrence of either cardiovascular death or heart failure hospitalization, and is the largest heart failure study ever done. Secondary endpoints are change in the clinical summary score for heart failure symptoms and physical limitations (as assessed by the Kansas City Cardiomyopathy Questionnaire) at 8 months; time to all-cause mortality; time to new-onset atrial fibrillation; and time to occurrence of renal dysfunction. It was initiated in December 2009 and in March 2014 the Data Monitoring Committee confirmed that patients given LCZ696 were significantly less likely to die from CV causes, leading to the trial being stopped early. The DMC also confirmed the primary endpoint had been met. 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 defenses 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. 26 million people across the US and Europe live with heart failure, facing high risk of death and poor quality of life. See links to Novartis press release, NEJM article and editorial, and popular press summaries below. Note that a video summary of the work is provided on the NEJM web site (www.nejm.org). [Press release] [NEJM article] [NEJM editorial] [Wall Street Journal article] [New York Times article] [Reuters article] [Huffington Post article]