Novartis' Heart Failure Medicine Cuts Cardiovascular Deaths by 20% In Landmark PARADIGM-HF Trial

By Ed Miseta, Chief Editor, Clinical Leader

At the European Society of Cardiology congress held this past weekend in Barcelona (and published simultaneously in the New England Journal of Medicine) Novartis revealed its investigational heart failure medicine LCZ696 was superior to ACE-inhibitor enalapril on key endpoints. The findings were the result of PARADIGM-HF, the largest heart failure study ever conducted. Findings showed 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 ACE-inhibitor enalapril. Patients received LCZ696 or enalapril on top of current best treatment.

LCZ696 is an ARNI (Angiotensin Receptor Neprilysin Inhibitor) that is a single complex that is composed of two different molecular points. One is an angiotensin receptor blocker called Valsartan, which is a drug Novartis has been using for a long time for hypertension and heart failure. The other is a Neprilysin Inhibitor. Once ingested, it breaks apart into the component parts.

Dr. Scott Solomon, Professor of Medicine, Harvard Medical School and Director of Noninvasive Cardiology at Brigham and Women’s Hospital and PARADIGM-HF Executive Committee member

“LCZ696 is a dual action drug that both inhibits the renin angiotensin system and blocks the enzyme Neprilysin that is responsible for the breakdown of the biologically active natriuretic peptides and other vasoactive substances that are part of the compensatory mechanism in heart failure,” says Dr. Scott Solomon, Professor of Medicine, Harvard Medical School and Director of Noninvasive Cardiology at Brigham and Women’s Hospital and PARADIGM-HF Executive Committee member. “The mainstay of heart failure treatment up until now has been essentially blocking this deleterious system, so this is really a new way to improve outcomes in patients with heart failure.”      

The magnitude of benefit received with LCZ696 (a twice a day tablet) against enalapril in HF-REF patients was highly statistically significant and clinically important. The investigation revealed the benefit of LCZ696 was seen early, was sustained and was consistent across subgroups. Specifically, 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).

“We tested LCZ696 in head-to-head fashion against what is essentially the gold standard of care in heart failure (the ACE-inhibitor enalapril) which is one of the most tested drugs and is considered a first line agent in patients with heart failure,” notes Solomon. “We randomly assigned over 8,400 patients to get LCZ696 or enalapril and followed them for an average of 27 months. We saw a markedly significant reduction in the primary endpoint, which was a combination of cardiovascular death and hospitalization, but also markedly significant reductions in each of those components.” Cardiovascular death was reduced by 20% while heart failure hospitalization was reduced by 21% as well. In addition, we reduced all-cause mortality by 16%. Those results are extraordinary in a trial of a new drug going head-to-head against an agent we know to be the gold standard of treatment in this disease.”      

“By demonstrating a very significant reduction in cardiovascular deaths while improving quality of life, Novartis’ new heart failure medicine, LCZ696, represents one of the most important cardiology advances of the last decade,” adds 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 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 effects of the overactive RAAS (renin-angiotensin-aldosterone system). 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 five years of a diagnosis of heart failure. Approximately half of 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. The most common adverse events with LCZ696 (incidence ≥10%) compared to enalapril were elevated serum potassium of more than 5.5 mmol/liter (16.1% vs. 17.3%), symptomatic hypotension (14.0% vs. 9.2%) and cough (11.3% vs. 14.3%).

Solomon notes Norvartis will be analyzing this data more closely over the next few months and expect to see even further evidence of benefits.  Novartis plans to file the New Drug Application for review with the U.S. FDA by the end of 2014.

About The PARADIGM-HF Study

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.11 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 current best treatment regimen. The primary endpoint is a composite of time to first occurrence of either cardiovascular death or heart failure hospitalization, and the trial 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 Kansas City Cardiomyopathy Questionnaire) at eight months; time to all-cause mortality; time to new onset atrial fibrillation; and time to occurrence of renal dysfunction. PARADIGM-HF 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, and that the primary endpoint was met, leading to the trial being stopped early.

About LCZ696 In Heart Failure

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 acts to enhance the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the effects of the overactive 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.

 Heart failure presents a major and growing health-economic burden that currently exceeds $30 billion in the United States, which accounts for both direct and indirect costs.