A paradigm shift is a word you rarely hear of in the field of medicine ; 

however this clinical trial

(research of benefits and risks of new drug in humans) certainly caused one. John V. Mcmurray and
team's findings- of their drug trial published in 2014- showed overwhelming benefits of a new drug
(LCZ696) compared to a previous drug of choice enalapril ( which is an Angiotensin Enzyme Receptor
inhibitor ACEI) in heart failure patients, leading to an abrupt end of the trial named PARADIGM -HF,
and rightly so (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] With
ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and
Morbidity in Heart Failure)

Heart failure may be classified into two forms: those with impaired "pumping" (systolic) function of
the heart and those with impaired "relaxing"(diastolic)function of the heart.  Both drugs were used
for those with impaired pump function; they work better in them.

The new drug (LCZ696) is a combination drug that consists of two different drugs namely valsartan
( angiotensin Receptor blocker- ARB) and sacubitril (nephrilysin inhibitor - NI). Both drugs work
synergistically to improve the heart’s ability to contract even when diseased, due to their intricate
hormonal and structural change function in heart muscles.

Over 30 years ago, patients with heart failure were found to benefit from the “old drug” enalapril.
Enalapril was shown to significantly reduce the symptoms of heart failure and improve survival. In
2010, scientists working on new drug (LCZ696) noticed it caused less serious side effects such as
swelling of the lips compared to drugs in a similar class (ARB/ACEI ). This led to the start of a new
clinical trial to see the long term effects of the new drug(LCZ696) in a larger group of heart failure
patients.

During the drug trial, researchers chose patients 18 year old and above with heart failure causing
mild to severe symptoms. Those who qualified based on this as well as other added criteria were
given enalapril and subsequently the new drug (LCZ696) to see the side effect profile. Patients who
had no unacceptable side effects were assigned equally into groups where neither patients nor
researchers knew exactly which drug a particular patient was taking (double blind trial). During this
period, scientists measured the likelihood of dying from diseases related to your heart and blood
vessels (Cardiovascular diseases) as well as hospitalizations. They also measured the time to death
from any cause.

The trial was stopped after 27 months when they realised overwhelming benefits for the group put
on the new drug. The research showed that- over the 27 month period -for every  1000 participants
treated with new drug about 47 more deaths or hospitalizations , 32 more deaths from
Cardiovascular(relating to heart and blood vessels) diseases alone and 28 more deaths from all
causes were prevented compared to enalapril (the old drug). This is overwhelming ; the (two)
combined drug sacubitril valsartan(LCZ696) was certainly better than the (one) drug enalapril.

The drug was quickly approved by US Food and drug authority (FDA)  for the market as the drug
Entresto in 2015. The critics were however not pleased.  They argued that the trial used a less
effective dose of the drug enalapril compared to target dose of previous trials. This may not be
accurate though since the average dose of enalapril achieved in PARADIGM-HF trial was the highest
ever achieved in a clinical trial.

In the end LCZ696 might not necessarily be the drug that finally "solved" heart failure but certainly a
formidable tool in our never ending quest to improve the quality of life and reduce the risk of death
in heart failure patients.
Citation Article

John V. Mcmurray,M.D., et al Angiotensin-Nephrilysin inhibition vs enalapril in Heart failure.

https://www.nejm.org/doi/full/10.1056/nejmoa1409077