Improving outcomes, survival in CHF

ARB-neprilysin inhibitor combination shows ‘overwhelming benefit’ over enalapril in preventing CV-related deaths and HF hospitalizations


Angiotensin converting enzyme (ACE) Inhibitors have long been established as a key treatment option in patients with chronic congestive heart failure (CHF) to improve their survival. Among ACE inhibitors, enalapril has been most notable with two landmark trials supporting its efficacy in reducing death risk and other benefits.

A new drug, however, has been shown to go one step further in improving long term outcomes in HF based on the results of an international multicenter trial which was prematurely terminated because of the convincing benefits noted in the group receiving the investigational product. The new study called PARADIGM-HF was published in the September 11 issue of the New England Journal of Medicine.

Authors of this new landmark HF study consists of internationally respected authorities on HF such as Prof. John McMurray of the University of Glasgow, in Scotland; and Prof. Milton Packer of the University of Texas Southwestern Medical Center, in Dallas.

The new drug, coded in the trial as LCZ696, consists of the neprilysin inhibitor sacubitril (AHU377) and the angiotensin receptor blocker (ARB) valsartan. Sacubitril is a prodrug that is activated to LBQ657 by de-ethylation via esterases. LBQ657 in turn inhibits the enzyme neprilysin, which is responsible for the degradation of atrial and brain natriuretic peptide, known petides which reduce blood volume.

In the clinical trial, the investigators determined how the hemodynamic and neurohormonal effects of this new drug compares to the ACE inhibitor enalapril in HF patients with a reduced ejection fraction of 40 percent or less. During the latter part of the trial, the EF criterion was even reduced further to 35 percent. The tolerability or side-effects of both drugs were also evaluated.

The double-blind trial randomized 8,443 patients with class II, II, or IV HF to receive either a 200mg twice daily dose of LCZ696 or a 10mg twice daily dose of enalapril, in addition to recommended standard therapy for HF.

According to its authors, the primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was mainly designed to detect a difference in the rates of death from cardiovascular causes.

After the 27-month median follow up period, the results showed that LCZ696 demonstrated overwhelming benefit prompting the steering committee to terminate the trial prematurely. The authors reported that the primary outcome occurred in 914 patients (21.8 percent) in the LCZ696 group and 1117 patients (26.5 percent) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95 percent confidence interval [CI], 0.73 to 0.87; P<0.001).

Of the 711 patients (17 percent) under LCZ696 who died, 558 (13.3 percent) died from cardiovascular causes. For the arm that received enalapril, 693 (16.5 percent) of 835 (19.8 percent) died of cardiovascular causes. The authors further noted that LCZ696 reduced the risk of hospitalization for HF by 21 percent, and also significantly decreased the symptoms and physical limitations of HF.

“The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions of patients with renal impairment, hyperkalemia, and cough than the enalapril group,” the authors reported. Cardiovascular mortality and heart failure hospitalization were effectively reduced by 20 percent.

VitalSigns Issue 67 Vol. 3, September 1-30, 2014

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