Jean Rouleau, MD FRCPC

1
Jean Rouleau, MD FRCPC

• Dean of the Faculty of Medicine, University of
  Montréal
• Montréal, Québec, Canada

2
Studies that Impact Therapy of CHF from Now to
2010

• Jean L. Rouleau, MDCardiologist
• Institut de Cardiologie de Montréal
• Dean, faculty of Medecine
• Université de Montréal

3
Inspecting the Data
I wonder where the therapy of CHF is going?
4
Disclosures Jean Rouleau

• Chair, STICH study-NIH.
• NIH Heart Failure Network RCC.
• TOPCAT executive, WARCEF steering committee, NIH.
• Consultant-NOVARTIS, Pfizer, BMS
• Executive committee- ASCEND study-Scios,
  ACCLAIM-2- Vasogen

5
Therapeutic Controversy
The use of foxglove is getting abroad, and it is
better the world should derive some instruction,
however imperfect, from my experience, than the
lives of men should be hazarded by its unguarded
exhibition, or that a medicine of so much
efficacy should be condemned and rejected as
dangerous and unmanageable. William Withering,
1785
6
FDR Presidential Portrait Served 1933-1945

• Long standing hypertension
• FDR was referred to Dr. Howard Bruenn, a
  cardiologist at Bethesda who, on 3/27/44 found
  him cyanotic, breathless, with an enlarged left
  ventricle and a BP of 186/108. Bruenn diagnosed
  hypertensive heart disease and wanted to give
  digitalis but was prohibited..by the surgeon
  general.
• CVA April 12, 1945 (a shock to his medical
  staff)
• www.doctorzebra.com

7
Modern Evolution of Heart Failure Therapies
Vasodilator Hypothesis
Barnard, Heart Transplant 1967
BBF described Ferreira, 1965
HF is dropsy
Furosemide available,1967
Framingham Study NEJM, 1971
Braunwald \ NEJM review, 1967

• Bedrest
• Dig
• Mercuriols

ACE-I Synthesis Cushman, 1977
1950
1971
1980
1967
Saralasin 1977
HydralazineMinoxidil/ISDN, 1976, Chatterjee
Prazosin Miller, 1977
Captopril Davis, 1979
Observational Studies
TNG (SL) Johnson, 1959
Hydralazine Judsin, 1956
Phentolamine Majid, 1971
Nitroprusside Guiha, 1974
Hexamethonium Kelly, 1953
Teprotide Curtis/Gavras, 1978
8
Modern Evolution of Heart Failure Therapies
Vasodilator Hypothesis
Barnard, Hearr Transplant 1967
BBF described Ferreira, 1965
Observational Studies Hexamethonium Kelly,
1953 Hydralazine Judsin, 1956 TNG (SL) Johnson,
1959 Phentolamine Majid, 1971 Nitroprusside
Guiha, 1974 HydralazineMinoxidil/ISDN
Chatterjee, 1976 Prazosin Miller,
1977 Saralasin 1977 Teprotide Curtis/Gavras,
1978 Captopril Davis, 1979
HF is dropsy
Furosemide available,1967
Framingham Study NEJM, 1971
Braunwald \ NEJM review, 1967

• Bedrest
• Dig
• Mercuriols

ACE-I Synthesis Cushman, 1977
1950
1971
1980
1967
9

• ? Vascular Resistance
• Na H2O retention
• Cardiotoxicity

• Inflammation
• Oxidative Stress
• Remodelling
• Ventricular
• Vascular

• ? Cardiac Output
• Congestion

Neurohumoral Activation

• Adrenergic
• RAA
• Vasopressin
• Endothelin

10
Modern Evolution of Heart Failure Therapies
Vasodilator Hypothesis
Neurohumoral Hypothesis
Positive Clinical Trials
CONSENSUS-1, 1987
COPERNICUS, 2001
US Carvedilol, 1996

• The Future
• Pharmacogenomics
• Prevention
• Others

CAPRICORN, 2003
CAPRICARN, 2001
SOLVD-P, 1992
EPHESUS, 2003
SOLVD-T, 1991
Merit-HF, 2000
VHEFT-II, 1991
ValHEFT, 2002
VHEFT-I, 1986
CHARM, 2003
CIBIS-II, 1999
RALES, 1999
TRACE, 1995
BHAT, 1982
SAVE, 1992
AIRE, 1993
DIG, 1997
1980
1990
2000
2005
VEST, 1993
FIRST, 1997
Equivocal Clinical Trials PRAISE-I, 1996 MDC,
1993 BEST, 2001 ELITE-II, 1997 OVERTURE,
2003 RENAISSANCE, 2002 ENABLE-II, 2001 OPTIMAL,
2003
CAST, 1989
OPTIME, 2002
PROMISE, 1991
MOXCON, 1999
RECOVER, 2001
Negative Clinical Trials
Italics Post MI Trials
11
Modern Evolution of Heart Failure Therapies
Vasodilator Hypothesis
Neurohumoral Hypothesis
Positive Clinical Trials BHAT, 1982 DIG,
1997 VHEFT-I, 1986 RALES, 1999 CONSENSUS-1,
1987 CIBIS-II, 1999 VHEFT-II, 1991 Merit-HF,
2000 SOLVD-T, 1991 COPERNICUS, 2001 SOLVD-P,
1992 CAPRICARN, 2001 SAVE, 1992 ValHEFT,
2002 AIRE, 1993 CAPRICORN, 2003 TRACE, 1995
CHARM, 2003 US Carvedilol, 1996 EPHESUS, 2003

• The Future
• Pharmacogenomics
• Prevention

1980
1990
2000
2005
VEST, 1993
FIRST, 1997
Equivocal Clinical Trials PRAISE-I, 1996 MDC,
1993 BEST, 2001 ELITE-II, 1997 OVERTURE,
2003 RENAISSANCE, 2002 ENABLE-II, 2001 OPTIMAL,
2003
CAST, 1989
OPTIME, 2002
PROMISE, 1991
MOXCON, 1999
RECOVER, 2001
Negative Clinical Trials
Italics Post MI Trials
12
COPERNICUS Beneficial Effects of Beta Blocker
Carvedilol on Risk of a Clinical Event Regardless
of Baseline SBP
All-cause Mortality
8595 mmHg
Interaction P 0.64
96105 mmHg
106115 mmHg
Death or CHF hospitalisations
116125 mmHg
gt125 mmHg
Interaction P 0.80
Hazard Ratio
Rouleau et al, JACC, 2004
13
COPERNICUS Dependence of the Beneficial Effects
of the Beta Blocker Carvedilol on Pre-treatment
Heart Rate for Total Mortality or CV
Hospitalisation
lt70
7079
Heart Rate, bpm
8089
9099
100
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Cox Model Hazard Ratio (95 CI)
14
Modern Evolution of Heart Failure Therapies
Vasodilator Hypothesis
Neurohumoral Hypothesis
Positive Clinical Trials
CONSENSUS-1, 1987
COPERNICUS, 2001
US Carvedilol, 1996
CAPRICORN, 2003
CAPRICARN, 2001
SOLVD-P, 1992
EPHESUS, 2003
SOLVD-T, 1991
Merit-HF, 2000
VHEFT-II, 1991

• The Future
• Pharmacogenomics
• Prevention

ValHEFT, 2002
VHEFT-I, 1986
CHARM, 2003
CIBIS-II, 1999
RALES, 1999
TRACE, 1995
BHAT, 1982
SAVE, 1992
AIRE, 1993
DIG, 1997
Negative Clinical Trials CAST, 1989 PROMISE,
1991 VEST, 1993 FIRST, 1997 MOXCON, 1999 RECOVER,
2001 OPTIME, 2002
1980
1990
2000
2005
Equivocal Clinical Trials PRAISE-I, 1996 MDC,
1993 BEST, 2001 ELITE-II, 1997 OVERTURE,
2003 RENAISSANCE, 2002 ENABLE-II, 2001 OPTIMAL,
2003
Italics Post MI Trials
15
Modern Evolution of Heart Failure Therapies
Vasodilator Hypothesis
Neurohumoral Hypothesis
Positive Clinical Trials
CONSENSUS-1, 1987
COPERNICUS, 2001
US Carvedilol, 1996
CAPRICORN, 2003
CAPRICARN, 2001
Equivocal Clinical Trials PRAISE-I, 1996 MDC,
1993 BEST, 2001 ELITE-II, 1997 OVERTURE,
2003 RENAISSANCE, 2002 ENABLE-II, 2001 OPTIMAL,
2003 CORONA, 2007
SOLVD-P, 1992
EPHESUS, 2003
SOLVD-T, 1991
Merit-HF, 2000
VHEFT-II, 1991

• The Future
• Pharmacogenomics
• Prevention

ValHEFT, 2002
VHEFT-I, 1986
CHARM, 2003
CIBIS-II, 1999
RALES, 1999
TRACE, 1995
BHAT, 1982
SAVE, 1992
AIRE, 1993
DIG, 1997
1980
1990
2000
2005
VEST, 1993
FIRST, 1997
CAST, 1989
OPTIME, 2002
PROMISE, 1991
MOXCON, 1999
RECOVER, 2001
Negative Clinical Trials
Italics Post MI Trials
16
CORONA

• Patients with severe CHF and a poor prognosis do
  not benefit from statin therapy
• Patients with CHF and a good prognosis likely
  benefit from statin therapy

17
FraminghamHF Survival by Gender
Men
1.0
1950-1969 1970-1979 1980-1989 1990-1999
0.8
0.6
Probabilityof survival
0.4
0.2
0.0
0
2
4
6
8
10
Yr
Women
1.0
1950-1969 1970-1979 1980-1989 1990-1999
0.8
0.6
Probabilityof survival
0.4
0.2
0.0
0
2
4
6
8
10
Yr
Levy, et al. N Engl J Med 20023471397.
18
Modern Evolution of Heart Failure Therapies
Vasodilator Hypothesis
Neurohumoral Hypothesis
Positive Clinical Trials
CONSENSUS-1, 1987
COPERNICUS, 2001
US Carvedilol, 1996
CAPRICORN, 2003
CAPRICARN, 2001

• The Future
• Pharmacogenomics
• Prevention
• Etc..

SOLVD-P, 1992
EPHESUS, 2003
SOLVD-T, 1991
Merit-HF, 2000
VHEFT-II, 1991
ValHEFT, 2002
VHEFT-I, 1986
CHARM, 2003
CIBIS-II, 1999
RALES, 1999
TRACE, 1995
BHAT, 1982
SAVE, 1992
AIRE, 1993
DIG, 1997
1980
1990
2000
2005
Devices MIRACLE MIRACLE-ICD SCD-HF COMPANION
CARE-HF
VEST, 1993
FIRST, 1997
Equivocal Clinical Trials PRAISE-I, 1996 MDC,
1993 BEST, 2001 ELITE-II, 1997 OVERTURE,
2003 RENAISSANCE, 2002 ENABLE-II, 2001 OPTIMAL,
2003
CAST, 1989
OPTIME, 2002
PROMISE, 1991
MOXCON, 1999
RECOVER, 2001
Negative Clinical Trials
Italics Post MI Trials
19
MADIT II Trial (CAD,LVEF30) Hazard Ratio (95
CI) Death From Any Cause
Moss et al. NEJM. 2002346877883.
20
SCD-HeFT CHF, NYHA 2-3, LVEF35Mortality by
Intention-to-treat
HR 97.5 CI P-Value Amiodarone vs.
Placebo 1.06 0.86, 1.30 0.529 ICD Therapy vs.
Placebo 0.77 0.62, 0.96 0.007
21
SCD-HeFT CHF, NYHA 2-3, LVEF35ICD vs. Placebo
Hazard Ratios
22
Meta-analysis of effect of CRT on mortality
Pooled hazard ratio from the COMPANION and
CARE-HF studies
COMPANION
0.76 (0.58, 1.01)
CARE-HF
0.64 (0.48, 0.85)
Pooled
0.70 (0.57, 0.85)
0.2
0.5
1
2
Favours CRT
Favours Control
European Journal of Heart Failure 2005 7 931936
23
General Treatment Strategies in HF
CABG, Surgical Ventricular Remodelling (SVR)
Mitral Valve Surgery
2 g Na diet
2 g Na diet
24
ACC/AHA Heart Failure Guidelines - 2005
25
HEART FAILURE The way forward

• Prevention
• Clarification of pathophysiology
• Pharmacogenomics and tailored therapy
• Volume overload strategies
• Non pharmacologic strategies
• Mechanical circulatory support
• Volume overload management
• Cell therapies

26

• ? Vascular Resistance
• Na H2O retention
• Cardiotoxicity

• Inflammation
• Oxidative Stress
• Remodelling
• Ventricular
• Vascular

• ? Cardiac Output
• Congestion

Neurohumoral Activation

• Adrenergic
• RAA
• Vasopressin
• Endothelin

27
Death or CHF Hospitalisation TNFa receptors
RENEWAL
25 mg 1x weekly
25 mg 2x weekly
25 mg 3x weekly
25 mg BIWTIW
1.01 (0.72, 1.41)
0.87 (0.61, 1.24)
RECOVER
1.21 (0.92, 1.58)
1.23 (0.94, 1.61)
RENAISSANCE
1.08 (0.87, 1.33)
1.10 (0.91, 1.33)
RENEWAL
Risk ratios and 95 CI from Cox model adjusted
for NYHA class and beta-blocker use
28
ACCLAIM Primary EP All Cause Mortality or
Cardiovascular Hospitalization
29
Summary of Primary and Select Secondary End
Points NYHA II Subgroup
Figures represent first event CV mortality was
pre-specified sudden death included as assumed
to be primarily cardiac in origin Sudden
cardiac death, nonfatal MI, nonfatal ischemic
stroke, unstable angina or coronary revasc.
30
Summary of Primary and Select Secondary End
Points NYHA II Subgroup
ACCLAIM-2
Figures represent first event CV mortality was
pre-specified sudden death included as assumed
to be primarily cardiac in origin Sudden
cardiac death, nonfatal MI, nonfatal ischemic
stroke, unstable angina or coronary revasc.
31
Matrix Metalloproteinase Inhibitors

• Premier Study LV remodelling post-MI
• 253 patients
• No benefit
• Increase in side effects musculoskelletal
• Probable increase in acute coronary syndromes
• I am not aware of encouraging human data of any
  type
• No future!

32
HEART FAILURE The way forward

• Prevention
• Clarification of pathophysiology
• Pharmacogenomics and tailored therapy
• Volume overload strategies
• Non pharmacologic strategies
• Mechanical circulatory support
• Volume overload management
• Cell therapies

33
PHARMACOGENOMICS

• Individualized medicine is clearly the way of the
  future.
• Single SNPs or polymorphisms are not the answer.
• The work defining how genetic data will be made
  useful clinically is yet to be completed.....we
  are only just begining.
• New more powerful tools are now coming into play,
  and will likely speed things up significantly

34
HEART FAILURE The way forward

• Prevention
• Clarification of pathophysiology
• Pharmacogenomics and tailored therapy
• Volume overload strategies
• Non pharmacologic strategies
• Mechanical circulatory support
• Volume overload management
• Cell therapies

35
ADHF neglected?
36
Tolvaptan, oral Vasopressin V2 Antagonist
(Diuresis)Median changes in body weight over
time in patients hospitalized for CHF
2
1
0
-1
-2
Change in body weight from baseline (kg)
-3


-4

-5
-6


-7

-8
Day 1
Discharge
Week 1
Last visit (60 days)
P 0.002 P 0.009 P 0.006 P
0.008 vs placebo group
JAMA 2004 291, 1963-71
37
Tolvaptan, oral Vasopressin V2 Antagonist
(Diuresis)Median changes in body weight over
time in patients hospitalized for CHF
2
1
0
-1
EVEREST, N4133, NEGATIVE
-2
Change in body weight from baseline (kg)
-3


-4

-5
-6


-7

-8
Day 1
Discharge
Week 1
Last visit (60 days)
P 0.002 P 0.009 P 0.006 P
0.008 vs placebo group
JAMA 2004 291, 1963-71
38
Calcium Sensitizers(also vasodilates via K
channels in SMC)
Levosimendan (n 38)
Prostaglandin E1 (n 35)
Baseline
24 h
48 h
Baseline
24 h
48 h
3.6 ? 0.1 24 ? 0.7 38 ? 1.4 317 ? 26 1403
? 61 72.2 ? 2 71.1 ? 1
4.7 ? 0.2 1.1 ? 0.1 20 ? 0.7 -4.2 ? 0.7 33 ?
1.3 -5 ? 0.8 239 ? 20 -78 ? 20 1063 ? 52 -340 ?
60 76 ? 2 5 ? 1 67 ? 2 -4 ? 1
4.6 ? 0.2 1.1 ? 0.2 20 ? 0.8 -4.4 ? 0.7 32 ?
1.3 -5 ? 0.9 240 ? 19 -77 ? 21 1090 ? 51 -313 ?
67 77 ? 2 4 ? 1 67 ? 2 -4 ? 2
3.4 ? 0.1 24 ? 0.7 38 ? 1.5 373 ? 35 1612
? 102 74 ? 2 74 ? 2
4.0 ? 0.2 0.6 ? 0.1 20 ? 0.8 -3.5 ? 0.5 34 ?
1.3 4 ? 0.8 297 ? 24 76 ? 23 1257 ? 59 -355 ?
75 74 ? 3 1 ? 2 69 ? 2 -7 ? 2
4.1 ? 0.2 0.6 ? 0.1 21 ? 0.9 -2.4 ? 0.7 34 ?
1.3 -4 ? 1.0 278 ? 21 -95 ? 32 1247 ? 59 -365 ?
91 77 ? 3 3 ? 2 71 ? 2 -5 ? 2
CO (L/min) ? from baseline PCP (mmHg) ? from
baseline PAPm (mmHg) ? from baseline PVR
(dynesscm-5) ? from baseline SVR
(dynesscm-5) ? from baseline HR (bpm) ? from
baseline MAP (mmHg) ? from baseline




SURVIVE, N1327 NEGATIVE TRIAL
p lt 0.0001 vs Baseline p lt 0.001 vs Baseline
p lt 0.0001 vs Levosimendan p lt 0.001 vs
Levosimeendan
European Journal of Heart Failure
39
Kaplan-Meier curves of 30-day mortality
associated with control and nesiritide therapies
based on NSGET, VMAC, and PROACTION studies
10
HR (95 CI) 1.86 (1.02 - 3.41) P 0.04
8
Nesiritide
6
Mortality ()
4
2
Control
0
0
10
20
30
Days
No. at risk Nesiritide Control
485 377
465 371
454 634
442 360
JAMA 2005 293 1900-1905
40
Kaplan-Meier curves of 30-day mortality
associated with control and nesiritide therapies
based on NSGET, VMAC, and PROACTION studies
10
HR (95 CI) 1.86 (1.02 - 3.41) P 0.04
8
Nesiritide
ASCEND Trial
6
Mortality ()
4
2
Control
0
0
10
20
30
Days
No. at risk Nesiritide Control
485 377
465 371
454 634
442 360
JAMA 2005 293 1900-1905
41
Adenosine Receptor Blockers

• Blockers of A1 et A2a receptors
• Promotes diuresis without reducing Glomerular
  Filtration Rate
• Phase 2 studies promising, Phase 3 studies are in
  the planning stages

42
Pipeline Drug Development Heart Failure What
Happened?
IPRESERVE Trial RED-HF TOPCAT Trial WARCEF
Trial DOSE Trial

• Phosphodiesterase-3 Inhibitor
• Enoximone (EMPOWER, ESSENTIAL, EMOTE)
• Immune Modulators
• Etanercept (RENAISSANCE, RECOVER)
• Infliximab (ATTACH)
• Immune modulator, VAS-991 (ACCLAIM)
• Miscellaneous
• AGE cross-link breaker, ALT-711 (DIAMOND,
  SAPPHIRE, SILVER)
• Nebivolol (SENIORS)
• BiDil (A-HeFT)
• Erythropoietin (EPOCH) darbepoetin
  (STAMINA-HeFT RED-HF)

• Selective Aldosterone Antagonist (SARA)
• Eplerenone (4E, EPHESUS)
• Endothelin Receptor Antaginst (ERA)
• Bosentan (REACH-1, ENABLE-1 -2)
• Tesozantan (RITZ-1 to -5)
• Darusentan (EARTH)
• Enrasentan (ENCOR)
• Vasopeptidase Inhibitors (VPI)
• Omapatrilat (OVERTURE, OCTAVE, OPERA)
• Natriuretic Peptides
• Nesiritide (PRECEDENT, VMAC, FUSION)
• Imidazoline-1 Rececptor Antagonist
• Moxonidine (MOXCON, MOXSE)
• Calcium Sensitizers
• Levosimendan (LIDO, RUSSLAN, REVIVE)

43
HEART FAILURE The way forward

• Prevention
• Clarification of pathophysiology
• Pharmacogenomics and tailored therapy
• Volume overload strategies
• Non pharmacologic strategies
• Mechanical circulatory support
• Volume overload management
• Cell therapies

44
Enhanced External Counterpulsation (EEP)

• PEECH study
• Non blinded
• Improved exercise capacity
• No increase in peak VO2 max
• The jury remains out

45
Obstructive apnea with heart failure Cardiac
effects of Continuous Positive Airway Pressure

• Control Group
  CPAP-treated group
• Baseline 1 month
  p Baseline 1 month p
• LVESD mm 573 572 ns
  552 521 0.009
• LVEF 292 302 ns
  253 342 0.001
• No significant differences in baseline
  values between control and CPAP-treated groups.
• P-values refer to comparisons of
  within-group baseline to one month values.
• p0.02 and p0.009 for between group
  comparisons

CANPAP, n258, NEGATIVE TRIAL
Kaneko Y et al, Floras J, Bradley D, NEJM
20033481233-1241
46
HEART FAILURE The way forward

• Prevention
• Clarification of pathophysiology
• Pharmacogenomics and tailored therapy
• Volume overload strategies
• Non pharmacologic strategies
• Mechanical circulatory support
• Volume overload management
• Cell therapies

47
VOLUME OVERLOAD Mechanical Strategies
JACC 200749675
48
VOLUME OVERLOAD Mechanical Strategies
CARRESS TRIAL
JACC 200749675
49
HEART FAILURE The way forward

• Prevention
• Clarification of pathophysiology
• Pharmacogenomics and tailored therapy
• Volume overload strategies
• Non pharmacologic strategies
• Mechanical circulatory support
• Volume overload management
• Cell therapies

50
CELL TRANSPLANTATION
51
Left ventricular volume and mass indices, global
LVEF, and late enhancement as determined by
contrast-enhancement MRI at baseline and 6
months follow-up
Late Contrast Enhancement (mL)
LVEDV index (mL/m2)
LVESV index (mL/m2)
Global LVEF ()
LVM index (g/m2)
Baseline Control BMC 6 months Control BMC Ch
ange Controls BMC BMC tx effect p value
81.4 (16.9) 84.2 (17.2) 84.9 (21.9) 91.7
(26.0) 3.4 (11.1) 7.6 (20.0) 4.0 (-4.4 to
12.5) 0.32
40.6 (16.9) 43.0 (14.7) 42.6 (23.5) 42.4
(23.9) 2.0 (11.1) -0.6 (14.9) -3.2 (-9.7 to
3.3) 0.33
51.3 ( 9.3) 50.0 (10.0) 52.0 (12.4) 56.7
(12.5) 0.7 (8.1) 6.7 (6.5) 6.0 (2.2 to
9.9) 0.0026
78.2 (18.3) 82.7 (18.7) 71.7 (14.2) 71.9
(14.6) - 6.5 (12.8) -10.8 (10.6) -2.5 (-7.3 to
2.3) 0.30
30.3 (17.4) 33.0 (21.1) 19.8 ( 9.8) 18.9
(12.2) -10.5 (10.6) -14.1 (13.0) -2.2 (-5.4 to
1.0) 0.18
Lancet 2004 364 141-8
52
Cardiac Regeneration

• Promising uncontrolled or small studies
• Major issues still need to be resolved..ie, what
  types of cells? What method of delivery? When to
  administer, How much to administer? What adjunct
  therapy? Is coronary restenosis enhanced by stem
  cell therapy?
• Major problem with severe ventricular
  arrhythmias, at least with some techniques at
  this time prophylactic AICDs being implanted at
  the same time as cells are inserted for certain
  types of cells (skeletal myoblasts)
• GCSF and SCF to mobilize ones own stem cells not
  promising
• The role of paracrine factors remains to be
  determined

53
General Treatment Strategies in HF
CABG, Surgical Ventricular Remodelling (SVR)
Mitral Valve Surgery
2 g Na diet
2 g Na diet
54
SURGICAL THERAPY FOR HEART FAILUREAn Early
Eclectic Evolution

• 1923 Mitral Valvotomy (Cutler)
• 1932 Thyroidectomy (Cutler)
• 1951 IMA-ischemic myocardium (Vineberg)
• 1952 Aortic valve prosthesis (Hufnagel)
• 1953 Cardiopulmonary bypass (Gibbon)
• 1954 LV Aneurysmectomy - closed (Bailey)
• 1958 LV Aneurysmectomy - open (Cooley)
• 1966 LVAD bridge-to-recovery (DeBakey)
• 1967 Human heart transplant (Barnard)

55
Role of Cardiac Surgery in CHF

• Indications for Coronary Artery Bypass Surgery
  (CABG)
• CABG vs PCI
• Role of Surgical Ventricular Restoration (SVR)
• Role in Mitral Regurgitation
• Role of Cardiac Transplant

56
ACC-AHA 2004 Guidelines for CABG Poor LV function

• Class I Patients with Left Main, Left Main
  equivalent prox LAD and prox Circ, prox LAD with
  2 or 3 vessel disease.
• Class 2a Significant viable, non-contracting,
  revascularizable myocardium and without above
  anatomic abnormalities.
• Class 3 Should not be performed in patients
  without evidence of intermittent ischemia and
  without evidence of significant revascularizable
  myocardium.

57
CASS Reduced LVEF(No ASA, No Beta Blocker, No
Statin, No ACEI, No ARB, No Aldosterone receptor
blocker, no Devices)
Medicine
CABG
1.0
0.93
0.90
0.88
0.86
0.79
0.86
0.82
0.81
0.75
0.72
0.65
Proportion Surviving
P 0.40
P 0.45
P 0.0094
42S 36M
37S 29M
8S 11M
8S 9M
1S 4M
28S 35M
26S 31M
13S 15M
23S 16M
Year
Year
Year
Passamani et al. NEJM. 1985.
58
COURAGE Trial

• 2287 patients with objective evidence of
  myocardial ischemia and significant CAD in US or
  Canada.
• LVEFgt30.
• Median follow-up 4.6 years.
• Primary endpoint death, myocardial infarction,
  stroke.

59
COURAGE TrialBaseline clinical and angiographic
charateristics (continued)
PCI group (N 1149)
Medical therapy group (N 1138)
P Value
ANGIOGRAPHIC Vessels with disease - no.
() 1 2 3 Disease in graft Proximal LAD
disease Ejection fraction
361 446 341 77 360
343 439 355 85 417
0.72 0.36 0.01 0.86
(31) (39) (30) (62) (31)
(30) (39) (31) (69) (37)
60.8 11.2
60.9 10.3
N Engl J Med 2007 356 1503-16
60
COURAGE Subgroup analyses
Rate for the primary outcome
No. of patients
Hazard ratio (95 CI)
PCI
Med. Tx
P Value
Overall Sex Male Female Myocardial
infarction Yes No Extent of CAD Multivessel
disease Single-vessel disease Smoking Current N
ot current Diabetes Yes No CCS angina class 0
or I II or III
2287 1947 338 876 1371 1581 700 653 1631 766
1468 964 1371
1.05 1.15 0.65 0.91 1.22 1.04 1.17 1.00 1.08
0.99 1.20 1.01 1.09
(0.87 - 1.27) (0.93 - 1.42) (0.40 - 1.06) (0.69
- 1.21) (0.93 - 1.60) (0.84 - 1.30) (0.76 -
1.80) (0.71 - 1.41) (0.86 - 1.36) (0.73 -
1.32) (0.92- 1.56) (0.75 - 1.38) (0.85 - 1.40)
0.19 0.19 0.18 0.23 0.17 0.21 0.15 0.20 0.19
0.25 0.17 0.17 0.20
0.19 0.18 0.26 0.25 0.14 0.21 0.12 0.21 0.18
0.24 0.15 0.20 0.18
0.03 0.15 0.65 0.71 0.33 0.73
0.25
0.50
1.00
1.50
1.75
2.00
PCI better
Med. Tx better
N Engl J Med 2007 356 1503-16
61
Reports of Coronary Revascularization by CABG
in Patients with LV Dysfunction Since 1994
Very small (n lt 100) Not randomized and
highly selected Most patients had angina
Few had overt symptoms of heart failure Most
had only mild LV dysfunction All reported from
imaging labs and surgical services
62
Patients where Role of CABG is Uncertain
Medical Therapy Better
Age
Non-cardiac illlness
LVEF
Reop
Equipoise
Scar
CHF
Viability
Angina
Surgical Therapy Better
CAD
Low
High
Intensity
Normal
Abnormal
Normalcy
63
ACC-AHA 2004 Guidelines for CABG Poor LV function

• Class I Patients with Left Main, Left Main
  equivalent prox LAD and prox Circ, prox LAD with
  2 or 3 vessel disease.
• Class 2a Significant viable, non-contracting,
  revascularizable myocardium and without above
  anatomic abnormalities.
• Class 3 Should not be performed in patients
  without evidence of intermittent ischemia and
  without evidence of significant revascularizable
  myocardium.

64
PARR-2 Trial Robert Beanlands et al, ACC March
2007

• FDG-PET guided therapy vs regular care in 430
  patients with a LVEFlt35 that were referred for
  revascularization.
• Patients with a LVEF 35, being considered for
  revascularization.
• Primary endpoint Cardiac death, MI, cardiac
  transplant, cardiac hospitalization.

65
PARR-2 Trial Robert Beanlands et al, ACC March
2007

• More patients in the FDG-PET group had CABG
• Follow-up at 1 year.
• Results 62 FDG-PET and 74 regular care patients
  had an event, p0.25.
• No difference in cardiac death, p0.25.
• Conclusion No advantage of PET guided decision
  to revasc. (but in patients without a recent
  coronary angiography (gt 6 months) FDG-PET may be
  helpful).

66
Role of Cardiac Surgery in CHF

• Indications for Coronary Artery Bypass Surgery
  (CABG)
• CABG vs PCI
• Role of Surgical Ventricular Restoration (SVR)
• Role in Mitral Regurgitation
• Role of Cardiac Transplant

67
NY state database (1997-2000) Hazard ratios for
death after CABG as compared to stenting
Two-vessel disease
Patients with diabetes
Patients with EF lt 40
Patients with EF 40
All patients
No disease of LAD artery Stenting group CABG
group Unadj. hazard ratio (95 CI) Adj. hazard
ratio (95 CI) Disease of nonproximal LAD
artery Stenting group CABG group Unadj. hazard
ratio (95 CI) Adj. hazard ratio (95
CI) Disease of proximal LAD artery Stenting
group CABG group Unadj. hazard ratio (95
CI) Adj. hazard ratio (95 CI)
5847 1309 1.29 (1.02-1.62) 0.75
(0.58-0.98) 5891 1690 1.05 (0.84-1.31) 0.76
(0.60-0.96) 6033 8410 0.97 (0.85-1.10) 0.75
(0.66-0.86)
1352 423 0.95 (0.65-1.37) 0.69
(0.46-1.03) 1485 513 0.70 (0.48-1.02) 0.59
(0.40-0.87) 1438 2472 0.87 (0.71-1.07) 0.71
(0.57-0.88)
451 212 1.09 (0.70-1.72) 0.95 (0.59-1.52) 610 2
78 1.15 (0.78-1.69) 1.01 (0.67-1.55) 803 1615 0.
70 (0.56-0.87) 0.64 (0.51-0.81)
5396 1097 1.18 (0.90-1.56) 0.69
(0.51-0.93) 5281 1412 0.89 (0.68-1.18) 0.67
(0.50-0.89) 5230 6795 1.00 (0.86-1.18) 0.82
(0.69-0.97)
NEJM 2005 352 2174-83
68
NY state database (1997-2000) Hazard ratios for
death after CABG as compared to stenting
Three-vessel disease
Patients with diabetes
Patients with EF lt 40
Patients with EF 40
All patients
Disease of nonproximal LAD artery Stenting
group CABG group Unadj. hazard ratio (95
CI) Adj. hazard ratio (95 CI) Disease of
proximal LAD artery Stenting group CABG
group Unadj. hazard ratio (95 CI) Adj. hazard
ratio (95 CI)
2166 4946 0.89 (0.74-1.06) 0.74
(0.62-0.90) 2165 20857 0.67 (0.59-0.77) 0.64
(0.56-0.74)
666 1824 0.77 (0.59-0.99) 0.65
(0.49-0.85) 644 7115 0.66 (0.53-0.81) 0.69
(0.55-0.86)
342 1196 0.61 (0.46-0.81) 0.64
(0.48-0.87) 399 5597 0.55 (0.44-0.69) 0.68
(0.54-0.85)
1824 3750 0.94 (0.75-1.17) 0.76
(0.60-0.96) 1766 15260 0.64 90.53-0.76) 0.60
(0.50-0.72)
NEJM 2005 352 2174-83
69
Difference in the approach to the lesion with
percutaneous coronary intervention and
coronary-artery bypass grafting
Percutaneous coronary intervention
Coronary-artery bypass grafting
Stenting addresses the existing lesion but not
future lesions
Bypass grafting addresses the existing lesion
and also future culprit lesions
Gersh, NEJM 2005 352 2235-2237
70
CABG vs PCI vs Medical Therapy in Patients with
CAD and LV Dysfunction

• The role of each therapeutic option varies
  according to the patient, the coronary anatomy
  and the co-morbidity.
• Some situations are clear for each therapy, but
  many are not.
• The role of PCI remains to be determined and is
  likely overused, particularly in patients with
  two vessel disease with proximal LAD, or three
  vessel disease.
• All three forms of therapy are improving rapidly,
  such that the available data needs to be
  continually updated.

71
Patients where Role of CABG is Uncertain
Medical Therapy Better
Age
Non-cardiac illlness
LVEF
Reop
STICH
Equipoise
Scar
CHF
Viability
Angina
Surgical Therapy Better
CAD
Low
High
Intensity
Normal
Abnormal
Normalcy
72
Role of Cardiac Surgery in CHF

• Indications for Coronary Artery Bypass Surgery
  (CABG)
• CABG vs PCI
• Role of Surgical Ventricular Restoration (SVR)
• Role in Mitral Regurgitation
• Role of Cardiac Transplant

73
SVR Technique
Incision into the scar of the dilated ventricle
Placement of a suture to exclude the scarred
segment
Completed repair with endocardial patch
LV
LV
Septum
A
B
C
patch
Incision site
JACC 2004 44 1439-45
74
RESTORE registry 1998-2003
100 50 0
69
Survival ()

• 1,198 patients at 12 hospitals
• Average of 4.4 years after anterior infarction
• 30 day mortality 5.3

0 1 2 3 4 5
Years
LVEF 0.30 ? 0.40 LVESVI 80 ml/m2 ? 57
ml/m2
Athanasuleas et al. JACC 2004
75
Survival based upon preoperative New York Heart
Association functional class
SVR for CHF due to Post-MI LV dilatation,
RESTORE group
100
I
95
II
87
80
III
70
60
IV
50

40
20
0
0
1
2
3
4
5
Years
Athanasuleas et al, JACC 2004 44 1439-45
76
SVR studies Baseline characteristics
77
STS Overall Procedural Morbidity and Mortality
for SVR
78
Preoperative Predictors of Death Major
Complications
79
Distribution of STICH Trial Patients Among
Randomisation Strata and Analysis Groups
CAD EF 0.35 HF
SVREligible?2,200 Pts
NO
YES
NO
Not in Trial
SVREligible?
Medical Eligibility
YES
YES
NO
R 225 Pts
R 850 Pts
R 1,350 Pts
5 CABG SVR 75 Pts
7 CABG SVR 425 Pts
1 MED 525 Pts
6 CABG 425 Pts
2 CABG 525 Pts
4 CABG 75 Pts
3 MED 75 Pts
Stratum A
Stratum B
Stratum C
Primary Hypothesis Coronary
Revascularization LV Restoration
Analysis Groups MED/CABG
1 3 / 2 4 CABG/CABG SVR 4 6 / 5
7
Patients 600/600 500/500
80
General Treatment Strategies in HF
CABG, Surgical Ventricular Remodelling (SVR)
Mitral Valve Surgery
2 g Na diet
2 g Na diet
81
HEART FAILURE The way forward

• Prevention
• Clarification of pathophysiology
• Pharmacogenomics and tailored therapy
• Volume overload strategies
• Non pharmacologic strategies
• Mechanical circulatory support
• Volume overload management
• Cell therapies