Monday, September 01, 2014


In Barcelona over the weekend ( European Society of Cardiology, annual scientific meeting ), an important heart failure trial result was announced. The PARADIGM-HF trial. It was also simultaneous published in the New England Journal of Medicine. ( Pharmas are so powerful nowadays that they can "convince" the editor to time their publication for maximal marketing effect ). I am surprise that it did not appear in Forbes magazine too.

But lets not be distracted by marketing gimmicks. This is an important study. It is actually the followup of a smaller study, PARAGON-HF, published earlier, which essentially showed the same. The PARAGON-HF study was on Treatment of Heart failure with preserved LV systolic function, which forms about 50% of heart failures.
Now back to PARADIGM-HF. Take a look at the authors of this paper. Novartis ( the company that manufactures LCZ 696 ) has assembled together a whose who in heart failure management. Drs John McMurray, Dr Milton Packer and Dr Karl Sweberg. Wow.
They recruited about 10.521 patients with class II,III and IV heart failure with LVEF <40 4="" 8="" 90="" a="" about="" and="" arm.="" as="" beta="" blocker="" by="" each="" enalapril="" expected.="" failure="" final="" given="" had="" heart="" in="" lcz696="" ll="" medical="" medications="" nbsp="" of="" on="" or="" patients.="" patients="" physicians.="" rct.="" selection="" standard="" the="" their="" therapy="" there="" this="" top="" usually="" was="" were="">90% has a diuretic including an aldosterone antagonist. 
Anyway, the trial was obviously positive, showing a 20% reduction in primary endpoint and 20% reduction in CV deaths and 16% reduction in all deaths. 
LCZ 696 is a combo pill of Valsartan ( ARB blocker ) and Neprilysin-Sacubitril ( an endopeptidase enzyme inhibitor ).

As usual such magic drugs must be thoroughly scrutinise by the FDA ( I hope that they do a good job and not be "rushed" by Novartis ).
There are obviously side effects. Not to forget that a previous drug of this almost same group ( Omapatrilat ), also a bradykinin inhibitor gave life threatening angioedema.
With Neprilysin, the side effects noted in PARADIGM-HF was symptomatic hypotension, which reach a p-value of 0.001 and a 2x raised creatinine level. These two side effects could prove troublesome as we see Heart Failure in the elderly ( the average age of PARADIGM-HF was 60 years ) who are already prone to symptomatic hypotension, and a raise creatinine.
Then of course, there is the issue of cost? How much will we have to pay for this drug? It is important to note that with PARADIGM-HF cost analysis, we have to treat 32 patients to save one CV death. It is also good to remember the good old drug called Spironolactone ( very cheap ) which in the RALES study also reduced CV death by 30%, except that spironolactone may cost painful breast enlargements.
When will LCZ696 reach us, assuming it crosses FDA, looks like 2016. By then it should have a nice sounding name.
We await more news, for better or for worse.
I must congratulate Novartis for a good piece of work. I am sure that there will be a place for LCZ 696

No comments: