Heart Failure: Future DirectionsHeart Failure: Future Directions

Marc A. Pfeffer, MD, PhDMarc A. Pfeffer, MD, PhDDzau Professor of Medicine, Harvard Medical SchoolDzau Professor of Medicine, Harvard Medical SchoolCardiovascular Division, Brigham & Women’s HospitalCardiovascular Division, Brigham & Women’s Hospital

Boston, MassachusettsBoston, Massachusetts

Disclosures: Marc A. Pfeffer, M.D., Ph.D., reports having serves as consultant to Aastrom, Abbott Vascular, Amgen, Cleveland Clinic, Concert, Daiichi Sankyo, Fibrogen, Genzyme, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Novartis, Novo Nordisk, Roche, Salix, Sanderling, Sanofi Aventis, Servier, and Teva and having received grant support from Amgen, Celladon, Novartis, and Sanofi­Aventis. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin­angiotensin system in survivors of MI with Novartis. Dr. Pfeffer’s shares are irrevocably transferred to charity.

Timeline of Landmark Heart Failure RCTs1990 2005

V­HeFTCONSENSUS

SOLVDSAVE

RALESCIBIS­2

MERIT­HF

COPERNICUSVal­HeFTCHARM

EPHESUSCOMPANION

2010

CARE­HFSCD­HeFT

HeartMate IIMADIT­CRT

SHIFTRAFT

EMPHASIS

1995 2000

We need a bigger pole!

0

16

32

40

24

8

Enalapril(n=4212)

360 720 10800 180 540 900 1260Days After Randomization

41874212

39223883

36633579

30182922

22572123

15441488

896853

249236

LCZ696Enalapril

Patients at Risk

1117

Kap

lan­

Mei

er E

stim

ate

ofC

umul

ativ

e R

ates

(%)

914

LCZ696(n=4187)

HR = 0.80 (0.73­0.87)P = 0.0000002

Number needed to treat = 21

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)

2014

PARADIGM-HF: All-Cause Mortality

41874212

40564051

38913860

32823231

24782410

17161726

1005994

280279

LCZ696Enalapril

Enalapril(n=4212)

LCZ696(n=4187)

HR = 0.84 (0.76­0.93)P<0.0001

Kap

lan­

Mei

er E

stim

ate

ofC

umul

ativ

e R

ates

(%)

Days After RandomizationPatients at Risk

360 720 10800 180 540 900 12600

16

32

24

8

835

711

2014

All Cause Mortality

Post–Hoc Analysis By Region

• Differences in:v Patient Populationsv Prognosisv Responses to Spiro:

• K+• Creatinine• Blood Pressure­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­Rz to spiro associated with reduced CV death

and HF hospitalizations, in pts from the Americas

2015

PARAGON­HF: study design

Target patient population: 4,300 patients with symptomatic HF (NYHA Class II–IV) and LVEF 45%

up to 2 weeks ~240 weeks

Valsartan 160 mg BID

LCZ696 200 mg BIDLCZ696 100 mg BID

On top of optimal background medications for co­morbidities (excluding ACEIs and ARBs)

Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events)

Valsartan 80 mg BID*Screening

3–8 weeks

Active run­in period

Double­blind treatment period

*Valsartan 40 mg BID (up to 2 weeks) followed by valsartan 80 mg BID as an optional starting run­in dose for those patients being treated with less than the minimum dose of ACEI or ARB at Visit 1.ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; BID=twice daily; CV=cardiovascular; HF=heart failure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association

Randomization 1:1

ICD

Risk factor reduction, patient and family education

Treat hypertension, dyslipidemia, diabetes. ACE inhibitors (or ARB) in selected patients

ACE inhibitors (or ARB) in all patients; Beta blockers in selected patients.

1’ Prevention

Stages of HF and treatment options for systolic heart failure

Jessup M and Brozena S2003

NORMAL

No symptomsNormal exerciseNormal LV

No symptomsNormal exerciseAbnormal LV

No symptoms ExerciseAbnormal LV

Symptoms ExerciseAbnormal LV

with treatmentSymptoms not controlled

AsymptomaticLV Dysfunction

Compensated HF

Decompensated Heart failure

Refractory HeartFailure

Stage A

Stage B

Stage C

Stage DNYHA Class (I–IV)

NYHA IV

Stage C

2001

The Cycle of Clinical Therapeutics The Cycle of Clinical Therapeutics

Adapted from Califf R et al. JACC 2002.

EducationEducation

Implementation

Public Health Improved

Guidelines

RCT

Epidemiology Hypothesis Pathophysiology

Societies, Regulators, Payers, Practitioners

Euro Heart Survey

Ann Intern Med. 2014 Jun 3;160(11):774-84

HR (97.5% CI ) P­ValueAmiodarone vs. Placebo 1.06 (0.86, 1.30 ) 0.529ICD Therapy vs. Placebo 0.77 (0.62, 0.96 ) 0.007

Sudden Cardiac Death

SCD­HeFT Heart Failure Trial

2004

Death or HospitalizationCOMPANION:

Abraham, W. T. et al. Nat. Rev. Cardiol. 11, 576–585 (2014)

Worldwide Heart Transplant Volume

Cyclosporine

J Heart Lung Transplant 2007;26:769

NEJM 2001;345(20):1435-43.

NEJM 2009;361(23):2241-51.

NEJM 2009;361(23):2241-51.NEJM 2001;345(20):1435-43.

J Heart Lung Transplantation 2014

ICD, LCZ

Risk factor reduction, patient and family education

Treat hypertension, dyslipidemia, diabetes. ACE inhibitors (or ARB) in selected patients

ACE inhibitors (or ARB) in all patients; Beta blockers in selected patients.

1’ Prevention

Stages of HF and treatment options for systolic heart failure

Jessup M and Brozena S2003

Gene therapy2011

2014

April 26, 2015Celladon Reports Negative Results for CUPID2 Trial of MYDICAR(R) in Advanced HeartFailure-Investigational gene therapy fails to meet primary and secondary endpoints –­SAN DIEGO, April 26, 2015 (GLOBE NEWSWIRE) ­­ Celladon Corporation (Nasdaq:CLDN) today announced that its Phase 2bCUPID2 trial did not meet its primary and secondary endpoints. CUPID2 is a randomized, double­blind, placebo­controlled,multinational trial evaluating a single, one­time, intracoronary infusion of the cardiovascular gene therapy agent MYDICAR®(AAV1/SERCA2a) versus placebo added to a maximal, optimized heart failure drug and device regimen.In the study, the primary endpoint comparison of MYDICAR to placebo resulted in a hazard ratio of 0.93 :95%CI (0.53, 1.65))

nature2001

Eur J Heart Fail 2012

N = 1317 2.70 (1.5, 3.9)

Metaanalysis of Bone Marrow Stem Cells post AMIChange in EF at 3­6 months

Lancet 2015; 385: 812–24

The War against Heart Failure: The Lancet LectureEugene Braunwald 2015

Which Cells/Factors?

How administer?

How many?

When?

To whom?

Regenerative Strategies

Safe and Effective Therapeutic Product

CSC GMP Facility (making a reproducible

product)

Dose and Regimen

RegulatoryBusiness Development

1979

1975

1980

1980

ER, extended release.

Adapted from: MERIT­HF Study Group. Lancet. 1999;353:2001­2007.CIBIS­II Investigators. Lancet. 1999;353:9­13.

Packer M, et al. N Engl J Med. 2001;344:1651­1658.

Follow­up (months) Time (days)

CIBIS­II

Log rank P=.00006

Bisoprolol

Placebo

n=2647

0 200 400 600 800

Prob

abili

ty o

f sur

viva

l

COPERNICUS

Surv

ival

(%)

34%Mortality: 34% 35%

Carvedilol

Placebo

P=.00014 (unadjusted)P=.0014 (adjusted)

n=2289

Months0 4 8 12 16 20 24 28

MERIT­HF

Cum

ulat

ive

mor

talit

y (%

) 20

15

10

5

0

P=.0062 (adjusted)P=.00009 (nominal)

Placebo

n=3991

.9

.8

.7

.6

.5

.4

.3

.2

.1

1.0

00 3 6 9 12 15 18 21

ER Metoprolol Succinate

Beta Blockers Decrease Mortality in Systolic HF

100

90

80

70

60

50

Improve ­pheno­geno­typing

by harvesting molecular biology

Novel therapies will be better targeted

Heart Failure Therapies

2009

80

90

100

110

120

130

140

150

160

170

198619871988198919901991199219931994199519961997199819992000200120022003

Year

Firs

t Hos

pita

lizat

ion

rate

(p

er 1

00,0

00 p

opul

atio

n)

Men Women

2009

ICD

Risk factor reduction, patient and family education

Treat hypertension, dyslipidemia, diabetes. ACE inhibitors (or ARB) in selected patients

ACE inhibitors (or ARB) in all patients; Beta blockers in selected patients.

1’ Prevention

Stages of HF and treatment options for systolic heart failure

Jessup M and Brozena S2003