PARADIGM-HF already underscored the mortality benefit of a new combo drug for patients with chronic heart failure. Now a study that looked into clinical outcomes gave it high scores for halting the progression of heart failure in survivors.
Last year, the PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) research team reported that the drug LCZ696 (Novartis) reduced the risk of death and hospitalization for heart failure in patients with reduced ejection fraction compared with conventional therapy using enalapril. LCZ696 combines the neprilysin inhibitor AHU377 and the ARB valsartan; enalapril is an ACE inhibitor.
PARADIGM-HF was terminated early after an independent Data and Safety Monitoring Board identified an overwhelming mortality benefit for LCZ696. Writing in the Jan. 6 issue of Circulation, Milton Packer, MD, of the University of Southwestern Texas Medical Center in Dallas, and colleagues detailed results from a follow-up study.
Their examination focused on the 4,187 patients treated with LCZ696 and the 4,212 who received conventional therapy with enalapril. They found a 16 percent incremental reduction in the risk of death with LCZ696 and a 12.6 percent reduction in the risk of death or hospitalization for any reason with the treatment.
LCZ696 outperformed enalapril across the board on measures of nonfatal worsening of heart failure, including worsening that required an intensification of outpatient therapy, worsening New York Heart Association functional class up to 12 months and emergency department visits.
The rate of first-time and repeat hospitalizations was lower in the LCZ696 group compared with the enalapril group. Packer et al found a 29 percent reduction in repeat hospitalization with LCZ696. Based on all hospitalizations, they calculated 15.6 percent fewer hospitalizations for any reason with LCZ696 compared with enalapril; 16 percent fewer hospitalizations for cardiovascular reasons; 23 percent fewer heart failure admissions; and 18 percent fewer stays in intensive care.
Patients treated with LCZ696 were less likely to receive intravenous positive inotropic agents, undergo cardiac transplant or need an implantable cardiac device compared with counterparts who received enalapril. They also were less likely to report a lowering in quality of life. Biomarker assessments favored to combo treatment over enalapril as well.
“[T]he PARADIGM-HF study is among the first trials to demonstrate a reduction of clinical worsening of surviving patients, which is not only of paramount importance to those afflicted with the disease and their families, but also to the physicians who care for them and the insurers who pay for the intensification of treatments,” Packer et al wrote. “The advantage of LCZ696 over enalapril in preventing clinical deterioration was apparent early in the trial and persisted for the duration of double-blind therapy.”
In an accompanying editorial, Henry Krum, MBBS, PhD, of Alfred Hospital in Melbourne, Australia, pointed out that the results were even more impressive, given that there were more survivors in the LCZ696 group. He also revisited adverse event results from the earlier study, which showed an increased risk of symptomatic positional hypotension with LCZ696. He added that this occurred even though the study excluded hypotensive patients in a run-in before randomization.
“Therefore, in the real world it may be expected that this adverse event will occur with even greater frequency and certainly needs to be carefully followed in postmarketing surveillance if/when the drug is approved,” Krum wrote.
The PARADIGM-HF trial was funded by Novartis.