BARCELONA – A new, dual-agent formulation for treating heart failure patients with reduced ejection fraction showed a dramatic benefit for cutting the rate of cardiovascular death and hospitalizations in an international, controlled, pivotal trial with more than 8,000 patients.
The superiority of the new compound, which combines the novel neprilysin-inhibitor drug sacubitril with the established angiotensin receptor (ARB) blocking drug valsartan, was so strong that it immediately loomed as the new cornerstone-drug of choice for heart-failure patients with reduced ejection fraction pending regulatory approvals, said Dr. Milton Packer at the annual congress of the European Society of Cardiology.
Dr. Milton Packer
Treatment with the new combination agent, currently known as LCZ696, doubled the cardiovascular-death benefit of the ACE inhibitor enalapril, while simultaneously edging out enalapril for safety and tolerability. Neprilysin is an endopeptidase that degrades several endogenous vasoactive peptides. Inhibiting this degradation process by treatment with LCZ696 boosts levels of these peptides and counters the neurohormonal overactivation that characterizes heart failure and leads to vasoconstriction, sodium retention, and maladaptive remodeling.
"This robust finding provides strong evidence supporting use of LCZ696 as the treatment of choice for heart failure instead of an ACE inhibitor or ARB" alone, said Dr. Packer, professor and chairman of clinical sciences at UT Southwestern Medical Center in Dallas. "The intent of this trial was to provide persuasive evidence that LCZ696 should replace current use of ACE inhibitors and ARBs as the cornerstone of heart failure treatment," said Dr. Packer, coprincipal investigator of the study.
Especially striking to several heart failure experts who heard the study results was the range of clinically important benefits seen when the new combination substituted for enalapril.
Dr. Mariell Jessup
"This is the first study in a long time where we saw not only a reduction in the combined endpoint of cardiovascular death and hospitalization, but also significant effect on each of these two endpoints individually as well as on all-cause mortality," commented Dr. Mariell Jessup, professor of medicine at the University of Pennsylvania in Philadelphia. The new trial "was really trying to upset the foundation of heart failure treatment that we’ve used for the last 2 decades, and it succeeded. We were hoping for a positive outcome; what we got was remarkable. It very convincingly showed that this drug has incredible promise," she said in an interview.
"This will be an important change," commented Dr. John G.F. Cleland, professor of cardiology at the University of Hull, U.K. "The science and medicine will make it hard not to switch everyone with low ejection fraction heart failure [and other features that mirror the study’s enrollment criteria] from an ACE inhibitor to this the moment it becomes available," he said in an interview. "This is now the drug of choice for any heart failure patient with persistently elevated natriuretic peptide and left ventricular systolic dysfunction."
The Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial randomized 8,399 patients with heart failure and a left ventricular ejection fraction of 40% of less to treatment with either 200 mg b.i.d. of LCZ696 or 10 mg b.i.d. enalapril plus other standard heart failure medications, including a beta-blocker (in 93%), a diuretic (in 80%) and a mineralocorticoid antagonist such as spironolactone (in about 55%). About 70% of enrolled patients had New York Heart Association class II heart failure, and another 24% had class III heart failure.
After a median treatment duration of 27 months, the primary combined endpoint of cardiovascular death or first hospitalization for heart failure occurred in 22% of the patients treated with LCZ696 and in 27% of those treated with enalapril, a 20% relative risk reduction that was statistically significant, and which showed a number needed to treat of 21 to prevent one of these primary endpoints. LCZ696 treatment also linked with a significant reduction in all-cause death, and a statistically significant and clinically meaningful improvement in patient quality of life as measured using the Kansas City Cardiomyopathy Questionnaire after patients had been on treatment for 8 months. Online publication of the full results occurred concurrent with Dr. Packer’s report at the meeting ( N.Engl. J. Med 2014;DOI: 10.1056/NEJMoa1409077 ).
While Dr. Packer highlighted the positive impact of LCZ696 on quality of life, he also stressed that the primary impact of treatment with LCZ696 is not to make patients feel better. "The major benefit of this drug is to change the natural course and rate of progression of heart failure. It should be used in patients with mild heart failure to reduce progression and death," he said.
"By switching patients from an ACE inhibitor to LCZ696 you can prolong patient survival. It is exciting to have a new drug" that can confer as many benefits as LCZ696, Dr. Jessup said.
PARADIGM-HF was sponsored by Novartis. Dr. Packer has been a consultant to Novartis as well as several other companies. Dr. Jessup had no disclosures. Dr. Cleland has received research support and honoraria from Sorin, St. Jude, and Medtronic.
Twitter: @mitchelzoler