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Novel Heart Failure Drug Cuts Mortality

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Heart failure patients treated with the investigative compound as LCZ696 significantly reduced events compared with patients treated with enalapril, researchers reported online in the New England Journal of Medicine.

In a trial that was truncated due to overwhelming outcomes in favor of the novel drug combination – the angiotensin receptor blocker valsartan plus the investigative neprilysin inhibitor sacubitril, including a 20% reduction in the risk of experiencing the composite primary endpoint of cardiovascular death and hospitalization for heart failure, reported of the British Heart Foundation at University of Glasgow.

The PARADIGM-HF trial, which included 8,442 patients, found that 21.8% of patients on LCZ696 experienced the primary endpoint compared with 26.5% of those on enalapril (P<0.001). A total of 711 patients on LCZ 696 died during the 27-month trial compared with 835 patients on enalapril (P<0.001), the authors wrote. The study results were also presented at the annual meeting of the European Society of Cardiology in Barcelona.

The patients, all of whom were diagnosed with New York Heart Association Class II, Class III or Class IV heart failure, were evenly assigned: 4187 to LCZ696 and 4212 to enalapril.

About 70% of the patients were diagnosed in Class II heart failure. The patients averaged 63.8 years of age, and about 21% were women; about 66% were white; 5% were black; 18% were Asian; about 58% of the patients were from Europe. Roughly 70% of the patients were diagnosed with hypertension; about 34% had diabetes; about 62% had been previously hospitalized for heart failure.

"The magnitude of the beneficial effect of LCZ696, as compared with enalapril, on cardiovascular mortality was at least as large as that of long-term treatment with enalapril, as compared with placebo," the authors wrote in their paper.

"This robust finding provides strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin-angiotensin system alone," they reported.

In an accompanying editorial in NEJM, professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia, suggested, "PARADIGM-HF may well represent a new threshold of hope for patients with heart failure. Efforts to design novel pharmacotherapies that exploit our growing knowledge of pathophysiological pathways are increasingly coming to the clinical arena.

"The beneficial results seen in PARADIGM-HF may apply to a wide spectrum of patients, even those currently receiving the best possible therapy," Jessup wrote.

She said that, in fact, PARADIGM-HF, may have lived up to its name – heralding a change in practice once the drug achieves FDA approval. "I think the PARADIGM heart failure trial is very exciting," she told ѻý. "It is the first new drug we have had in over a decade and I do think it has the potential of changing the practice of care."

Jessup noted that the trialists included a run-in period to make sure that people in the study tolerated both drugs in the study. "They determined that LCZ696 was as well tolerated as enalapril," she said.

In the trial, McMurray noted that there were increases in side effects among those on the new drug treatment. For example, symptomatic hypertension was experienced by 588 patients in the LCZ696 group and by 388 patients in the enalapril patients (P<0.01).

However, elevated serum creatinine – an increase of 2.5 mg/dl – was experienced by 139 patients on LCZ696 and by 188 patients taking enalapril (P=0.007). Elevated serum potassium – greater than 6.0 mmol/liter - was experienced by 181 patients on LCZ696 versus 236 in the control arm (P=0.007).

Angioedema occurred in 10 LCZ696 patients and five enalapril patients (P=0.19). Airway compromise did not occur in any patient in either cohort, the researchers reported.

From the American Heart Association:

Disclosures

The study was sponsored by Novartis.

Jessup disclosed no relevant relationships with industry.

McMurray disclosed relevant relationships with Novartis, CardioMEMs, St. Jude Medical, Relypsa, Reata. Dr. Packer disclosed relevant relationships with Novartis, AMAG, Amgen, Bio Control, CardioKinetics, CardioMEMs, Cardiorentis, Daiichi, Janssen, sanofi.

Primary Source

New England Journal of Medicine

McMurray J et al, "Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure," NEJM online, August 30, 2014,

Secondary Source

New England Journal of Medicine

Jessup M, :Neprilysin Inhibition -- A Novel Therapy for Heart Failure," NEJM online, August 30, 2014.