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Tuesday, December 29, 2015

Is sacubitril a "game changing" breakthrough or approved on basis of a stacked deck trial or something in between?

A  number of medical commenters and pundits have claimed game changer status for sacubitril but also the trial that lead to its approval has been accused of being not a fair test. Two general types of the tricks of the trade that can be employed to make a comparison between treatment better than it really is  are 1) stack the desk and 2) cook the books (AKA  various sometime obscure statistical slights of hand)

In this instance I cannot comment on the second but others have suggested that there was at least a little bit of deck stacking.

Lets look and what was compared with what.

The drug that the FDA approved  is named Entresto and is a combo pill consisting of a first in class drug named sacubitril and valsartan which is a  well proven Angiotensin receptor blocker which has been proven effective in the treatment of heart failure (HF), Sacubitril inhibits neprilysin which in turn is a inhibitor of natriurectic  hormones .The new combination pill is named Entresto.

Entresto was compared with the ACE inhibitor,enalapril.

If someone wanted to determine if the addition of sacubitril  to valsartan was safe and effective and better than valsartan alone why not compare that combination with valsartan ?. Why choose a drug from a different class than valsartan?

 In the ParadigmHF trial, 8442  patients with class 11-IV NYHA heart failure with ejection fractions less than 40%. were treated with either Entresto or with  Enalapril at a dose of 10 mg twice a day.

 So how big was the difference between the two treatment groups? 26.5 % of the control group versus 21.8% of the enalapril treatment group were hospitalized for heart failure. A difference to be sure but enough of a difference to be heralded as a game changer?

But there is as usual more to the story- now there are expressions of concerns about some unusual potential side effects of the breakthrough medication involving some breakthrough complications in  the eye and the brain.see here

Also see here for a JAMA commentary about the concern of a potential increase risk of Alzheimer disease  by inhibiting the action of neprilysin in its putative  role in amyloid degradation. Not to worry though- a projected trial to look into that issue should be ripe for publication circa 2022. See here for a further  discussion of some criticism of the trial including how externally valid is it (how well does it represent real life treatment of HF) and how representative was the dose of the comparative drug.

 Larry Husten  comments on the number of "game changers" in cardiology in 2015 in his posting entitled " 2015 the year we finally cured heart disease".

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