invest 31415 from the yahoo board wrote this excellent...

invest 31415 from the yahoo board wrote this excellent piece:

Wow... I still have to dive in , take a closer deeper read at the trial design and the results, but my impression so far is amazing. So I bet some of the investors or readers here are confused. What happened? Trial didn't meet primary endpoint?... but did improve survival?... what's going on here?...

Well ... here's an attempt for a very simple way to look at it:

The primary endpoint for the trial (and several other trials in CHF) was to measure in general if treated patients arrive LESS times to admissions due to non fatal heart failure events. Basically , in layman language , counting how many times they admitted to a hospital with some event related to their heart failure disease. There are many reasons for why such an admission can happen, some are severe, some are less. So the logic here is to simply count all of them together and assume that a "good" drug will reduce their total number.

Note, however, that this is not measuring mortality, but something else. Why? Why measure this surrogate outcome? ... well... sometimes trials don't go for the holy grail, but instead aim at a more modest result. At an outcome that is believed to be a proxy for the real measure (in this case mortality from heart problems is the real important endpoint, and the proxy endpoint is the number of HF related admissions). This is done when it is believed it will be hard to prove the holy grail result, but it may be easier to prove the proxy result. In CHF it was SO hard to prove an improvement in mortality in the last years (cross several trials), that the FDA felt OK with the proxy, thinking it's better than nothing and better than letting all CHF trials fail, while getting something at least.

So... back to our story here... what happened?...

It seems that rex-L treatment did not reduce the number of HF related admissions significantly.

However it did lower the next VERY IMPORTANT outcomes:

(1) It lowered the number of SEVERE events not ending with death: namely MI or stroke not ending with death by 60% !!!!! (p value 0.002 !!!!!).

(2) It lowered the number of any heart related death by 60% !!!!! (p value 0.037 , I'm guessing not lower than that due to sample size and overall number of deaths in the trial, but this is very significant).

(3) It very significantly slowed the disease and prevented patients moving from stage II to stage III (!!!!)

Those results, and esp, no (2) and no (1) are the HOLY GRAILs of treating CHF .... so the trial did not pass the proxy endpoint (will have to read a full report/paper to understand why and what happened), but it did pass the much more important and harder to pass mortality endpoint, and lowered the SEVERE events !!

Let me say it in another way .... the designers of this trial did not believe in rex-L as much as they could !!!, Had they known this could be what's happening here I can assure you they would have gone for the primary goal of mortality and reduction in MACE events. For sure. As this is the golden path to approval. This is what matters to physicians (and FDA) most above anything else: prevent deaths, and prevent major events. They went for a proxy outcome, as this is what people are doing in these CHF trials, when they know how hard it is to improve the real thing (mortality , MACE) and they try to improve something else.

This is by all means an amazing outcome for the trial. To me this is a surprise to the good side. I'm surprised this did not pass the primary endpoint (is it maybe because they prevented major events and deaths but that came along with a few more admissions for these patients???), but I'm even more surprised to see 60% !!!! reductions in MACE and deaths !!! 60% !!!!!! how long has it been since you've seen a drug reducing the number of MI or strokes by 60% ??? or reducing the number of HF deaths by 60% ???? I've never seen something like this with a drug for CHF. This is close to a miracle. They put it on secondary because they did not believe it could happen.

All this with caution - as we need to get more information and learn better what happened here, get a paper out , see all the tables, all the numbers, and understand. But this can be a new era for CHF patients. Nothing less than that.

GLTA