Management of Patients After Revascularization

1
Management of Patients After Revascularization

• Jonathan Sackner-Bernstein, M.D.
• Clinical Scholars Program
• North Shore University Hospital
• Manhasset, New York

2
Plaque The Primary Lesion

• H.G. Burkitt, Wheaters Basic Histopathology, 1996

3
Progression of Coronary Disease
Cleveland Clinic Foundation
4
Angiogram Does Not Detect Unstable Plaques

• H.G. Burkitt, Wheaters Basic Histopathology, 1996

5
IVUS is Sensitive Detector of CAD
Fatty Streak in 17 yr old
Vulnerable Plaque in 32 yr old

• Tuzcu Circ 2001

6
Most Adults Have Coronary Disease
Prevalence of CAD Using IVUS ()

• Tuzcu Circ 2001

7
Atherosclerosis Starts by Our 20s

• Aorta Right Coronary Artery
• Prevalence
• ()
• n 204
• PDAY Study

8
Which Plaques to Bypass,Which Pose Risk?

• H.G. Burkitt, Wheaters Basic Histopathology, 1996

9
Angiographic Stenosis Does Not Predict Infarction
of MI Patients
Falk, Circulation 1995
10
Atheroma Composition in Deaths Due to Coronary
Disease
Davies, Br Heart J 1993
11
Therapeutic Focus Post-Revascularization
Treated Stenoses and Atherosclerosis

• Restenosis and graft patency
• Native circulation

12
Revascularization Does Not Eliminate Riskfrom
Coronary Disease

• Atherosclerosis is not a localized process
• Angiograms do not detect mild plaques
• Calcium scores do not detect unstable plaques

13
Ischemic Risk Reduced with High Dose Atorvastatin
Patients With Ischemic Event
Pitt, NEJM 1999
14
Statins Reduce the Risk of Ischemic Events in
Chronic CAD
25
p 0.03
20
15
Ischemic Event
10
5
0
0
6
12
18
Time (months)
Pitt, NEJM, 1999
15
Effect of Aggressive (LDL 135) vs. Moderate
(LDL 95)Therapy on Progressive Atherosclerosis
post-CABG
D
Post-CABG, NEJM 1997
16
Statins Reduce the Risk of Repeat
RevascularizationAfter CABG
30
p 0.03
20
Event
10
0
0
1
2
3
4
Time (years)
Aggressive
Moderate
Post-CABG Investigators, NEJM, 1997
17
Angiotensin Localizes to Plaque Rupture Site

• Adapted from Schieffer Circ 2000

18
ACE Inhibition Post Revascularization Reduces Risk

• Ramipril Placebo RR
• (n 580) (n 579) (95 CI)
• CV Death, MI, HF, AP 36 41 ? 10
• (? 41, ? 43)
• CV Death, MI, HF 8 18 ? 58
• (? 7, ? 80)
• CV Death, MI 2 9 ? 78
• (? 12, ? 92)
• CV Death, HF 7 17 ? 61
• (? 11, ? 92)

APRES, JACC 2000
19
Therapeutic Targets and Tools Post-Revascularizati
on

• Atherosclerosis
• Hypertension
• Arrhythmias
• Thrombosis

20
Therapeutic Targets and Tools Post-Revascularizati
on

• Atherosclerosis
• Hypertension
• Arrhythmias
• Thrombosis

• Statin
• ACE inhibitors (ARB)
• Beta-blockers
• Aspirin (clopidogrel)

21
Statins Reduce Events Even With Good LDL

• HPS, Lancet 2002

22
ACE Inhibition Reduces Plaque Lipid Content
Fennessy, Atherosclerosis 1994
23
ACE Inhibition Reduces Risk in CAD
Placebo
Perindopril
Lancet 2003
24
Beta-Blockers Prevent Lipid Deposition

• Blood Serum Aortic ACAT Pressure Cholesterol Cho
  lesterol Expression (mmHg) (mg/dl) (mg/g) (pmol/
  min/mg)

Chobanian Circ Res 1985
25
Beta-Blockers Stabilize Plaques
MonocyteAdherence( total)

• Oxidized LDL enhances monocyte infiltration
• Carvedilol blocks LDL oxidation
• Carvedilol does not reverse plaque invasion
  already oxidized LDL

Ctrl 0 0.3 1 3 10 10 Carvedilol
(uM) LDL ox-LDL
Yue, Eur J of Pharm 1995
26
Beta-Blockers Reduce Risk of Sudden Death
10
Risk ? 26
Risk ? 40
Risk Sudden Death
Risk ? 28
Risk ? 56
5
Risk ? 30
0
US Carvedilol
Merit-HF
MAPPHY (HTN)
Copernicus
BHAT
Placebo Beta-blocker

• Am J Hypertension 1991, JAMA 1993,NEJM 1996,
  Lancet, 1999

27
Who Is Undergoing Revascularization?

• Acute Coronary Syndrome
• Chronic CAD

28
Post-Infarction Patients withPreserved
Ventricular Function

• How well do we know the data?

29
Is Any Beta-Blocker Good Enough for an Acute MI?

• Goteborg MIAMI ISIS-1
• Metoprolol Metoprolol Atenolol
• (n 1,395) (n 5,778) (n 16,027)

Dead
Time (days)
Lancet 1981, AJC 1985, Lancet 1986
30
Are Beta-Blockers Interchangeable Long-term?

• Timolol Propranolol Metoprolol
• Norwegian BHAT LIT
• (n1884) (n3837) (n2395)

Per Cent Mortality
Time (months)
NEJM 1981, JAMA 1982, Eur Heart J 1987
31
Beta-Blockers Are Not Interchangeable

• Atenolol IV PO for 1 week cost-effective
• Metoprolol IV PO for 2 weeks not effective
• Metoprolol IV PO for 3 months effective
• Metoprolol PO long-term not effective
• Timolol PO long-term effective
• Propranolol long-term effective

32
Post-Infarction Patients withVentricular
Dysfunction
33
Carvedilol Reduces Risk Post-Infarctionin
Patients with Left Ventricular Dysfunction

• Death CV
• Death

1.0
0.9
Percent Event-free
0.8
0.7
0.6
0.5
Time (years)
Lancet 2001
34
CAPRICORN Effect on Recurrent MI
Excluding endpoints during admission for index
MI.
The CAPRICORN Investigators. Lancet.
200135713851390. Data on file, GlaxoSmithKline.
35
CAPRICORN Arrhythmias and Events

• Atrial Ventricular Sudden
• Arrhythmias Arrhythmias Death

1.0
0.9
Percent Event-free
0.8
Risk ? 59 p lt 0.0001
Risk ? 76 p lt 0.0001
Risk ? 26 p 0.099
0.7
0.6
0.5
2
0
1
2
0
1
2
0
1
Time (years)
Lancet 2001
36
Evidence-Based Acute and Long-term Management of
Patients post-Infarction
Measure EF
Myocardial injury
ramipril, perindopril timolol, propranolol
Preserved Function
If within 24 hr ACE inhibitor IV metoprolol or
atenolol Aspirin Statin Clopidogrel
carvedilol, captopril, lisinopril, ramipril,
trandolapril
Impaired Function
Asymptomatic
carvedilol, ramipril, enalapril, trandolapril,
eplerenone
Symptomatic
37
Patients with Left Ventricular Dysfunction

• Does it matter which beta-blocker?

38
Beta-Blockers Can Reduce Risk of Death

• CAPRICORN US CARVEDILOL CIBIS II MERIT-HF COPERNI
  CUS
• (n 1959) (n1094) (n2647) (n3991) (n2289)

Lancet 2001, NEJM 1996, Lancet 1999, NEJM 2001
39
Should Clinical Practice Reflectthe Results of
Clinical Trials?

• Gusto

p lt 0.008 Risk ? 14
NEJM 1993, NEJM 2004
40
Are There Differences Between Beta-Blockers?

• COMET study design
• 3,100 patients
• Class II-IV heart failure
• Systolic dysfunction
• Randomized to carvedilol 25 bid or metoprolol
  tartrate 50 bid
• Primary outcomes
• All-cause mortality
• All-cause mortality all-cause hospitalization

41
COMET All-Cause Mortality

• Poole-Wilson, Lancet 2003

42
COMET Risk of Cardiovascular andNon-Cardiovascul
ar Death
Poole-Wilson, Lancet 2003
43
COMET Mode of Death
Poole-Wilson, Lancet 2003
44
COMET Mode of Death
Metoprolol
Carvedilol
Poole-Wilson, Lancet 2003
45
COMET Effect on Composite Endpoints

• Death Death Death CV Death Death
• All Hosp CV Hosp Xplant, MI, HF MI, HF, UA,
  Arrhy HF

80
80
80
80
80
60
60
60
60
60
40
40
40
40
40

• Risk
• 12
• p 0.013

• Risk
• 7
• p 0.097

• Risk
• 10
• p 0.022

• Risk
• 6
• p 0.12

• Risk
• 11
• p 0.019

20
20
20
20
20
0
0
0
0
0
Time ( months)
Poole-Wilson, Lancet 2003
46
COMET Risk of Ischemic Events
Mortality ()
Time (years)
Metoprolol
Carvedilol

• Poole-Wilson, Lancet 2003

47
COMET Risk of New Onset Diabetes
Incidence New Diabetes
25

• Carvedilol Metoprolol RR (CI) p
• 122/1151 149/1147 0.78 0.04
• (10.6) (13) (0.61,0.99)

HR 0.78 (0.61, 0.99) p 0.04
20
15
10
5
0
0
1
2
3
4
5
Time (years)
Poole-Wilson, Lancet 2003
48
Acute and Long-term Management of Patients
withLeft Ventricular Dysfunction and Heart
Failure
Measure EF
Control Blood Pressure, Risk Factor
Modification ramipril, perindopril, timolol,
propranolol (CAD)
Heart Failure Diagnosis
Preserved Function
carvedilol, enalapril, lisinopril, ramipril,
trandolapril
Optimize Volume
Impaired Function
Asymptomatic
carvedilol, spironolactone (NYHA 3-4),
enalapril, ramipril, trandolapril
Symptomatic
49
Optimal Management of Patients Post-Revascularizat
ion

• Clinical trials provide the evidence
• Best practices change
• Make decisions to optimize outcome

50
Evidence or Guidelines?

• What are the optimal treatment targets?

51
Cardiac Risk Factors Practical Approach

• Scientifically Patients Easily
• Cant Change Wont Change Modifiable
• Your genes Smoking Blood pressure
• (family history) Sedentary lifestyle Cholesterol
• Gender Obesity/overweight Diabetes
• Age

52
Evidence for Blood Pressure Targets

• 1950s Risk lowest for BP lt 120/80
• 1970s Risk lowest for BP lt 118/77
• 2001 Risk lowest for BP lt 120/80
• 2003 Risk lowest for BP lt 115/75

53
Are Statins Interchangeable for Patients
withAcute Coronary Syndromes?

• Prove-It

Per Cent Event
Time (months)
NEJM 2004
54
Diabetic Complications Relate to HgA1c Level
Triple
Risk of Complications Compared to risk if HgA1c lt
6
Double
5
6
7
8
9
10
Glycohemoglobin ()
Before It Happens To You
55
Evidence or Guidelines?

• What are the optimal treatment targets?
• What are the optimal tools?

56
All Patients Should Receive ACE Inhibitors
CONSENSUS (NYHA IV)
SOLVD Tx(NYHA II-III)
SAVE (Asym LVD)
HOPE (At Risk)
RiskDeath 40
RiskDeath 16
Risk Death 19
Risk MM ? 22
0.6
0.5
0.4
0.3
0.2
0.1
p 0.002
p lt 0.005
p lt 0.02
p lt 0.001
1
1
2
3
4
2
4
3
2
1
4
3
2
1
3
4
Time (years)
NEJM 2000, 1993, 1993, 1987
57
All Patients Should Receive Beta-blockers

• CAPRICORN
• (n 1959)

Time (years)
Lancet 2001, NEJM 1996, Lancet 1999, NEJM 2001
58
Statins Reduce Risk of MI, CVA and Death
Independent of Baseline LDL Level
LDL Level Before Starting on Statin Therapy
Before It Happens To You
59
Safety of Simvastatin in HPS

• Parameter Simvastatin Placebo
• n 10,269 10,267
• Liver Function
• 24x ULN 139 (1.35) 131 (1.28)
• gt4x ULN 43 (0.42) 32 (0.31)
• Elevated CK
• 410x ULN 19 (0.19) 13 (0.13)
• gt10x ULN 11 (0.11) 6 (0.06)
• Myopathy
• No rhabdomyolysis 5 (0.05) 1 (0.01)
• Rhabdomyolysis 5 (0.05) 3 (0.03)
• Lancet 2002

60
Evidence or Guidelines?

• What are the optimal treatment targets?
• What are the optimal tools?
• Are drugs within a class interchangeable?

61
Are Drugs Within a Class Interchangeable?

• ACE inhibitors?

• Benazepril Placebo p
• n 300 283
• Death 8 1 0.04
• Sudden Death 3 1
• MI 3 0
• Pulmonary Embolus 1 0
• Variceal Bleed 1 0

Benazepril Placebo p n 300 283 Death 8 1 0.04 Sud
den Death 3 1 MI 3 0 Pulmonary Embolus 1 0 Varicea
l Bleed 1 0
AIPRI Study, NEJM 1996
62
Are Drugs Within a Class Interchangeable?
Risk of Death
Risk of New Diabetes

• ACE inhibitors? Perhaps not.
• Beta-blockers in HF?

40
Risk ? 17 p0.0017
Risk ? 22 p 0.04
40
30
30
20
20
prolong life 1.4 yrs
10
10
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Time (years)
Metoprolol
Carvedilol
Poole-Wilson, Lancet 2003
63
Are Drugs Within a Class Interchangeable?

• Timolol Propranolol Metoprolol
• Norwegian BHAT LIT
• (n1884) (n3837) (n2395)

• ACE inhibitors? Perhaps not.
• Beta-blockers in HF? No.
• Beta-blockers post-MI?

Cumulative Mortality Rate
64
Are Drugs Within a Class Interchangeable?
Prove-It

• ACE inhibitors? Probably not.
• Beta-blockers in HF? No.
• Beta-blockers post-MI? No.
• Statins for dyslipidemia?

Event
Time (months)
65
Are Drugs Within a Class Interchangeable?

• ACE inhibitors? Probably not.
• Beta-blockers in HF? No.
• Beta-blockers post-MI? No.
• Statins for dyslipidemia? No.

66
The Challenge

• Consider what the patient expects and wants
• Reiteration of our standard approaches?
• Patients want optimized care, based on risks and
  benefits for them.

67
Targets and Tools to Deliver Optimal Care

• Targets
• Blood pressure of 115/75
• LDL of 100 (or lt 80 in high risk)
• HDL of 40 (men) or 50 (women)
• HgA1C of 6 (unless hypoglycemia)

68
Targets and Tools to Deliver Optimal Care

• Targets
• Blood pressure of 115/75
• LDL of 100 (or lt 80 in high risk)
• HDL of 40 (men) or 50 (women)
• HgA1C of 6 (unless hypoglycemia)
• Tools (make evidence-based, optimal selections)
• ACE inhibitors, beta-blockers and diuretics
• Statins
• Aspirin

69
Long-term Management of Patients
Post-Revascularization
atorvastatin, simvastatin, pravastatin ramipril,
perindopril, timolol, propranolol, DM
carvedilol?
Measure EF
PCI CABG
Preserved Function
Stabilization Anti-platelet BP control Risk
Factor Mod
Impaired Function
atorvastatin, simvastatin, pravastatin enalapril,
ramipril, trandolapril carvedilol, eplerenone,
sprironolactone
70
Clinical Goals are Paramount

• Scientifically based optimal care will minimize
  risk.

Scientifically based strategies to minimize the
risk of a heart attack or stroke. This book will
save lives. Valentin Fuster, MD, PhD