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Heart failure treatment: Entresto has shown to reduce the risk of cardiovascular death and hospitalization

Entresto ( Sacubitril / Valsartan ), previously known as LCZ696 has been approved by Health Canada for the treatment of heart failure with reduced ejection fraction ( HFrEF ) in patients with NYHA Class II or III, to reduce the incidence of cardiovascular death and heart failure hospitalization.
The approval of the treatment is based on results from the 8,442-patient PARADIGM-HF study which was stopped early when it showed Entresto significantly reduced the incidence of cardiovascular death versus ACE-inhibitor Enalapril ( Enapren ), a standard of care treatment.

Entresto was granted a Priority Review by Health Canada due to the positive nature of the results demonstrated by the PARADIGM-HF study. In the study, the benefit of Entresto was seen early, and patients with reduced ejection fraction who were given the treatment were more likely to be alive and less likely to have been hospitalized for heart failure than those given Enalapril.

Heart failure is a debilitating and life-threatening disease in which the heart cannot pump enough blood around the body. Symptoms such as breathlessness, fatigue and fluid retention can appear slowly and worsen over time, significantly impacting quality of life. More than 600,000 Canadians have heart failure and it is responsible for 9% of all deaths in Canada or about 22,000 per year 5 which is almost equal to the number of deaths from breast, colorectal, prostate and pancreatic cancer combined. It is the second leading cause of hospitalization in Canada for patients over 65.

Entresto is a first-in-class medicine containing Sacubitril, a neutral endopeptidase inhibitor and Valsartan, an angiotensin II AT1 receptor blocker. A twice-a-day tablet, it has a unique mode of action which is thought to reduce the strain on the failing heart by enhancing the protective neurohormonal systems of the heart ( NP system ) while simultaneously suppressing the harmful system ( the RAAS ).

Entresto is indicated for treatment of heart failure with reduced ejection fraction in patients with NYHA ( New York Heart Association ) Class II or III heart failure to reduce the incidence of cardiovascular death and heart failure hospitalization. Ejection fraction is a measurement of how well the heart is pumping blood. About half of heart failure patients have a reduced ejection fraction.

Entresto should be administered in combination with other heart failure therapies, in place of an angiotensin-converting enzyme inhibitor ( ACEi ) or angiotensin II receptor blocker ( sartan ). Entresto should be initiated, and up-titration conducted by a physician experienced with the treatment of heart failure.

Analysis of the safety data from PARADIGM-HF showed Entresto side effects were manageable in the study. Fewer patients on Entresto discontinued study medication for any adverse event compared to those on Enalapril ( 10.7% vs 12.2%, respectively ). The Entresto group had more hypotension and non-serious angioedema but cough, elevation of serum creatinine and serum potassium levels were reported less frequently in the Entresto group than in the Enalapril group.

PARADIGM-HF was a randomized, double-blind, phase III study evaluating the efficacy and safety profile of Entresto versus Enalapril ( a widely studied ACE inhibitor ) in 8,442 patients with HFrEF. The baseline characteristics showed that the patients enrolled were typical HFrEF patients with NYHA class II-IV heart failure.
Patients received Entresto or Enalapril in addition to the current best treatment regimen.
The primary endpoint was a composite of time to first occurrence of either cardiovascular death or heart failure hospitalization, and was the largest heart failure study done to date.
The PARADIGM-HF results showed that Entresto, when added to current optimal care and compared to adding the ACE-inhibitor Enalapril to optimal care: reduced the risk of death from cardiovascular causes by 20% ( p=0.00004 ); reduced first heart failure hospitalizations by 21% ( p=0.00004 ); reduced all heart failure hospitalizations by 23% ( p=0.0004 ); reduced the risk of all-cause mortality by 16% ( p=0.0005 ).
Overall there was a 20% risk reduction on the primary endpoint, a composite measure of cardiovascular death or heart failure hospitalization ( p=0.0000002 ). The effect was seen early and was generally consistent across subgroups. ( Xagena )

Source: Novartis, 2015