European Society of Cardiology

European Society of Cardiology

August 30, 2014
2 min read

PARADIGM-HF: New drug superior to ACE inhibition

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BARCELONA, Spain — LCZ696, an angiotensin receptor-neprilysin inhibitor, was superior to ACE inhibition with enalapril for the reduction of death and HF hospitalization in patients with HF and reduced ejection fraction.

LCZ696 (Novartis) consists of the angiotensin receptor blocker valsartan bonded to the neprilysin inhibitor sacubitril, Milton Packer, MD, professor and chair of the department of clinical sciences at University of Texas Southwestern Medical Center, Dallas, said at the ESC Congress.

“The current gold-standard cornerstone of treatment of HF is an ACE inhibitor … which has been shown to have an effect on survival in HF. [PARADIGM-HF] was designed to stand on its own to provide compelling evidence that would convince physicians to replace the current use of ACE inhibitors and angiotensin receptor blockers with LCZ696,” Packer said.

Milton Packer, MD

Milton Packer

The trial enrolled 8,442 patients with NYHA class II, III or IV HF and an ejection fraction ≤40% who were randomly assigned to receive LCZ696 400 mg daily or enalapril 20 mg daily in addition to standard care. The mean age of the patients was 63.8 years, one-fifth were women and 66% were white.

In April, Novartis announced the early closure of PARADIGM-HF after it met the primary composite endpoint — CV death or first incidence of HF-related hospitalization — and also showed a significant reduction in the risk for CV death.

At the end of the study, the primary outcome had occurred in 21.8% of patients assigned LCZ696 vs. 26.5% of patients assigned enalapril (HR=0.8; 95% CI, 0.73-0.87).

Seventeen percent of patients assigned LCZ696 and 19.8% of patients assigned enalapril died from any cause (HR=0.84; 95% CI, 0.76-0.93). Death from CV causes occurred in 13.3% of patients assigned LCZ696 vs. 16.5% assigned enalapril (HR=0.8; 95% CI, 0.71-0.89). PARADIGM-HF was designed as a CV mortality trial, Packer said at a press conference.

“The magnitude of the beneficial effect of LCZ696, as compared with enalapril, on CV mortality was at least as large as that of long-term treatment with enalapril, as compared with placebo,” the researchers wrote in The New England Journal of Medicine.

In other results, LCZ696 reduced the risk for HF hospitalization by 21% compared with enalapril (P<.001). The study drug was also associated with improved symptoms and physical limitations of HF (P=.001).

Safety data indicate that patients assigned LCZ696 had higher rates of hypotension and nonserious angioedema than patients assigned enalapril. Cough, serum creatinine ≥2.5 mg/dL and serum potassium >6 mmol/L were reported less frequently in patients assigned LCZ696 (P<.05 for all). The researchers also reported no increase in risk for serious angioedema. The LCZ696 group had lower rates of study discontinuation due to an adverse event (10.7% vs. 12.3%; P=.03) or renal impairment (0.7% vs. 1.4%; P=.002).

“For the last 25 years, the magnitude of the effect of ACE inhibitors on CV mortality (17% to 18%) has created an ethical mandate for their use in all patients with chronic HF who could tolerate treatment with these drugs,” Packer said. “The finding that LCZ696 has a 20% greater effect on CV mortality than ACE inhibitors strongly supports the conclusion that LCZ696 should replace current use of ACE inhibitors and angiotensin receptor blockers in the management of HF.” – by Katie Kalvaitis

For more information:

Packer M. Hot Line I. Cardiovascular Disease: Novel Therapies. Presented at: the European Society of Cardiology Congress; Aug. 30-Sept. 3, 2014; Barcelona, Spain.

McMurray JJV. N Engl J Med. 2014;doi:10.1056/NEJMoa1409077.

Disclosure: PARADIGM-HF was supported by Novartis. Packer reports consulting for AMAG, Amgen, BioControl, CardioKinetix, CardioMEMS, Cardiorentis, Daiichi Sankyo, Janssen Pharmaceuticals, Novartis and Sanofi Aventis.