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Title: Before It Happens To You Choosing Between the Evidence and the Guidelines Jonathan SacknerBernstein,


1
Before It Happens To YouChoosing Betweenthe
Evidence and the Guidelines Jonathan
Sackner-Bernstein, MDJanuary 2004
2
Definition of Evidence-Based Medicine
  • Application of scientific and clinical
    information to the development of preventative,
    diagnostic and therapeutic plans.
  • Sources of information should be hierarchical
  • Randomized Clinical Trials
  • Controlled mechanistic studies
  • Prospective observational studies
  • Epidemiology
  • Case series
  • Clinical experience

3
Preventive Cardiology Standard of Care
  • Lifestyle modifications
  • BP lt 140/90
  • lt 135/85 for HF or renal insufficiency
  • lt 130/80 for DM
  • LDL Cholesterol lt 100 (or lt 130, lt 160)
  • HgA1c lt 7
  • ASA (75 325 mg daily)
  • ACE inhibitors (coronary or vascular disease)
  • Beta-Blockers (post-MI and ACS patients)

Smith et al, Circulation 2001
4
Lifestyle Management The Ornish Way
  • Vegetarian diet, stress management and yoga in
    patients with symptoms refractory to medical
    therapy, using treatments from 1970s
  • Studies show
  • 48 patients enrolled in randomized phase, less
    than ¾ completed study
  • Completers showed significant regression of
    coronary atherosclerosis
  • JAMA, 1998

5
Therapeutic Lifestyle Change DASH Study
  • Dietary Approach to Stop Hypertension was a
    short-term trial evaluating the effects of a
    prepared meal plan on hypertension. The diet can
    be complex to implement, but it does help a
    little with blood pressure control.
  • Initial Fruit Fruit Vegetables
  • BP Vegetables ?fat, ?K (DASH)
  • Hypertension 144 / 89 ? 7/3 ? 11/6
  • Pre- 126 / 83 ? 1/0 ? 4/2
  • Hypertension
  • NEJM 1997

6
Therapeutic Lifestyle Change PREMIER Study
  • The Premier study showed modest blood pressure
    benefit over 6 months, but no lifestyle
    modification study has shown reduced risk of
    clinical events.
  • Initial Behavioral Behavioral Modification
  • BP Modification DASH
  • Hypertension 144 / 88 ? 5/2 ? 6/4
  • Pre- 130 / 83 ? 3/2 ? 3/2
  • Hypertension
  • JAMA 2003

7
The Lifestyle Evidence
  • Exercise, weight loss, stress reduction have
    modest impact.
  • No clinical outcomes studies prove clinical
    benefit of therapeutic lifestyle change (studies
    focus on surrogate endpoints)
  • Quitting smoking has major impact, but is very
    difficult.

8
The Lifestyle Myth
  • People cant change, so recommending lifestyle
    will rarely do much good.
  • Even if someone can change, it has little effect.

9
Evidence or Guidelines?
  • How big are the risks?
  • What are the optimal treatment targets?
  • What are the optimal tools?
  • Are the benefits class effects?

10
Evidence or Guidelines?
  • How big are the risks?

11
Calculating Risk from Framingham Scores
  • 52 year old man without diabetes, no history of
    hypertension, who does not smoke.
  • Lipids
  • Cholesterol 224
  • HDL 39
  • LDL 148

12
Calculating Risk from Framingham Scores
  • Risk of MI within 1 year is 0.8.
  • Since one year mortality post-MI is 25, his risk
    of death within 1 year of MI is 0.2, 1 in 500.

http//hin.nhlbi.nih.gov/atpiii/evalData.asp
13
Calculating Risk from Framingham Scores
  • 56 year old woman, non-smoker, without diabetes,
    but with borderline blood pressure of 142/80.
  • Lipids
  • Cholesterol 232
  • HDL 49
  • LDL 153

14
Calculating Risk from Framingham Scores
  • Risk of MI within 1 year is 0.4.
  • Since one year mortality post-MI is 25, her risk
    of death within 1 year of MI is 0.1, 1 in 1,000.

http//hin.nhlbi.nih.gov/atpiii/evalData.asp
15
The Risk of Cardiac Death is High
  • Risk of MI Risk of Death
  • within 1 yr within 1 year from MI
  • 52 yo man 1 in 125 1 in 500
  • 56 yo woman 1 in 250 1 in 1,000
  • How big is this risk?

16
The Risk of Cardiac Death is High
  • Risk of death from MI within a year
  • 52 yo man 1 in 500
  • 56 yo woman 1 in 1,000

17
The Risk of Cardiac Death is HighWhat Action is
Recommended?
  • Risk of death from MI within a year
  • 52 yo man 1 in 500
  • 56 yo woman 1 in 1,000
  • Compare to lifetime risks of death from
  • an airplane crash 1 in 659,000
  • bad medical care 1 in 83,000
  • a car accident 1 in 6,500
  • Recommendations?
  • Walsh J, True Odds 1998, NCEP/ATP-3, JNC-7

18
The Risk of Cardiac Death is HighWhat Action is
Recommended?
  • Risk of death from MI within a year
  • 52 yo man 1 in 500
  • 56 yo woman 1 in 1,000
  • Compare to lifetime risks of death from
  • an airplane crash 1 in 659,000
  • bad medical care 1 in 83,000
  • a car accident 1 in 6,500
  • Recommendations?
  • 52 yo man aspirin lifestyle change
  • 56 yo woman lifestyle change
  • Walsh J, True Odds 1998, NCEP/ATP-3, JNC-7

19
Classification of Heart Failure (AHA/ACC)
  • Stage Description
  • A at high risk- HTN, CAD, DM, FH (age gt50)
  • B structural heart disease no signs or
    symptoms
  • C current or prior symptoms of HF
  • D marked symptoms of HF at rest despite
    maximal therapy
  • Circ 2001

20
Cardiac Risk Factors Standard Teaching
  • Age
  • Sex
  • Family History
  • Hypertension
  • Hypercholesterolemia
  • Smoking
  • Diabetes
  • Obesity (sedentary lifestyle)

21
Stage C/D Heart Failure is a Bigger Riskthan
Colon Cancer
10,000
8,000
Incidence Per 100,000
6,000
4,000
2,000
0
Age (years)
Heart Failure (Stage C/D)
Colorectal Cancer
  • Kannel, Am Ht J, 1991, NCI, SEER, 2001

22
For Women, Coronary Disease (Stage A HF)Is a
Bigger Risk than Breast Cancer
12,000
Coronary Heart Disease
10,000
8,000
Prevalence (per 100,000)
6,000
4,000
Breast Cancer
2,000
0
30
40
50
60
70
Age (years)
National Cancer Institute and American Heart
Association
23
Atherosclerosis Starts by Our 20s
  • Aorta Right Coronary Artery
  • Prevalence
  • ()
  • n 204
  • PDAY Study

24
By Now, We Have Coronary Disease
Prevalence of CAD Using IVUS ()
  • Tuzcu Circ 2001

25
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

26
Risks of Cardiovascular Disease are Increased
Even If You Are Only a Little Overweight
  • 10 20
  • Overweight

20 30 Overweight
J Chronic Diseases, 1978
27
Evidence or Guidelines?
  • How big are the risks?
  • What are the optimal treatment targets?

28
What is Optimal Blood Pressure?
  • JNC-7
  • Optimal blood pressure
  • Target is 115/75
  • Target blood pressure
  • Target is 135/90
  • Target for diabetics and renal insufficiency
  • Target is 13080

29
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

30
Higher Risk of MI, CVA or CV Death in
Prehypertension (above 120/80)
  • Women

Men
Normal 120-130 Systolic
High Normal 130-139 Systolic
Normal 120-130 Systolic
High Normal 130-139 Systolic
Vasan, NEJM, 2001
31
Structural Changes of the Heart Occur in White
Coat Hypertension
? Risk 270
Likelihood of Changes in Heart Structure
? Risk 90
People Whose Blood Pressure is High in the
Doctors Office
People with High Blood Pressure
Muscholl BMJ, 1998
32
Goal Blood Pressure Should Be 115/75
  • Cause Ages Death Relative Risk
  • Stroke
  • 40-49 414 0.36 (0.32-0.40)
  • 50-59 1372 0.38 (0.35-.040)
  • 60-69 2939 0.43 (0.41-0.45)
  • 70-79 4327 0.50 (0.48-0.52)
  • 80-89 2636 0.67 (0.63-0.71)
  • IHD
  • 40-49 1022 0.49 (0.49-0.53)
  • 50-59 5594 0.50 (0.49-0.52)
  • 60-69 10450 0.54 (0.53-0.55)
  • 70-79 10852 0.60 (0.58-0.61)
  • 80-89 5649 0.67 (0.64-0.70)
  • Prospective Studies Collaboration, Lancet 2003

0.25 0.35 0.5 0.7 1.0
33
Coronary Death is Less Likely When Blood Pressure
is Minimized
? 256 x ? 128 x ? 64 x ? 32 x ? 16 x ? 8 x ? 4
x ? 2 x 1 x
Age (years) 80-89 70-79 60-69 50-59 40-49
Risk of CHD Death
120 140 160 180 Systolic Blood Pressure
  • Lancet 2002

34
What is Optimal Blood Pressure?
  • JNC-7
  • Optimal blood pressure
  • Target is 115/75
  • Target blood pressure
  • Target is 135/90
  • Target for diabetics and renal insufficiency
  • Target is 13080
  • Optimal
  • 115/75 or
  • at least 20/10 reduction

35
What is Optimal LDL-Cholesterol?
  • ATP-3/NCEP
  • Coronary Heart Disease
  • Target is 100 mg/dl
  • 2 Risk Factors
  • Target is 130 mg/dl
  • 0-1 Risk Factors
  • Target is 160 mg/dl

36
Good LDL Levels Do Not Minimize Risk
3.0
2.5
Risk of Heart Attack, Bypass or Angioplasty
Women
2.0
1.5
Men
1.0
0.5
70
100
130
160
190
LDL Level
ARIC Study, 10 yr follow-up of 45-64 year olds
37
Lower LDL Targets Minimize Risk
  • Coronary Events at 1 Year
  • Based on Level of LDL
  • (4S trial)

25 20 15 10 5 0
Per Cent Coronary Events
77 96 116 135 154 174
LDL Level Measured
4S Investigators
38
Aggressive Management Reverses Plaques
Effects of Pravastatin and Atorvastatin in the
REVERSAL Study
  • Nissen, AHA 2003

Pravastatin
Atorvastatin
39
What is Optimal LDL-Cholesterol?
  • ATP-3/NCEP
  • Coronary Heart Disease
  • Target is 100 mg/dl
  • 2 Risk Factors
  • Target is 130 mg/dl
  • 0-1 Risk Factors
  • Target is 160 mg/dl
  • Optimal
  • Target lt 100 mg/dl or
  • High risk lt 80 mg/dl

40
What is Optimal HgA1c Target?
  • ADA
  • 7

41
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
42
What is Optimal HgA1c Target?
  • ADA
  • 7
  • Optimal
  • 6

43
Why Do We Follow the Standard Targets?
  • We have been duped about TLC impact.
  • Cost-effectiveness is important for society
    (statin example gt 500 per year is too much)
  • Risk-benefit analysis does not accurately reflect
    the safety of the available medicines (statins,
    ACE inhibitors, beta-blockers and aspirin)
  • We trust the committees too much.

44
Evidence or Guidelines?
  • How big are the risks?
  • What are the optimal treatment targets?
  • What are the optimal tools?

45
ACE Inhibition Reduces Risk
Effect of Ramipril in HOPE
25
20
with event
15
10
5
0
N Engl J Med, 2000
46
ACE Inhibitors Reduce Risk in Patients with
Normal EF
Effect of Ramipril in HOPE
25
Risk ? 27 p lt 0.0001
Risk ? 25 p lt 0.001
20
with event
15
Risk ? 30 p 0.003
Risk ? 33 p 0.01
10
5
0
MI/Stroke/ CV Death
CV Death
MI
Stroke
G. Dagenais, ESC 1999
47
ACE Inhibition Reduces Risk in CAD
Placebo
Perindopril
48
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

49
Effect of Candesartan in Heart Failure
Cause-Specific Mortality
All-cause Mortality
30
30
CV Risk ? 13 p 0.006
Risk ? 10 p 0.032
CV
20
Cumulative Incidence ()
20
10
10
Non-CV
0
0
0
1
2
3
4
0
1
2
3
4
Time (years)
Time (years)
  • CHARM, Lancet 2003

50
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

51
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
52
Statins Reduce the Risk of Stroke
Before It Happens To You
53
LDL Reduction Markedly Reduces Risk
Initial LDL 160
160
130
100
130
100
80
80
Target LDL
Women (45-64 years old)
Men (45-64 years old)
Before It Happens To You, ARIC
54
Its Too Late for Primary Prevention
  • By mid-life, we all have lipid-laden atheromas in
    our arterial walls.
  • 100,000,000 American adults have LDL gt 100
  • 150,000,000 American adults have BP gt 120/80
  • Preventative cardiology should focus on reversing
    functional and structural abnormalities.

55
Evidence or Guidelines?
  • How big are the risks?
  • What are the optimal treatment targets?
  • What are the optimal tools?
  • Are the benefits class effects?

56
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
57
Are Drugs Within a Class Interchangeable?
COMET Trial
  • ACE inhibitors? Perhaps not.
  • Beta-blockers in HF?

40
Risk ? 17 p0.0017
30
20
prolonged life 1.4 yrs
10
0
0
1
2
3
4
5
Time (years)
Metoprolol
Carvedilol
58
Are Drugs Within a Class Interchangeable?
Incidence New Diabetes (COMET Trial)
  • ACE inhibitors? Perhaps not.
  • Beta-blockers in HF?

Time (years)
59
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?

p lt 0 .005
p NS
p lt 0 .0005
Cumulative Mortality Rate
0
24
36
12
0
24
36
12
0
6
18
12
Time (months)
60
Are Drugs Within a Class Interchangeable?
  • ACE inhibitors? Probably not.
  • Beta-blockers in HF? No.
  • Beta-blockers post-MI? No.
  • Statins for dyslipidemia?
  • Lovastatin ? events
  • Fluvastatin ? restenosis
  • Simvastatin ? events
  • Pravastatin ? events
  • Atorvastatin ? events
  • Cerivastatin ? risks
  • Rosuvastatin ? LDL, risks?

61
Are Drugs Within a Class Interchangeable?
  • ACE inhibitors? Probably not.
  • Beta-blockers in HF? No.
  • Beta-blockers post-MI? No.
  • Statins for dyslipidemia? No.

62
The Challenge
  • Consider what the patient expects and wants
  • Reiteration of our standard approaches?
  • Data-based evolution of treatment?
  • Optimized care, based on risks and benefits for
    the individual.

63
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
  • ACE inhibitors, beta-blockers and diuretics
  • Statins
  • Aspirin

64
Before It Happens To You
  • Scientifically based strategies to minimize the
    risk of a heart attack or stroke. This book will
    save lives.
  • Valentin Fuster, MD, PhD
  • An elegant and practical game plan for real
    health challenges. Education without admonition
    for both patients and doctors.
  • Mehmet Oz, MD
  • A unique book that emphasizes maximum risk
    reduction, even for those who, like me, have
    trouble making a consistent effort at diet and
    exercise.
  • Gervasio Lamas, MD
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