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Diabetes, Hypertension, and Renal Insufficiency in PostMyocardial Infarction Cardiovascular Risk

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NHANES III for US adults aged 20-74 identified 60% of men and 50% of women as being overweight ... CAPRICORN. Major Coronary Events ... – PowerPoint PPT presentation

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Title: Diabetes, Hypertension, and Renal Insufficiency in PostMyocardial Infarction Cardiovascular Risk


1
Diabetes, Hypertension, and Renal Insufficiency
in Post-Myocardial Infarction Cardiovascular Risk
  • William T. Abraham, MD, FACP, FACC
  • Chief, Division of Cardiovascular Medicine
  • Associate Director, Davis Heart Lung Research
    Institute
  • The Ohio State University
  • Columbus, Ohio

2
The Scope of Myocardial Infarction
  • Approximately 1.1 million Americans will have a
    new or recurrent MI this year, and over 45 will
    die from it1
  • Approximately 40 of MIs are accompanied by LV
    dysfunction with or without clinical HF2
  • Approximately 22 of male and 46 of female MI
    victims will be disabled with HF within6 years3

HFheart failure MImyocardial infarction. 1.
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001.2. Kober L et al. Am J
Cardiol. 1998811292-1297. 3. American Heart
Association. Heart Disease and Stroke
Statistics2003 Update. 2002 p 120
3
Predictors of Post-MI Mortality
  • LV Ejection Fraction1
  • RR Interval2
  • CK-MB3
  • Heart Rate4
  • BUN4
  • Age1
  • Diabetes5
  • Hypertension6

1. Hammermeister KE et al. Circulation.
197959421-430. 2. Pedritti RF et al. Int J
Cardiol. 19996883-93. 3. La Vecchia et al. J
Invasive Cardiol. 200113689-693. 4. Rich MW et
al. Am J Med. 1992927-13. 5. DaCosta A et al.
Eur Heart J. 2001221459-1465. 6. Richards AM
et al. J Am Coll Cardiol. 2002391182-1188.
4
Progression of Cardiovascular Disease
Triglycerides
LDL HDL
Stroke
Diabetes
Visceral Fat
MI
Insulin Resistance
Hyper-insulinemia
Death
Angiotensin II
HF
CHD
SympatheticActivity
ESRD
Hypertension
Metabolic Syndrome
Morbid States
LDLlow-density lipoprotein HDLhigh-density
lipoprotein MImyocardial infarction
CHDcongestive heart failiure HFheart failure
ESRDend-stage renal diseaseAdapted from Arch
Intern Med. 2000 1601277-1283.
5
Metabolic SyndromeNCEP ATP III Definition
Three or more of the following criteria
Risk Factor
Defining Level
  • Abdominal obesity Waist Circumference
  • Men
    102 cm (40 in)
  • Women
    88 cm (35 in)
  • Triglycerides ?150
    mg/dL
  • HDL cholesterol
  • Men
  • Women
  • Blood pressure
    ?130 / ? 85 mm Hg
  • Fasting glucose
    ?110 mg/dL

Ford ES et al. JAMA. 2002287356-359.
6
Prevalence of Metabolic Syndrome Sex, Race, or
Ethnicity
40
35
30
25
Prevalence ()
20
15
10
5
0
Men
Women
NHANES III, 1988-1994.Ford ES et al. JAMA.
2002287356-359.
7
Prevalence of Metabolic Syndrome Age and Sex
50
Men
Women
40
30
Prevalence ()
20
10
0
20-29
30-39
40-49
50-59
60-69
70 or
NHANES III, 1988-1994.Ford ES et al. JAMA.
2002287356-359.
8
Percent Risk of Diabetes Per 1-kg Increase in
Body Weight
9
4.5
Risk of Diabetes ()
Population Level1 (National Sample of
Adults)
BRFSS Study2
BRFSSBehavioral Risk Factor Surveillance
System. 1. Ford ES et al. Am J Epidemiol.
1997146214-222. 2. Mokdad AH et al. Diabetes
Care. 2000231278-1283.
9
Recent Trends in Obesity
  • Body Mass Index (BMI) of 25 to 29.9 defines
    overweight, and 30 defines obesity
  • NHANES III for US adults aged 20-74 identified
    60 of men and 50 of women as being overweight
  • 20 of men and 25 of women are obese
  • The prevalence of overweight and obesity is
    higher in Hispanic men, and higher in Black and
    Hispanic women
  • Prevalence of overweight is 13-15 in children
    6-12 years, and 11-12 in those 12-17 years

Cooper R et al. Circulation. 20001023137-3147.
10
CHD Mortality Rates Based on Risk-Factor Status
140
Nondiabetic Diabetic
120
100
80
CHD Death Rate per 10,000 Person-Years
60
40
20
0
0
1
2
3
Risk Factors
Age-adjusted CVD death rates by risk factors for
men screened for the Multiple Risk Factor
Intervention Trial (MRFIT). Stamler J et al.
Diabetes Care. 199316434-444.
11
The Diabetic Hypertensive Is atEspecially High
Risk
  • For CV disease
  • Two-thirds of people with diabetes mellitus
    dieof some form of heart or blood vessel
    disease1
  • For MI
  • Diabetic patients without a previous MI have as
    high a risk of MI as nondiabetic patients with a
    previous MI2
  • For CHF
  • In the DIGAMI trial, 66 of total mortality
    among diabetics was due to heart failure3

DIGAMIDiabetes mellitus Insulin-Glucose Infusion
in Acute MI CHFcoronary heart disease
CVcardiovascular MImyocardial infarction. 1.
American Heart Association. 2002 Heart and Stroke
Statistical Update 2001.2. Haffner SM et al. N
Engl J Med. 1998339229-234.3. Malmberg K et
al. Eur Heart J. 1996171337-1344.
12
Incidence of CHD Events Based on Diabetic Status
P50
45.0
Nondiabetics with no prior MI Nondiabetics with
prior MI Diabetics with no prior MI Diabetics
with prior MI
40
30
Incidence During 7-Year Follow-up ()
P20.2
18.8
20
10
3.5
0
n69
n1304
n169
n890
Events per 100 Person/Years
3.0
0.5
7.8
3.2
Haffner SM et al. N Engl J Med. 1998339229-234.
13
Post-MI Outcomes in Hypertensivesand
Normotensives
100
100


90
90
Event-Free Survival ()
Event-Free Survival ()
80
80
Heart Failure
Death
70
70
1000
750
500
0
250
250
1000
750
500
0
Days
Days
Group
Group
Event
Event
NT 453 416 299 224 179 (25) HT 275 236 165 120 89
(34)
NT 453 424 311 239 194 (25) HT 275 255 186 136 103
(26)
Event-free Survival Curves for Postdischarge
All-Cause Mortality (death) and Postdischarge
Heart Failure Requiring Readmission to Hospital
(Heart Failure) in Normotensive (NT) and
Hypertensive (HT) Patients After Acute Myocardial
Infarction
Richards AM et al. J Am Coll Cardiol.
2002391182-1188.
14
Intensive Blood-Glucose vs ConventionalTreatment
in Type 2 Diabetes
Favors
Favors
intensive
conventional
Log-rank
0.1
1
10
P
RR (95 CI)
value
Clinical End Point
Any diabetes-related end point
0.88 (0.790.99)
0.029
Diabetes-related deaths
0.90 (0.731.11)
0.34
All-cause mortality
0.94 (0.801.10)
0.44
MI
0.84 (0.711.00)
0.052
Stroke
1.11 (0.811.51)
0.52
Amputation or death from PVD
0.65 (0.361.18)
0.15
Microvascular disease
0.75 (0.600.93)
0.0099
PVDperipheral vascular disease RRrelative
risk. UKPDS Group. Lancet. 1998352837-853.
15
Blood Pressure Control inType 2 Diabetes
Any Diabetes-relatedEndpoint
Diabetes-relatedDeath
MicrovascularEndpoints
HeartFailure
MyocardialInfarction
RenalFailure
Stroke
0
-10
-20
-21
-24
-30
Risk Reduction ()
-32
-40
-37
-42
-44
-50
-56
-60
Benefits of 144/82 vs 154/87
-70
UKPDS Group. UKPDS 38. Br Med J. 1998317703-713.
16
Role of Neurohormonal Activation inCVD Risk and
Progression
Insulin Resistance
Hyperinsulinemia
High Blood Pressure
Norepinephrine
Angiotensin II
Adrenal Medullary Activity
HDL Triglycerides
Increased CV Risk, Atherogenesis, Progressive CVD
Adapted from Reaven GM et al. N Engl J Med.
1996334374-381.
17
Deleterious Effects of Angiotensin II

Angiotensin II

CNS
Dypsogenia
Vaso-

Ý
AVP
constriction
Efferent

Constriction

Mesangial

Na

Contraction
Retention
Myocardial

Vessel


IncreasedNorepinephrineRelease
Hypertrophy
Hypertrophy
Ý

Aldosterone
18
Effect of ACE Inhibitors on Mortality in Post-MI
LVD or Heart Failure
Mortality
Trial
ACEI
Controls
RR (95 CI)
Chronic CHF
CONSENSUS I
39
54
0.56 (0.340.91)
SOLVD (Treatment)
40
35
0.82 (0.700.97)
SOLVD (Prevention)
15
16
0.92 (0.791.08)
Post-MI
SAVE
25
20
0.81 (0.680.97)
AIRE
17
23
0.73 (0.600.89)
TRACE
0.78 (0.670.91)
35
42
SMILE
6.5
8.3
0.78 (0.521.12)
Average
21
25
ACEIangiotensin-converting enzyme inhibitor
RRrelative risk. Garg R et al. JAMA.
19952731450-1456.
19
SNS Pathophysiology
Injury to the Heart (eg, myocardial infarction)
? Levels of Norepinephrine
Negative Cardiac Effects
Negative Renal Effects
Negative Vascular Effects
?1
b1
b1
b2
?1
?1
Cardiac Injury Hypertrophy Arrhythmias
Activation of RAS
Sodium Retention
Vasoconstriction
Disease Progression
20
Beta-Blockade Post-MISystematic Review and
Meta-Regression Analysis
Long Term
0.77 (0.70, 0.84)
Short Term
0.95 (0.88, 1.02)
IV
0.87 (0.61, 1.22)
ISA
1.19 (0.96, 1.47)
Post vs Pre 1982
1.04 (0.82, 1.28)
Propranolol
0.71 (0.59, 0.85)
Timolol
0.59 (0.46, 0.77)
Metoprolol
0.80 (0.66, 0.96)
Acebutolol
0.49 (0.25, 0.93)
1
3
0.33
Beta-blocker Better
Placebo Better
OR Mortality
No US Post-MI Indication Freemantle N et al. Br
Med J. 19993181730-1737.
21
Beta-Blockers in Diabetic CAD Patients
  • Bezafibrate Infarction Prevention Study
  • 2723 Patients with type 2 diabetes and CAD
  • After 3 years, a 43 reduction in cardiac events
    with beta-blockers (7.8 vs 14)
  • 42 reduction in cardiac mortality
  • Increasing divergence of survival curves with time

Survival
Time (Years)
P log rank .0001
Jonas M et al. Am J Cardiol. 1996771273-1277.
22
Effect of Beta-Blockers on Insulin Sensitivityin
Hypertensive Patients
Celiprolol
Carvedilol
Dilevalol
Pindolol
Atenolol
Metoprolol
Propranolol
-40
-20
0
20
40
Change Above or Below Baseline ()
Jacob S et al. Am J Hypertens. 1998111258-1265.
23
CAPRICORN Major Coronary EventsCarvedilol
Post-Infarct Survival Control in Left Ventricular
Dysfunction
Log-RankP Value
Nonfatal MI
0.59
0.014
All-Cause Mortality/Nonfatal MI
0.71
0.002
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Hazard Ratio/95 CI
The CAPRICORN Investigators. Lancet.
20013571385-1390.
24
CAPRICORN Similar Effect of Carvedilol in
Post-MI Diabetic, Nondiabetic, and HTN Patients
  • 437 (22) patients with diabetes 1055 (54) with
    HTN

50
40
29
26
30
23
Risk Reduction of Carvedilol Compared With
Placebo ()
20
P.013
P.002
P.067
10
0
DiabeticSubgroup
EntirePopulation
HypertensiveSubgroup
All-Cause Mortality or Nonfatal MI
HTNhypertension.
25
Cardiovascular Events or Death Relative Risk
Study
Design
Therapies
RR Odds Ratio
ABCD
RCT
Nisoldipine vs enalapril
5.5
2.1-14.6
FACET
RCT
2.04
1.05-3.84
Amlodipine vs fosinopril
Isradipine vs
MIDAS
RCT
2.71
1.07-6.86
hydrochlorothiazide
Nifedipine
EPESE
Cohort
3.27
1.40-7.62
vs beta-blocker
Calcium antagonist
Alderman
Case-control
6.85
1.5-31.3
vs other agents
Calcium antagonist
Lindberg
Cohort
2.26
1.05-4.87
vs beta-blocker
ABCDAppropriate Blood Pressure Control in
Diabetes FACETFosinopril vs Amlodipine
Cardiovascular Events Trial MIDASMulticenter
Isradipine Diuretic Atherosclerosis Study
EPESEEstablished Populations for
Epidemiologic Studies of the Elderly
RCTrandomized controlled trial RRrelative risk.
Pahor M et al. The Lancet.1998351689-690.
26
Comparative Effects of Carvedilol Versus
Metoprolol on Renal Blood Flow (mL/min)
1200
1000
800
Renal Blood Flow (mL/min)
Baseline
600
6 Months
400
P0.01
200
0
Placebon4
Metoprololn6
Carvediloln10
27
Comparative Effects of Carvedilol Versus
Metoprolol on Glomerular Filtration Rate (mL/min)
120
100
80
Baseline
Glomerular Filtration Rate (mL/min)
60
6 Months
P0.04
40
20
0
Placebon4
Metoprololn6
Carvediloln10
28
Evolution to Cardiovascular Events
HTN
SNS-RAS
SNS-RAS
MetabolicSyndrome(Insulin Resistance, Diabetes)
Cardio-myopathy
MyocardialInfarction
Heart Failure
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