Novel Agent Slows HF Progression

The novel angiotensin-neprilysin inhibitor LCZ696 appeared to reduce hospitalizations and a wide range of heart failure disabilities and symptoms in exploratory analyses of the PARADIGM-HF trial.

The drug cut hospitalizations for worsening heart failure by a relative 23% fewer (P<0.001) and emergency department visits for worsening heart failure by 34% compared with guideline-recommended doses of the ACE inhibitor enalapril (P=0.001), Milton Packer, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues found.

The latest analysis reported online in Circulation: Journal of the American Heart Association and simultaneously at the American Heart Association meeting in Chicago showed that the drug:

• Reduced the need for intensification of HF medication by a relative 16% (P=0.003)
• Reduced the rate of intensive care by 18% (P=0.005)
• Cut the likelihood of IV positive inotropic agents by 31% (P<0.001)

There was also a nonsignificant trend for a relative 22% lower risk of getting an HF device or cardiac transplantation compared with the ACE inhibitor group (P=0.07).

Those effects on clinical deterioration were in addition to the 20% reduction in cardiovascular mortality seen in primary findings from the trial.

The novel drug, which was tested at a dose of 200 mg twice daily versus enalapril 10 mg twice daily, was also superior in reducing death from any cause (P<0.001).

PARADIGM-HF enrolled 8,442 patients with Class II, III, or IV heart failure and an ejection fraction of less than 40% (which was later amended to less than 35%). The study randomized 4,187 patients to LCZ696 and 4,212 to enalapril.

"The effect of LCZ696 to stabilize the course of heart failure is likely to have important ramifications for both quality of life and resource utilization in this disorder," the researchers concluded.

However, mining the data could be dangerous, warned Clyde W. Yancy, MD, MSc, a heart failure specialist and chief of cardiology at Northwestern University, despite his praise for the primary findings from PARADIGM-HF.

Yancy pointed out that "when you have a positive study like PARADIGM, we expect that all the substudies are also going to be positive, and I have no problem when we confine ourselves to prespecified secondary analyses, but when we get involved in 'exploratory' analysis, we need to be careful because the way to kill this 'PARADIGM' is by overselling it."

Self-rated symptoms scores also suggested that LCZ696-treated patients felt more stable, as reflected by significantly fewer having a 5-plus point worsening in the KCCQ total symptom score compared with the enalapril group at 4, 8, and 12 months (P=0.002, P=0.001, and P=0.03, respectively).

And feeling better "is a significant factor in the life of a heart failure patient," Mary Norine Walsh, MD, medical director at St. Vincent Medical Group Cardiology in Indianapolis, told MedPage Today.

"Not since the era of beta-blocker HF studies have we had a new class of agent for this condition that not only met its primary efficacy endpoint but also resulted in a stand-alone mortality benefit compared with conventional therapy, and did so with an acceptable safety profile," Henry Krum, MBBS, PhD, wrote in an editorial accompanying the Circulation paper.

"What was missing from the PARADIGM-HF main results article, however, was the clinical impact of the novel intervention, an angiotensin receptor neprilysin (or neutral endopeptidase) inhibitor (ARNi), over the period of follow-up post-randomization," Krum added.

There have been no approvals of oral drugs for heart failure since 2005 when BiDil (hydralazine-isosorbide dinitrate) was approved, which explains why PARADIGM-HF's 3.2% absolute reduction in death or hospitalization was greeted as a major breakthrough.

From the American Heart Association:

• SS14: Late-Breaking Clinical Trials

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