neprolysin

7/25/2019 neprolysin

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We may need another medicine - to treat euphoria

Resemblance to past wonder drugs and their descent from medical stage is there. Let's hope it is different

this time.

SANDIPK!AR PA"#L $ Ph%sician & IN"#RNAL !#DIIN# $ Disclosure( None

)IA*+ IL

September ,- /0,1

BNP

!a% 2NP be useless to differentiate the cause of shortness of breath in patients who are ta3ing

Angiotensin4Nepril%sin Inhibition5

Dha6al Nai3 $ Resident $ Disclosure( None

September ,- /0,1

New Hope for Heart Failure Patients

Seems reall% promising777 I hope it comes out soon and at reasonable price777

*ILL#R!+ DI#8#ID# !D $ Ph%sician & #ND+RIN+L+*9 DIA2#"#S !#"A2 $ Disclosure( None

)AA2+ Argentina

September ,- /0,1

The atrial natriuretic inhibitor and the brown adipose tissue

+ne of the more e:iciting e:pectati6es is that the new inhibitors of the metaboli;ation of atrial natriuretic

peptides < nepril%sin= could induce lipol%sis and augment the change of the white adipose tissue in brown

adipose tissue. In patients with diabetes obesit% and cardiac failure < a great percentage of m% patients=

this could be a wonderful wa% to reduce insulinresistanceobesit% and mitigates s%mptoms of cardiac

failure. ardiac natriuretic peptides act 6ia p-> !APK to induce the brown fat thermogenic program in

mouse and human adipoc%tes 2ordicchia?.In6est /0,/(,//<-= ,0//&,0-@ ardiac Natriuretic Peptides

+besit% and Insulin Resistance( #6idence from "wo ommunit%&2ased Studies.!a% Kahn

?#!(/0,,(@<,0=-/1/&-/1 "hirt%&+ne No6el 2iomar3ers as Predictors for linicall% Incident Diabetes

Salomaa Plos +ne April /0,0

RA?IB AR+RA $ Student $ Disclosure( None

A!RI"SAR India

September ,, /0,1

The rise and fall of medical discoveries !

ndoubtedl% PARADI*!&)C has shown an outstanding result in a disease li3e )C which is also 3nown

as epidemic of ardiolog%.Soin another wa% the rise of Nepril%sin can be seen as a disco6er% of the /,st

entur% 7)opefull% this wonder drug is able to pro6e its metal in li3el% and e:pected future trials of this

drug with time tested and well tried A#Is in different and 6aried aetiologies of heart failure 7SAAD AL&SAKKAL !D $ Ph%sician & #ND+RIN+L+*9 DIA2#"#S !#"A2 $ Disclosure( None

!AS+N +)

September ,, /0,1

With CHFcurb your enthusiasm !

)eart failure is a sad chronic frustrating condition when all medications at the end fails.No wonder

e6er%one welcome new drug with great fanfare since it is based on intuiti6e ph%siolog%."he drug is clearl%



beneficial but let us use reason to put things in real life perspecti6e ( !ortalit% from )C with low eection

fraction ma% e:ceed E10 in 1 %ears. sing absolute reduction ratios is modest( A#FAR2 has decreased

this reall% b% around E><E/0 of E10= Spironolactone b% e:tra EG <E-0 of A#FAR2=and de6ices b% an

added E- <E/0 of A#FAR2=All together added in appropriate indication will decrease mortalit% b%

E,>. "his new drug will decrease mortalit% and hospitali;ation b% an added E1 <E/0 better than A#F AR2= after E/0 withdrawal rate from the trial for side effects Is this a true cause for celebration5 what if

this turned out after 1 %ears follow up to be li3e !ilrinone7 Let us wait the ne:t two real life studies after 1

%ears of follow up ."hen we could trul% celebrate. Proceed with e:treme caution.

!ario outinho $ Ph%sician & ARDI+BASLAR DIS#AS# $ Disclosure( None

2ra;il

September ,, /0,1

ittle too low"

#nalapril half of ma:imum dose compared to ma:imum dose of 6alsartan plus nepr%lisin 5 Hell No6artis

must ha6e had a role on this decision. +r not 5 I thin3 this is not a definiti6e stud%. Haiting for more.

RALC )AS!ANN !D $ Ph%sician & P)AR!A#"IAL !#DIIN# $ Disclosure( None

*erman%

September ,, /0,1

#C$%&Neprilysin evaluation ur'ently needed

As recentl% shown b% meta&anal%ses AR2s are inferior to A#Is in reducing mortalit% in chronic heart

failure or diabetes mellitus patients. I wonder whether an A#IFNepril%sin treatment would be superior to

the AR2FNepril%sin treatment. "hus as alread% mentioned below b% R. Heinstein the e6aluation of the

combined use of an A#&Inhibitor and Nepril%sin is urgentl% needed to ensure that an e6en better

treatment regime will not be 3ept bac3. )owe6er I am afraid that commercial interests will interfere with

such a stud%.DABID #BANS $ +ther $ Disclosure( None

CALL+N NB

September ,0 /0,1

(i'nificant Problems in (tudy )esi'n

Hhile apparentl% impressi6e this stud% is not compelling and its design not reassuring. A couple of brief

important problems among the man% that could be ad6anced for this stud%( <,= ontrol subects were

R#IR#D to discontinue their current meds which often had much higher more therapeutic doses of

enalapril. "here are stud% designs that could ha6e a6oided this significant confounding 6ariable. </=

People seem to be gushing o6er the Jrelati6eJ decrease in mortalit% which of course is not true for an%

real indi6idual patient. "he A2S+L"# benefit was ust a bit under -E better if one reads the stud%

carefull%. !ore independent better ualit% designs are needed before this seemingl% miraculous

combination of drugs becomes the standard of care.

?+)N PIPPIN !D $ Ph%sician & ARDI+BASLAR DIS#AS# $ Disclosure( None

DALLAS "

September ,0 /0,1

oaded dice*



It is an established dodge among pharma companies to compare their drugs to suboptimal or under&

dosed comparati6e therapies and that is what happened here. If No6artis wants to compare their drug to

current best therap% then best A#I M beta bloc3er at therapeutic doses should be the comparator rather

than a subtherapeutic dose of an older A#I. "his report does not document a therap% that is eui6alent

or superior to current best therap%.?#SS 2IAN+ !D $ Ph%sician & ARDI+BASLAR DIS#AS# $ Disclosure( None

?AKS+NBILL# CL

September ,0 /0,1

+uo vadis C,.

F,0F/0,1 R" are the bases of much of what we do in the clinic to implement e6idence&based medicine.

)owe6er while better than obser6ational studies or retrospecti6e studies the% do no alwa%s e:plain

mechanisms remo6e biases or a6oid confounders.. Crom the abo6e pre6ious comments one sees the

man% issues that lie ahead for L8@@. . "hese are etiolog% of )C echocardiograph%F!RIFnuclear of )C

percentage of patients with L222 h%potensi6e effects of L8@@ dissection of the relati6e contributions

of drugs< A#IAR2s 2eta bloc3ers Diuretics Aldosterone antagonistsID R"= patient compliance

with pol%pharmac% industrial support of R" prospecti6e cit% and communit% medical application of the

new guideline and cost of this prematurel% labeled Jre6olutionar% 'approach to treatment of the failing

heart. "he abo6e paragraph indicates the difficulties of a of multiparametric multi6ariate discriminant

anal%sis to prospecti6el% answer a comple: new approach to a maor clinical problem.

)I!!A"RA+ 2AHASKAR !D $ Ph%sician & #!#R*#N9 !#DIIN# $ Disclosure( None

!A)AD India

September ,0 /0,1

(pectrum of on'oin' process

I must congratulation to authors bringing a 6ersatile agent for to impro6e the heart failure therap%.)owe6er because of awareness of h%pertension ischemic. )eart disease. "he true incidence of

refractor%. )eart failure is reduced considerabl%. Still. Diuretics digo:in and. Ace inhibitors remains gold

standard. Cor rural setting moreo6er. "hese drugs are easil% a6ailable at rural setting. +ne should not

shift to ad6ance line of treatment unless a trial of these drug are gi6en to start with initial therap% .

)owe6er. If. No agents are helpful the last resort of phlebotom% does benefits

*+LD#N CANA !D $ Ph%sician & IN"#RNAL !#DIIN# $ Disclosure( None

)arare 8imbabwe

September 0 /0,1

#etiolo'y of heart failure

the uestion of aetiolog% of heart failure remains an important one esp when tr%ing to appl% these results

in sub saharan africa where most heart failure is due to h%pertensi6e heart disease dilated

cardiom%opath% <a highl% heteregeous group= and rheumatic heart diease. the results loo3 6er%

impressi6e

sudhir agarwal $ Ph%sician $ Disclosure( None

September 0G /0,1

P#/#)%01-HF Trial



It is a landmar3 stud% and this drug is going to be a game changer in treatment of S%stolic heart failure .

"his drug showed benefit e6en in stable )C patients and will replace A# inhibitor treatment in )C .

"his drug should be included in *uidelines for )C treatment right awa% and also in ualit% ore

!easures in )C patients . In long term b% reducing the hospitali;ation it might pro6e to be cost

effecti6e treatment for )C patients . I am nor sure if cost effecti6it% datas can be deri6ed from thisstud% . I am loo3ing forward to start this drug to m% )C patients . "han3s

*+PAL *)+S) !D $ Resident & IN"#RNAL !#DIIN# $ Disclosure( None

B#LL+R# India

September 0G /0,1

# N$W #CH%$2$1$NT %N H$#/T F#%3/$ T/$#T1$NT

*reat achie6ement in the heart failure treatment histor% Results are comparable to )+P# trial. 2ut it

would ha6e been more realistic if stud% group ha6e compared A#IFNepril%sin 6s A#I. Still we are

loo3ing forward for the wonder drug to be a6ailable as earl% as possible in the mar3et.

?A9A)ANDRAN DA!+D)ARAN !D $ Ph%sician & IN"#RNAL !#DIIN# $ Disclosure( None

)#NNAI "A!IL NAD India

September 0G /0,1

HF

It would ha6e been interesting if we had a bbloc3er arm and ace arm . Hhat was the etiolog% of )C5 Do

all paitents with )C benefit5

RA9!+ND AR+NS+N !D $ Ph%sician & ARDI+BASLAR DIS#AS# $ Disclosure( None

"#L ABIB Israel

September 0@ /0,1

Was the control dru' comparative*

Analagous to Dr. Saha's comment m% immediate reaction was that I would been more con6inced if the

<admittedl% impressi6e= results had been achie6ed b% comparing the trial drug combination to Balsartan

,@0 mg twice dail% <as in the trial drug= "he A#I used <#nalapril ,0mg 2ID= was not onl% not eui6alent

in class to the trial drug AR2 component but also half the ma:imum recommended dose of #nalapril <10

mgFda%= while the Balsartan component of the trial drug was the ma:imum recommended dose

<-/0mgFda%= "his factor alone could at least partl% account for the lesser amount of renal d%sfunction and

h%per3alemia noted with the trial drug.

bruno schnet;ler $ Ph%sician $ Disclosure( None

Swit;erland

September 0@ /0,1

could a lar'er use of %C) or C/T have affected the net clinical benefit *

ongratulation for this landmar3 stud% which ma% well transformed our clinical practice. According to the

discussion of the e:perts il seems <unpublished results= that sudden death is also decreased. ould %ou

comment on the rather low use of ID and R"&D or R"&P in this high ris3 patients population. Hhat

was the percentage of patients with a Left 2225 Do %ou thin3 that a wider use of these de6ices ma%

ha6e change the net clinical benefit 5 "han3 %ou for %our answer.

+SA!A A!IN !D $ Ph%sician & A2D+!INAL RADI+L+*9 $ Disclosure( None



K)A!IS !S)9"&A2)A Saudi Arabia

September 0@ /0,1

#C$ &N$P/%4(%N

I D+ )+P# I" HILL 2# ")# +N# ......H# HILL HAI" AND S## ..../,E R#D"I+N +C

)+SPI"ALI8A"I+N..7 0E R#D"I+N IN !+R"ALI"9 ..

DABID 2I)ARI !D $ Ph%sician & RI"IAL AR# !#D <IN" !#D= $ Disclosure( None

S9DN#9 Australia

September 0 /0,1

Who paid for this study*

I note this stud% was supported b% No6artis7 )ence this was industr% sponsored7 I thin3 we need at least

another two independent studies to confirm these remar3able results.

I !AR*ARA ISA2#LLA $ Student $ Disclosure( None

A")#NS *reece

September 0 /0,1

$cho features - #dministration warnin'

It would also be interesting to get some echocardiographic data published for these patients. It might help

us clarif% the mechanism of the drug's beneficial action. As far as the lac3 of an A#IFnepril%sin arm is

concerned apparentl% there is a high ris3 of serious angioedema with this combination that is wh% it was

not included in the trial. In fact there is a warning that an% patient on A#I should be 3ept off the drug for

- da%s before switching to AR2Fnepril%sin in 6iew of this potentiall% life & threatening side effect.

RABI A*ARHALA !D $ Ph%sician & RI"IAL AR# !#D <IN" !#D= $ Disclosure( None

HINS"+N SAL#! N

September 0 /0,1

Concurrent heart failure therapy

Hhile the results are impressi6e I would li3e to 3now what happened to the concurrent )C therap% during

the trial. 2aseline rates of beta&bloc3er and other therapies were eui6alent in both arms at baseline but

did this hold true throughout the stud% period5 "his is potentiall% an important confounder. "han3 %ou.

RI)ARD H#INS"#IN !D $ Ph%sician & ARDI+BASLAR DIS#AS# $ Disclosure( None

R+KBILL# !D

September 01 /0,1

comparin' #/B&Neprilysin to #C$

Since A#I are still considered ,st line therap% most cardiologists I ha6e discussed this trial with would

ha6e been more comfortable with an A#IFNepril%sin arm in the trial. It seems the onl% reason that

Balsartan was used was because it was sponsored b% No6artis. Although this seems to be a re6olutionar%

brea3through in )C management optimal therap% still has not been established.

SA!IR SA)A !D $ Ph%sician & ARDI+BASLAR DIS#AS# $ Disclosure( None

SNDSBALL Sweden

September 01 /0,1

# true 'ame chan'er



"o me this is a sensational trial that reminds me of the )+P# trial presented at the A meeting man%

%ears ago in Anaheim A. I hope that the drug would soon be a6ailable in the # region as well as in

the S. I feel 6er% fortunate to witness li6e the two mile stone trials presented in two sides of the Atlantic

< and the Pacific=. Loo3ing forward to being one of the first cardiologists to offer this drug to m% patients.

"han3s.

neprolysin

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