Investigational heart failure drug cut cardiovascular deaths by 20% vs. ACE-inhibitor in study

Dr Solomon

Patients with heart failure and reduced ejection fraction treated with an investigational angiotensin receptor neprilysin inhibitor (ARNI) are more likely to reduce cardiovascular death and heart failure hospitalization than those given ACE inhibitors or ARBs as first-line therapy in heart failure, according to data presented at the European Society of Cardiology congress in Barcelona, Spain, and published simultaneously in the New England Journal of Medicine.  

In PARADIGM-HF, the ARNI LCZ696 was more beneficial to patients than ACE-inhibitor enalapril on key end points, according to Novartis, the study sponsor. 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 while simultaneously suppressing the effects of the overactive renin-angiotensin-aldosterone system.

LCZ696 is comprised of 2 molecular parts, the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in an equimolar ratio. Once ingested, the drug breaks apart into its components. Valsartan blocks the angiotensin type I receptor and the active form of the neprilysin inhibitor blocks the enzyme neprilysin that is responsible for the breakdown of the biologically active natriuretic peptides and other biologically active vasopeptides. This dual action both inhibits the deleterious effects of an activated renin angiotensin system and augments natural compensatory mechanisms in heart failure.

“The strategy of PARADIGM-HF was to test a therapy that could replace a current therapy, rather than test a novel therapy that would mean more drugs for patients to take,” said trial investigator Scott Solomon, MD, professor of medicine, Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital and PARADIGM-HF Executive Committee member.

Enalapril has previously been shown to reduce cardiovascular death and hospitalizations for heart failure in heart failure patients.

The researchers enrolled more than 8,400 patients in the largest heart failure trial yet conducted and randomly assigned them to LCZ696 200 mg twice daily or enalapril 10 mg twice daily. They followed patients an average of 27 months. The trial was stopped early by the data safety monitoring board in March for overwhelming efficacy. They found that compared to the gold-standard enalapril, LCZ696 reduced the primary end point of cardiovascular death or heart failure hospitalization by 20%, cardiovascular death by 20%, heart failure hospitalization by 21% and all cause death by 16%. All of these were highly statistically significant.

In addition, patients in the LCZ696 had significant improvement in quality of life, measured by the Kansas City Cardiomyopathy Questionnaire. There was less renal impairment, less hyperkalemia and less cough in the patients who received LCZ696. While hypotension was more frequent in the LCZ696 arm, discontinuation due to hypotension was no different, and overall discontinuations were lower in the LCZ696 arm. 

“This is the first heart failure trial in which a new therapy was tested against an ACE inhibitor and proved superior,” according to Dr Solomon. “Patients who received LCZ696 lived longer, had fewer heart failure hospitalizations and felt better, with fewer overall side effects or discontinuations. The study was indeed designed so that, if positive, LCZ696 would replace ACE inhibitors and ARBs as first-line therapy in heart failure. The potential benefit will be seen in lives saved, reduced hospitalizations for heart failure and overall improved quality of life in these patients.  We haven’t yet completed a formal cost-effectiveness analysis, but these data will be forthcoming. There is no question that the reduction in hospitalization and lost productivity will be cost saving.”

Heart failure remains a disease in which patients have a marked increased risk of dying and being hospitalized, with enormous burden to them, their families, and society.

“Despite enormous advances in heart failure therapy over the past 20 years, there’s enormous need for new therapies to decrease this burden,” Dr Solomon said. 

Related:

Heart-related hospitalizations, deaths reduced due to coordinated care efforts