University of Groningen

Novel therapies in heart failureLiu, Licette Cécile Yang

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Precision Medicine in Heart Failure ○  33

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CHaPTeR 1A Novel Approach to Drug Development in Heart Failure: Towards Personalized Medicine

Licette C.Y. Liu, Adriaan A. Voors, Mattia A. E. Valente, and Peter van der Meer

Canadian Journal of Cardiology. 2014 Mar;30(3):288-95

aBsTRaCT

Evidence-based treatment has succeeded in improving clinical outcomes in heart failure. Nevertheless, morbidity, mortality and the economic bur-den associated with the syndrome remain unsatisfactorily high. As most landmark heart failure studies included broad study populations, current recommendations dictate standardized, universal therapy. While most patients included in recent trials benefit from this background treatment, exceeding this already significant gain has proven a challenge. The early identification of responders and non-responders to treatment could result in improved therapeutic effectiveness, while reduction of unnecessary exposure may limit harmful and unpleasant side effects. In this review, we examine the potential value of currently available information on differen-tial responses to heart failure therapy – a first step towards personalized medicine in the management of heart failure.

Keywords heart failure, personalized medicine, pharmacogenetics, proteomics, biomarkers, systems biology

Precision Medicine in Heart Failure ○  35

1

INTRoDuCTIoN

Heart failure is a growing public health problem in industrialized nations. With a prevalence of approximately 1-2%, and >10% of sufferers over the age of 70, heart failure remains one of the most common causes of morbidity and mortality.1

Despite advances in therapy, prognosis is poor and the economic burden associated with the syndrome remains unsatisfactorily high. Current guidelines are based on the results of large, carefully controlled clinical trials, and thus recommendations provide standardized, universal therapy.1 The majority of current heart failure patients benefit from this background treatment, and negative or neutral results are becoming more commonplace in heart failure randomized clinical trials. Additionally, use of both cardiovascular and non-cardiovascular medication has increased among heart failure patients in recent years;2 polypharmacy multiplies the risk of adverse drug effects and drug interactions, and may influence therapeutic compliance.These factors call for exploration of alternative approaches to the development of novel therapies in heart failure. Identifying responder profiles during early phases of drug development could increase the likelihood of trial success and allow physicians to select more appropriate and effective treatments for their patients, while limiting the risk of unpleasant and harmful side-effects. In this review, we present several ex-amples illustrating the association between clinical information and response to treat-ment. We believe this information should be considered fully, and used to distinguish responders from non-responders prior to treatment. The ideal is the development of an inexpensive, patient-friendly, widely and easily applicable method for the delivery of ‘personalized’ treatment to individual heart failure patients.

ClINICal CHaRaCTeRIsTICs

Differences in therapeutic response may be related to differences in clinical charac-teristics, such as race, sex, heart failure etiology or co-morbidities. Such differences are often examined via post-hoc subgroup analyses of large randomized clinical trials. Risk ratios across subgroups are generally presented as forest plots – a graphical display of the relative strength of a treatment effect. Though most such analyses fail to demonstrate differential responses, heterogeneity in treatment effects based on clini-cal characteristics is certainly not unusual, as illustrated by a number of studies.3-10

36 ○  Chapter 1

Race

As phenotype derives from the expression of genotype, racial differences in thera-peutic response are likely based on differences in neurohormonal mechanisms and genetic profiles. Some studies have described racial differences in response to heart failure therapy (Table 1). However, these data should be interpreted with caution, as most studies were either small or retrospective in nature.

Sex differences

Sex-related differences have been described in patients with heart failure. Women tend to have different clinical characteristics, heart failure etiology and biomarker profiles than men. 11-15 The female sex hormone estrogen also has significant effects on several aspects of cardiac physiology.16 Therefore, sex-related differences in drug response may be expected, as illustrated by retrospective analyses by the Digitalis Investigation Group trial (Table 1).6

Heart failure etiology

Ischemic heart failure and non-ischemic heart failure arise from different patho-physiological mechanisms, therefore their response to treatment may also differ.17 Determining etiology may help in selecting initial drug therapy in some cases, e.g. bromocriptine as potential therapy for acute severe peripartum cardiomyopathy18 or iron chelation as treatment for seconary iron-overload cardiomyopathy.19

Variable response to β-blockers, Angiotensin Converting Enzyme (ACE)-inhibitors, calcium antagonists and phosphodiesterase 3 inhibitors has been described in patient groups with different heart failure etiologies.7,17 Although most of these observations are drawn from subgroup analyses, they underscore the potential for such differential treatment effects.

Heart failure with reduced vs. preserved ejection fraction

Pharmacological interventions with proven efficacy in heart failure with reduced ejec-tion fraction (HFrEF) have failed to improve morbidity and mortality in heart failure with preserved ejection fraction (HFpEF).20 Of particular interest are the marked dif-ferences in outcomes between HFrEF and HFpEF in studies with Renin Angiotensin Aldosterone System (RAAS)-inhibiting agents (Table 1). Treatment with ACE-inhibitors, for example - a cornerstone in the management of heart failure - did not result in reduced mortality or heart failure hospitalization in patients with HFpEF.8 Similar disappointing results were recently presented for the mineralocorticoid receptor antagonist spironolactone - another key evidence-based heart failure therapy - during late-breaking clinical trial sessions at the 2013 American Heart Association Congress (TOPCAT).85 The observed differences in therapeutic response between patients with

Precision Medicine in Heart Failure ○  37

1

Tabl

e 1

• D

iffer

entia

l the

rape

utic

resp

onse

bas

ed o

n cl

inic

al c

hara

cter

istic

s

auth

or an

d Pu

blica

tion

Date

Clin

ical T

rial

abbr

eviat

ion

stud

y Des

ign

nst

udy p

opul

atio

nM

ain re

sults

Refe

renc

es

Zhou

et al

., 19

89Pr

ospe

ctive

clin

ical

trial

2010

Chi

nese

men

10 A

mer

ican

white

m

en

Chin

ese m

en h

ad a

grea

ter s

ensit

ivity

to

prop

anol

ol co

mpa

red

to w

hite

men

.

3

Exne

r et a

l., 2

001

Stud

ies o

f Lef

t Ve

ntric

ular

Dy

sfunc

tion

SOLV

DM

atch

ed-co

hort

desig

n19

9680

0 bl

ack p

atien

ts11

96 w

hite

pat

ients

Enala

pril

was a

ssoc

iated

with

a re

duct

ion

in h

eart

failu

re h

ospi

taliz

atio

ns am

ong

white

pat

ients

, but

not

amon

g bl

ack

patie

nts

4

Cars

on et

al.,1

999

Vaso

dilat

or-

Hea

rt Fa

ilure

Tr

ials

V-H

eFT

I & II

Retro

spec

tive a

nalys

is14

49V-

HeF

T I

180

blac

k pat

ients

480

white

pat

ients

V-H

eFT

II21

5 blac

k pat

ients

574

white

pat

ients

Onl

y whi

te p

atien

ts ex

perie

nced

surv

ival

bene

fit fr

om an

alapr

il th

erap

y com

pare

d wi

th h

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sorb

ide d

initr

ate.

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rbid

e din

itrat

e was

eff

ectiv

e in

blac

k pat

ients

onl

y, co

mpa

red

with

plac

ebo

5

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ore e

t al.,

200

2Di

gita

lis

Inve

stig

atio

n Gr

oup

(DIG

) Tr

ial

DIG

trial

Retro

spec

tive a

nalys

is68

0015

19 w

omen

5281

men

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xin th

erap

y was

asso

ciate

d wi

th

incr

ease

d m

orta

lity r

isk am

ong

wom

en

only

6

Felke

r et a

l., 2

003

Out

com

es o

f a P

rosp

ectiv

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ial o

f In

trave

nous

M

ilrin

one f

or

Exac

erba

tions

of

Chr

onic

Hea

rt Fa

ilure

OPT

IME-

HF

Retro

spec

tive a

nalys

is92

245

8 isc

hem

ic he

art

failu

re p

atien

ts46

4 no

nisc

hem

ic he

art f

ailur

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ients

Trea

tmen

t with

milr

inon

e was

asso

ciate

d wi

th p

rolo

nged

hos

pita

lizat

ion

and

high

er m

orta

lity i

n pa

tient

s with

isc

hem

ic he

art f

ailur

e

7

Clela

nd et

al.,

2006

Perin

dopr

il in

El

derly

Peo

ple

with

Chr

onic

Hea

rt Fa

ilure

PEP-

CHF

Rand

omize

d co

ntro

lled

trial

850

Patie

nts w

ith h

eart

failu

re w

ith p

rese

rved

eje

ctio

n fra

ctio

n

Perin

dopr

il th

erap

y did

not

resu

lt in

re

duct

ions

in m

orta

lity a

nd h

eart

failu

re

hosp

italiz

atio

n

8

38 ○  Chapter 1 Precision Medicine in Heart Failure ○  39

1

Tabl

e 1

• D

iffer

entia

l the

rape

utic

resp

onse

bas

ed o

n cl

inic

al c

hara

cter

istic

s (c

ontin

ued)

auth

or an

d Pu

blica

tion

Date

Clin

ical T

rial

abbr

eviat

ion

stud

y Des

ign

nst

udy p

opul

atio

nM

ain re

sults

Refe

renc

es

Mas

sie et

al.,

2008

Irbes

arta

n in

H

eart

Failu

re

with

Pre

serv

ed

Ejec

tion

Frac

tion

Stud

y

I-PRE

SERV

EDo

uble-

blin

d ra

ndom

ized

cont

rolle

d tri

al

4128

Patie

nts w

ith h

eart

failu

re w

ith p

rese

rved

eje

ctio

n fra

ctio

n

Irbes

arta

n di

d no

t res

ult i

n a r

educ

tion

of th

e com

posit

e end

poin

t of a

ll-ca

use m

orta

lity a

nd ca

rdio

vasc

ular

re

hosp

italiz

atio

n co

mpa

red

with

plac

ebo

9

Yusu

f et a

l., 2

003

Cand

esar

tan

in

Hea

rt fa

ilure

: As

sess

men

t of

Redu

ctio

n in

M

orta

lity a

nd

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bidi

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CHAR

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rved

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blin

d ra

ndom

ized

cont

rolle

d tri

al

3023

Patie

nts w

ith h

eart

failu

re w

ith p

rese

rved

eje

ctio

n fra

ctio

n

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tmen

t with

cand

esar

tan

did

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lt in

impr

ovem

ents

in ca

rdio

vasc

ular

de

ath

and

hear

t fail

ure h

ospi

taliz

atio

ns

com

pare

d wi

th p

laceb

o

10

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et al

., 20

14Tr

eatm

ent

of P

rese

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rdiac

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nctio

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eart

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re w

ith an

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dost

eron

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tago

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TOPC

ATDo

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blin

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laceb

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allel

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p st

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3445

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nts w

ith h

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failu

re w

ith p

rese

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ctio

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tmen

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spiro

nolac

ton

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ced

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italiz

atio

ns b

ut fa

iled

to sh

ow

bene

fit in

mor

talit

y

85

38 ○  Chapter 1 Precision Medicine in Heart Failure ○  39

1

HFrEF and HFpEF might be explained by different underlying pathophysiological mechanisms.

Atrial fibrillation

While treatment with β-blockers has been shown to reduce mortality and morbidity in patients with heart failure1, no such benefit was seen in heart failure patients with atrial fibrillation.21-25 There is some evidence from retrospective studies that patients in sinus rhythm profit more from treatment with β-blocker than patients with atrial fibril-lation, though this has yet to be confirmed in properly designed, prospective clinical trials.21-25 Heart failure guidelines still recommend β-blockers as first-line treatment in patients with atrial fibrillation. 1

geNeTICs

The exploration of the human genome26-28 and ongoing developments in genomics allow us to study differential gene expression patterns in the development of heart failure. Genome-wide association studies allow rapid scanning of the genome for small variations and determination of whether these single nucleotide polymor-phisms (SNPs) are associated with phenotype. Several genes have been identified with greater expression in certain cardiomyopathies, such as dilated cardiomyopathy29 and hypertrophic cardiomyopathy30. In current clinical practice, genetic testing is used to identify relatives of patients with a mutation-associated cardiomyopathy who are also at risk of developing it but do not express the phenotype, to diagnose metabolic/myocardial storage diseases mimicking hypertrophic cardiomyopathy, and for immu-nodiagnostics and immunomonitoring in heart transplants (e.g. AlloMap® testing).31 However, the growing use of genomic data is associated with a number of ethical and privacy issues. Genome sequencing may reveal information about the health of participants and their families, while its significance is not always clear-cut. Current developments – including gene patenting and privacy concerns – demand updated ethical and legal frameworks, and should be addressed by medical professionals, patients, policy makers, and governments.

Pharmacogenetics

Pharmacogenetics is the study of the effects of genomic polymorphisms on clinical drug response. The importance of applying genomic testing to the evaluation of

40 ○  Chapter 1

therapy response was first recognized in oncology.32,33 In cardiology, several genetic variations have been shown to be associated with differential response to therapy (Table 2). These examples illustrate how genomic polymorphisms may aid in identify-ing responders and non-responders.

Adrenergic receptor polymorphisms

Several pharmacogenetic effects of adrenergic receptor polymorphisms on response to heart failure therapy have been described (Table 2). Variance in β1-, β2- and α2c-adrenergic receptor have been shown to be associated with differential response to β-blocker therapy.34-39 These studies underscore that genetic variation may play a role in response variability. It should be stressed, however, that most findings were obtained via retrospective analyses and as a whole do not provide sufficient evidence to guide treatment based on genetic testing. Prospective research is required to determine whether these findings are replicable.

Genetic variation in the angiotensin converting enzyme

ACE gene insertion/deletion (I/D) polymorphisms have been associated with the level of enzyme activity, with allele deletion resulting in higher levels of ACE.40 Thus, ACE D/D carriers have higher RAAS activity. Several studies suggested that the ACE D/D variant is associated with the development of heart failure and a poorer prognosis in patients with manifest heart failure.41,42 Therapeutic response to ACE-inhibitors is

Table 2 • Genotype polymorphisms associated with drug response in heart failure

genotype polymorphism Phenotype Heart failure drug response References

Glycine49 β1-AR vs.serine49 β1-AR

Glycine-49 β1-AR genotypes display enhanced agonist-promoted desensitization and down-regulation compared to serine-49 β1-AR

Survival in glycine49 β1-AR carriers without β-blockade was similar to that of serine49 β1-AR carriers with β-blockade

34,35,82

Glutamine27 β2-AR vs. glutamic27 β2-AR

Glutamine27 β2-AR has been found tobe resistant to agonist-promoted down regulation

Greater response to carvedilol in glutamic27 β2-AR carriers compared to glutamine27 β2-AR carriers

36,37,83

Threonine164 β2-AR vs. isoleucine164 β2-AR

Isoleucine-164 associated withdecreased response to β-blockade

Isoleucine164 β2-AR carriers treated with β-blockade have a higher mortality rate compared with isoleucine164 β2-AR carriers without beta blockade

38

Insertion/deletion polymorphismα2c-adrenergic receptor

Deletion variant α2cDel322-325 resultsin dysfunction of autoinhibition of the central and peripheral nervous system, leading to an increased release of norepinephrine

In patients with α2cDel322-325 in presence with argine-389 β1-AR, treatment reatment with β-blockade resulted in greater improvement in left ventricular ejection fraction compared with other genotypes

39,84

β1-AR: β1- adrenergic receptor; β2-AR: β2-adrenergic receptor

Precision Medicine in Heart Failure ○  41

1

minimal in ACE D/D carriers compared to ACE I/I carriers, suggesting an interaction between ACE genotype and response to ACE-inhibition in patients with heart failure. 43

Endothelin-1

Endothelin-1, a potent vasoconstrictor peptide expressed by vascular endothelium and cardiomyocytes, promotes cardiomyocyte contractility and hypertrophy. 44 After the β-blocker evaluation of Survival Trial (BEST)45 was terminated early, data became available to serve as a resource for studies investigating genetic interactions. In bucindolol-treated patients, two SNPs in the endothelin-1 gene , the G/A IVS-4 variant and Lys198Asn variant that are in tight linkage disequilibrium, were found to be associ-ated with prognosis.46 However, the exact role of these SNPs in this pharmacogenetic interaction remains to be clarified by future research.

Candidate genes associated with chemotherapeutic cardiotoxicity

Cardiotoxicity is a serious adverse drug reaction to several chemotherapeutic agents, such as doxorubicin and trastuzumab (Herceptin).47,48 Current options for predicting the risk of chemotherapy-induced cardiotoxicity are limited. Several candidate genes have been associated with the risk of chemotherapeutic cardiotoxicity. Some gene variants have been associated with an increased risk; for example, genetic polymor-phisms encoding NAPDH oxidase and doxorubicin efflux transporter ABCB1/MDR1 and variance in the HER2 genotype (Ile/Val) are associated with an increased the risk of developing cardiotoxicity.49,50 Other gene variants were found to be protective; in children, a variant in the SLC28A3 gene was associated with protection against cardiotoxicity.51

PRoTeoMICs aND BIoMaRKeRs

Previously mentioned studies illustrate how genomic mapping may contribute to identifying responders and non-responders. However, as one gene can code for multiple proteins, biomarkers may provide additional information. In recent years, the investigation of heart failure-related biomarkers has increased exponentially.52 Most studies examine the prognostic implication of biomarkers.52 However, several biomarkers have also been shown to be related to drug response. The following ex-amples illustrate how knowledge certain biomarkers levels can be used to determine drug response and to monitor treatment.

42 ○  Chapter 1

Pre-treatment biomarkers levels and therapeutic response

Plasma renin activity

ACE-inhibitors have been shown to be more effective in patients with higher pre-treatment plasma renin activity (PRA).53,54 In heart failure patients, the effects of ACE-inhibition were greater in individuals with high pre-treatment renin levels.54 These results imply that patients with higher neurohormonal activity would respond better to neurohormonal blocking agents, and underline the potential value of assessing pre-treatment levels of substances blocked by specific therapies. It should be noted however that there are studies suggesting that determining PRA prior ACE-inhibitor treatment would only be helpful in Caucasian populations.55

Arginine vasopressine

Tolvaptan, an arginine vasopressine (AVP) antagonist, had no overall effect on mor-bidity and mortality in heart failure patients.56 Studying pre-treatment AVP levels did not reveal heterogeneity in treatment response.57 However, the instability and rapid metabolism of AVP may have complicated these analyses.58 Copeptin, the C-terminal portion of pro-AVP, is more stable and easy to measure, and has therefore been pro-posed as a reliable biomarker that mirrors AVP levels.58 A phase III randomized clinical trial investigating the therapeutic efficacy of tolvaptan in patients with high copeptin levels is currently ongoing (ACTIVATE, NCT01733134).

Cardiac extracellular matrix markers

Procollagen type I amino-terminal peptide (PINP), procollagen type I carboxy-terminal peptide (PICP), and plasma procollagen type III amino-terminal peptide (PIIINP) are markers of collagen synthesis and can be used to monitor cardiac extracellular matrix (ECM) turnover. In one post-hoc study, heart failure patients with high baseline ECM levels experienced a greater benefit from treatment with spironolactone.59

Biomarker-guided therapy

Natriuretic peptides

Brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are the most studied biomarkers for biomarker-guided therapy. Results on efficacy are conflicting, with some studies confirming initial positive findings,60-63 while others yielded nega-tive results.64-69 In a meta-analysis, natriuretic peptide-guided therapy was associated with a significantly lower risk of all-cause mortality and heart failure hospitalization

Precision Medicine in Heart Failure ○  43

1

compared with usual clinical care.70 A large, randomized clinical trial comparing usual care with NT-proBNP guided care is ongoing (GUIDE-IT, NCT01685840).

Hemoconcentration

Hemoconcentration, defined as increasing hematocrit, is considered a surrogate marker for changes in intravascular volume status during fluid extraction.71,72 There-fore, hemoconcentration can be used to gauge the effectiveness of diuretic therapy in acute decompensated heart failure. Several studies have shown that hemoconcentra-tion is associated with improved outcomes in heart failure.73-76

MicroRNAs

MicroRNA (MiRNA) are small, non-coding RNAs that regulate protein expression by inhibiting translation or promoting degradation of target messenger RNA.77 Several different miRNA expression patterns associated with the development of heart failure have been described.78 miRNA are also proving worthwhile potential therapeutic targets. MiRNA mimics and antisense miRNA oligonucleotides may restore miRNA levels by replacing or inhibiting miRNA activity, respectively.79 Some miRNAs are also detectable in peripheral tissue, such as blood and urine, and could be used to monitor heart failure therapy.80 A recent animal study by Dickinson et al. found that circulating miRNA levels change in response to treatment, indicating miRNA levels could be helpful in monitoring heart failure treatment.81

FuTuRe PeRsPeCTIves

We have presented several studies exemplifying how certain pre-treatment clinical information may assist in determining drug response. However, the underlying ques-tion this approach seeks to answer is: ‘How can we distinguish potential responders from non-responders?’ An answer to this question requires in-depth understanding of the complex biological interactions in heart failure. Systems biology is an emerging approach that reaches beyond reductionism, in which every structure and function of genes and proteins is studied in isolation. The foundation of systems biology is the concept that genes and proteins act in concert in complex networks that result in organizational units, and focuses on the study of higher order interactions between fundamental biological elements which determine the expression and appearance of health and disease. A large, prospective observational study employing a systems biol-ogy approach - including clinical, laboratory, genomic and proteomic data - to evaluate which heart failure patients have poor clinical outcomes despite proven evidence-

44 ○  Chapter 1

based heart failure therapy is currently underway (BIOSTAT-CHF, http://www.biostat-chf.eu/). The identification of responder and non-responder profiles in BIOSTAT-CHF and other studies should always be followed by prospective randomized clinical trials to confirm hypotheses. In addition, we believe that development programs for novel heart failure drugs should include responder/non-responder analyses. For logistical and practical reasons, such analyses can only be based on surrogate endpoints, and should also be based on biological plausibility. The first step in testing this approach would be retrospective, hypothesis-generating analyses in previously conducted randomized trial populations, comparing pre-defined responder and non-responder profiles and examining associations between these profiles clinical outcomes. Ob-served pathogenic associations may thus lay the groundwork for further research to identify responders and non-responders. The ultimate goal is the development of a risk stratification model to distinguish between the two groups prior to treatment. Current studies define the patient population of interest at an early stage, based solely on assumptions. We are of the opinion that phase II studies should include a wider variety of patients in order to not only establish the correct dose, but also identify the right patient, based in part on a systems biology approach. This will increase the likelihood of success in phase III trials.In conclusion, there is a pressing need to distinguish responders from non-responders to pharmacological therapy in an early phase. Investigations in this direction should not be limited to clinical characteristics alone, but may be greatly enhanced by genomic and proteomic information. Using the full breadth of available data in designing future studies may result in a more targeted approach, leading to larger effects in responders while minimizing needless therapy in non-responders, serving the ultimate goal of improved personalized treatment for each and every patient.

Precision Medicine in Heart Failure ○  45

1

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