Prevention is the Best TreatmentPrevention is the Best Treatment

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 Sanofi-Aventis. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in survivors of MI with Novartis. Dr. Pfeffer’s shares are irrevocably transferred to charity.

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

Effects of Treatment on Morbidity in HypertensionVA Cooperative Study Group on Antihypertensive Agents

143 men (DBP 115 to 129 mm Hg), mean follow-up ~18 months, 29 events

Placebo group(n=70)

HCTZ + Reserpine + Hydralazine HCl group

(n=73)Total events 27 2 Deaths (all CV) 4 0 Class A events* 10 0 Other treatment failures 7 1

Class B events† 6 1 CHF 4 0

*

Required treatment with known active agents and permanent removal from protocol assigned

therapy (nature of events included dissecting aortic aneurysm, sudden death, ruptured AAA,

fundi striate hemorrhage and papilledema, CHF, elevated BUN, rehospitalization,

cerebrovascular accident, and others)†

Did not require permanent discontinuation of protocol treatments (nature of events included MI,

CHF, cerebrovascular thrombosis, and TIA

VA Cooperative Study Group. JAMA 1967;202(11);1028-33

42 Randomized Controlled Trials

Low-Dose Diuretics vs Placebo

CHDCHF

StrokeCVD events

CVD mortality

Total mortality

0.79 (0.69-0.92)0.51 (0.42-0.62)0.71 (0.63-0.81)0.76 (0.69-0.83)0.81 (0.73-0.92)

0.90 (0.84-0.96)

0.002<0.001<0.001<0.001

0.001

0.002

Outcome

RR (95% CI)

p-value

Favors low-dose diuretics

Favorsplacebo

0.4 0.6 0.8 1.0 1.2 1.4Relative Risk

2003

Antihypertensive Rx CHF

SHEP Cooperative Research Group. JAMA 1991;265:3255–64Dahlöf B et al. Lancet 1991;338:1281–5

SHEP

n

2365

2371

0.46

CHF

48

102

(0.33 to 0.65)

STOP

n

812

815

0.49

CHF

19

36

Active

Placebo

Relative

risk

Fatal or Nonfatal Stroke Heart Failure

HR = 0.70(0.49-1.01)

HR = 0.36(0.22-0.58)

Target blood pressure 150/80 mmHg

The Trial: International, multi centre, randomised double-blind placebo controlledInclusion Criteria: Aged 80 or more,Systolic BP; 160 -199mmHg+ diastolic BP; <110 mmHgPrimary Endpoint: All strokes (fatal and non-fatal)

2008

Lewis EF. JACC 2003;42(8):1446-53

CARE: Multivariable Predictors ofHeart Failure

PEACE: Development of HF

Age 65 to <75 years (vs <65)

1.89 (1.4 - 2.5)

<0.00

Age ≥75 years (vs <65)

3.15 (2.2 - 4.5)

<0.00

Hx of Diabetes

2.10 (1.6 - 2.7)

<0.00

Body Mass Index (>30 kg/m2)

2.09 (1.5- 3.0)

<0.00

Current smoker

1.86 (1.3 - 2.6)

<0.00

Hx of Stroke/TIA

1.82 (1.3 - 2.6)

<0.00

eGFR (ml/min/m2) <60

1.67 (1.3 - 2.2)

<0.00

Hx of Hypertension

1.62 (1.3 - 2.1)

<0.00

Hx of CABG

1.58 (1.2 - 2.0)

<0.00

LVEF 40–50% (vs ≥50)

1.40 (1.0 - 1.9)

0.03Angina Symptom (CCS)

1.40 (1.1 - 1.8)

0.009Hx of Myocardial Infarction

1.39 (1.1 - 1.8)

0.01Randomization to Trandolapril

0.73 (0.57-0.93)

0.01

Lewis EF et al. Circulation: Heart Failure 2009;2:209-16

Baseline Characteristics

HR (95% CI)

p-value

Placebo n = 228/2223 (10.3%)Simvastatin n = 184/2221 (8.3%)p <0.015

Stages of HF and treatment options for systolic heart failure

Jessup M and Brozena S. N Engl J Med 2003

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

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

Years following MI0 2 4 6 8 10 12 14 16 18 20

Cupples et al. The Framingham Study. NIH Publication 1987;87:2703

MI male

Cum

ulat

ive

prob

abili

ty

of e

vent

The Framingham Heart Study: 1987Risk of Heart Failure After MI

(Age 35 to 94 at Diagnosis)

0

0.1

0.2

0.3

0.4

0.5

MI femaleMatched maleMatched female

1992

The

SAVETrial

Mortality and CHF MorbidityMortality and CHF Morbidity1992

The

SAVETrial

All-Cause Mortality

Years

Pro

babi

lity

of E

vent

0

0.05

0.1

0.15

0.2

0.25

0.3

0 1 2 3

0.35

0.4

4

ACE-I

Placebo

ACE-I299522501617892223

Placebo297121841521853138

OR: 0.74 (0.66–0.83)

ACE-I: 702/2995 (23.4%)

Placebo: 866/2971 (29.1%)

4

TRACEEchocardiographicEF £ 35%

AIREClinical and/or radiographic signs of HF

SAVERadionuclideEF £ 40%2000

Flather, Yusuf, Kober, et al.

LV DysfunctionLV Dysfunction(Progressive)(Progressive)

MI

Asymptomatic

Remodeling

SymptomaticCHF

Sudden Ischemic Sudden Pump failure

50

40

30

20

10

00 6 12 18 24 30 36 42 48

p=0.0036

Months

Mortality (%)

PlaceboEnalapril

Treatment

P=NSPrevention

1992

1991

2003

1 2 3 4 5

14

12

10

8

6

4

2

Follow-Up (Years)

%

Heart Failure or Death

Heart Failure

HR Death post-HF = 9.8 (95% CI 7.7 – 13.5)

HF: 68 of 243 (28%) died within 3.5 years

Vs.

No HF: 252 of 3617 (7%) died within 5 years

2003

CARECARE

2003

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

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

Superior doctors prevent the disease.Mediocre doctors treat the disease before evident.Inferior doctors treat the full blown disease.

- Huang Dee: Nai-Ching (2600 B.C. 1st Chinese Medical Text.)

Stages of HF and treatment options for systolic heart failure

Jessup M and Brozena S. N Engl J Med 2003

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

Heart FailureHeart Failure

Sustained Hyperfunction

·Congenital· Valvular·Hypertension

· Idiopathic·Nutritional· Infectious·Autoimmune· Toxic· Infiltrative

Loss of Contractile

Tissue

Ischemic Coronary

Artery Disease

Myopathic and Interstitial Processes

GENETICSGENETICS