New Frontiers in CVD Risk Management: Optimizing Outcomes in Patients with Multiple Cardiovascular Risks - PowerPoint PPT Presentation


Title: New Frontiers in CVD Risk Management: Optimizing Outcomes in Patients with Multiple Cardiovascular Risks


1
New Frontiers in CVD Risk ManagementOptimizing
Outcomes in Patients with Multiple Cardiovascular
Risks
2
US population at high risk
Hypercholesterolemia
Hypertension
Diabetes
  • 14.6 million diagnosed
  • 6.2 million undiagnosed
  • 65 million
  • 27 million not treated
  • 106.9 million
  • 94 million not treated

Patients with CHD/stroke 18.4 million/y Direct
105.7 billion/y Indirect 93.2 billion/y
Total cost 198.9 billion/y
AHA. Heart Disease and Stroke Statistics2005
Update. Hajjar I and Kotchen TA. JAMA.
2003290199-206. Ford ES et al. Circulation.
20031072185-9.CDC. www.cdc.gov/diabetes/pubs/pd
f/ndfs_2005.pdf.
Total-C 200 mg/dL BP 140/90 mm Hg FBG 126
mg/dL
3
Development and progression of CVD

Age, gender, smoking, inactivity,
obesity, cholesterol, BP, glucose
Risk factors
? Oxidative stress
? Endothelial function? EPCs
Genetic factors
Functional alterations
Structural alterations
Clinical sequelae
EPCs endothelial progenitor cells
Adapted from Pepine CJ. Am J Cardiol.
200188(suppl)5K-9K.
4
Genetics augment effects of environmental risk
factors
ENVIRONMENT
Inactivity Diet Psychosocial Stress
Culture
Obesity
Hypertension
Diabetes
GENES
GENES
Inadequate Medical Care
STROKE / MI
GENES
5
Cardiovascular risk factors, adults 5564 years
Men
19881994
Hypertension
19992002
Obesity
High cholesterol
One or more risk factors
Women
Hypertension
Obesity
High cholesterol
One or more risk factors
0
20
40
60
80
100
Prevalence ()
CDC. www.cdc.gov/nchs/ppt/hus/HUS2005.ppt.
6
Synergistic interaction of traditional multiple
risk factors on CVD risk
SBP (mm Hg)
50
44
110
150
120
160
40
130
170
33
5-year CVD risk per 100 people
140
180
30
24
18
20
12
10
6
3
lt1
0
Reference
TC 270 mg/dL
Smoker
HDL 39 mg/dL
Male
Diabetes
60 yearsof age
Additive risk factors
Jackson R et al. Lancet. 2005365434-41.
TC total cholesterol
7
Obesity decreases life expectancy regardless of
smoking
Framingham Heart Study
Female smokers
Female nonsmokers
1.0
1.0
0.8
0.8

0.6
Proportionalive
0.6
0.4
0.4
0.2
0.2
0.0
0.0
0
10
20
30
40
0
10
20
30
40
Follow-up (years)
Follow-up (years)
Obesity and smoking risks are equivalent
Peeters A et al. Ann Intern Med 200313824-32.
8
Decline in smoking vs rise in obesity A
trade-off?
Smoking rate
0.4
0.35
0.3
0.25
Proportionof population
0.2
0.15
0.1
Obesity rate
0.05
0
1970
1974
1978
1982
1986
1990
1994
1998
2002
Year
Gruber J and Frakes M. J Health Econ. Published
online ahead of print. www.sciencedirect.com.
9
Development and progression of CVD
Risk factors
? Oxidative stress
? Endothelial function? EPCs
Functional alterations
Structural alterations
Clinical sequelae
Adapted from Pepine CJ. Am J Cardiol.
200188(suppl)5K-9K.
EPCs endothelial progenitor cells
10
Traditional CVD risk factors
  • Family history
  • Older age
  • Male gender
  • Smoking
  • Physical inactivity
  • Overweight/obesity
  • Total-C/LDL-C/HDL-C/TG
  • BP
  • Glucose

Adapted from Stampfer MJ et al. Circulation.
2004109(suppl)IV3-IV5.
11
Selected emerging biomarkers
Lipids Lp(a) apoA/apoB Particle size/density
Inflammation CRP SAA IL-6 IL-18
TNF Adhesion mols Lp-PLA2 CD40L CSF
Hemostasis/Thrombosis Homocysteine tPA/PAI-1
TAFI Fibrinogen D-dimer
CSF colony-stimulating factor
MPO myeloperoxidase
Adapted from Stampfer MJ et al. Circulation.
2004109(suppl)IV3-IV5.
TAFI thrombin activatable fibrinolysis inhibitor
12
LDL infiltration triggers inflammatory response
Coronaryartery
Endothelium
LDL
Activation
Accumulation of cholesterol
Uptake
Macrophage
Modification
Retention
Hansson GK. N Engl J Med. 20053521685-95.
13
Role of ox-LDL in macrophage recruitment
Coronaryartery
Endothelium
Migration
Adhesion
Monocyte
Inflammation. tissue damage
Differentiation
Endotoxins,heat-shock proteins, oxidized LDL,
others
Macrophage
Toll-likereceptor
Inflammatory cytokines, chemokines,
proteases,radicals
Hansson GK. N Engl J Med. 20053521685-95.
14
Hypertension increases atherogenic lipoprotein
content of arterial vessel walls
Atherogenic VLDL, VLDL-R,IDL, LDL
BP
Pressure-driven convection
Intima- Enhanced LP penetration media
LP retention
Pressure-induced distension
Stretching
Intima- media
LP lipoprotein
Sposito AC. Eur Heart J Suppl. 20046(suppl
G)G8-G12.
15
AT1 and LOX-1 receptor cross-talk promotes
adhesion molecule expression
Interaction between RAAS and dyslipidemia
Monocyte adhesion
LOX-1
EC
?
?NO
Oxygen
AT1R
?
Angiotensin II LDL Oxidation Cytokines
Platelet Aggregation Monocyte Adhesion
Angiotensin II
?
Growth Factors
?
?
Ox-LDL
Fibroblasts
?
LDL
Smooth Muscle Cells













SRs scavenger receptors
Adapted from Singh BM and Mehta JL. Arch Intern
Med. 20031631296-304.
EC endothelial cell
16
Lipoprotein-associated phospholipase A2 (Lp-PLA2)
Produced by inflammatory cells
  • Hydrolyzes oxidized phospholipids to generate
  • proinflammatory molecules
  • Lysophosphatidylcholine
  • Oxidized fatty acids

Upregulated in atherosclerotic lesions where it
co-localizes with macrophages
Macphee CH et al. Curr Opin Lipidol.
200516442-6.
17
Studies demonstrating association of Lp-PLA2
with incident CHD
Findings
Subjects
Study
RR 1.18 (1.05-1.33) per 1 SD ?
WOSCOPS subgroup LDL-C 174232 mg/dL 580 cases,
1160 controls
Packard et al
HR 1.78 (1.33-2.38)tertile 3 vs tertile 1
General population 608 cases, 740 controls
Ballantyne et al
HR 1.23 (1.02-1.47) per 1 SD ?
General population 97 cases, 837 controls
Koenig et al
HR 1.97 (1.28-3.02)4th vs 1st quartile
General population 418 cases, 1820 controls
Oei et al
Packard CJ et al. N Engl J Med.
20003431148-55.Ballantyne CM et al.
Circulation. 2004109837-42.Koenig W et al.
Circulation. 20041101903-8.Oei H-HS et al.
Circulation. 2005111570-5.
Adjusted relative risk (RR) or hazard ratio (HR)
18
EPC number/function correlates with endothelial
function
N 45 healthy males, mean age 50.3 y, no CVD
3
0
2
0
EPCs(colony-formingunits)
1
0
0
L
o
w
M
i
d
H
i
g
h
Flow-mediated dilation
Hill JM et al. N Engl J Med. 2003348593-600.
EPCs endothelial progenitor cells
19
EPC number has prognostic importance
N 507 males with CAD, mean age 66 y
1.00
Group 3 (high EPC level)
0.98
Group 2 (medium EPC level)
Event- free survival (CV mortality)
0.96
0.94
Group 1 (low EPC level)
0.92
P 0.01
0.90
0
100
200
300
365
0
Follow-up (days)
Werner N et al. N Engl J Med. 2005353999-1007.
EPC endothelial progenitor cell
20
Arterial stiffness Cause and consequence of
atherosclerosis
Endothelial damage mechanical fatigue
?Pulsepressure
?Sympathetic modulation
?Central wave reflection
Atherosclerosis
?Large arterystiffness
Adapted from Dart AM and Kingwell BA. J Am Coll
Cardiol. 200137975-84.
21
Correlation between number of risk factors and
arterial distensibility
N 803, mean age 30 y
7.5
Linear trend P lt 0.0001
? Brachial artery distensibility occurs long
before clinical manifestations of CVD appear
7
Brachial artery distensibility(? / mm Hg)
6.5
6
5.5
0
3
1
4
2
5
Number of CV risk factors
Urbina EM et al. Am J Hypertens. 200518767-71.
Bogalusa Heart Study
22
Peripheral arterial stiffness is associated with
subclinical atherosclerosis
N 256
50
P lt 0.0001 for trend
40
30
Thigh arterial compliance
20
10
0
Q1
Q3
Q2
Q4
MRI resultsQuartile of abdominal aorta wall
thickening
Maximum volume change
X 50
Herrington DM et al. Circulation. 2004110432-7.
Brachial pulse pressure
23
Pleiotropic effects of statins
? Coagulation
? Endothelial progenitor cells
? Platelet activation
? Endothelial function
? Effects on collagen
? NO bioactivity
Statins
? Reactive oxygen species
? MMPs
? AT1 receptor
? VSMC proliferation
? Macrophages
? Inflammation
? Immunomodulation
? Endothelin
Liao JK. Am J Cardiol. 200596(suppl 1)24F-33F.
MMPs matrix metalloproteinases
24
High-dose statin treatment reduces Ox-LDL markers
MIRACL study subgroup analysis, N 2341 with
ACS, atorvastatin 80 mg for 16 weeks
Mean
95 CI
ApoB-100
Atorvastatin
33.0 34.2, 31.8
Placebo
5.8 4.6, 7.0
Total apoB-OxPL
Atorvastatin
29.7 31.5, 28.0
Placebo
0.2 2.3, 1.9
Total apoB-IC IgG
Atorvastatin
29.5 31.9, 27.0
Placebo
2.1 1.1, 5.4
Total apoB-IC IgM
Atorvastatin
25.7 28.1, 23.3
Placebo
13.2 9.3, 17.3
40
20
0
20
40
change
OxPL oxidized phospholipids IC-IgG, -IgM
immune complexes with IgG and IgM,
respectively Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering
Tsimikas S et al. Circulation. 20041101406-12.
25
Statin treatment reduces Lp-PLA2
100
87.1
73.5
80
62.2
60
Plasma Lp-PLA2 activity(nmol x mL-1 x min-1)
42.3
40
20
0
Type IIA dyslipidemia (n 55)
Type IIB dyslipidemia(n 21)
Atorvastatin 20 mg, 4 mos
Baseline
Tsimihodimos V et al. Arterioscler Thromb Vasc
Biol. 200222306-11.
P lt 0.001 vs baseline
26
Statins increase circulating EPCs
N 15 with CAD treated with atorvastatin 40 mg
for 4 weeks
700

600

500
  • Postulated mechanism
  • Activation of
  • PI3-K/Akt pathway
  • Endothelial NO synthase

EPCs(cells/mm2)
400

300
200
100
n 13
n 12
n 14
n 12
n 15
0
0
7
14
21
28
Treatment (days)
Vasa M et al. Circulation. 20011032885-90. Liao
JK. Am J Cardiol. 200596(suppl)24F-33F.
P lt 0.05 vs baseline
27
Intensive lipid lowering improves arterial
compliance
N 22 with ISH treated with atorvastatin 80 mg
for 3 months
P 0.03
0.5
Systemic arterial compliance (mL/mm Hg)
0.4
0.3
0.0
Placebo
Atorvastatin
Ferrier KE et al. J Am Coll Cardiol.
2002391020-5.
28
Comparative effects of statin and ezetimibe on
EPCs and endogenous antioxidant system
N 20 with HF treated with simvastatin 10 mg or
ezetimibe 10 mg for 4 weeks
Extracellular superoxide dismutase
EPCs
P lt 0.05
NS
P lt 0.05
NS
160
450
120
Number per high power field
Endothelium-bound ecSOD activity
300
80
(U x mL-1 x min-1)
150
40
0
0
Pre
Post
Pre
Post
Pre
Pre
Post
Post
Statin
Ezetimibe
Statin
Ezetimibe
Group
Pre baseline Post 4 weeks
Landmesser U et al. Circulation. 20051112356-63.
29
Neuroprotection with statins in stroke model
Occlusion of middle cerebral artery in rats
Post-treated with statin after occlusion
Pre-treated with statin before occlusion
Vehicle
Simvastatin
24 hrs
24 hrs
48 hrs
48 hrs
Statin effect accompanied by eNOS upregulation in
cerebral blood vessels
Sironi L et al. Arterioscler Thromb Vasc Biol.
200323322-7.
Ischemic areas indicated by arrows
30
Pleiotropic effects of BP-lowering agents
ACEIs/ARBs
CCBs
? Fibrinolysis
? NO
? Mononuclear cell migration
? MMP activity
? Collagen matrix formation
BP-loweringagents
? Endothelial function
? Cholesterol depositionin membrane
AHTNagents
? Plaque stability
? Arterial compliance
Both
? Platelet aggregation
? Oxidative stress
? Inflammation
? VSMC proliferation
Lonn E et al. Eur Heart J Suppl. 20035(suppl
A)A43-A8.Wassman S and Nickenig G. Eur Heart J
Suppl. 20046(suppl H)H3-H9. Mason RP et al.
Arterioscler Thromb Vasc Biol. 2003232155-63.
MMP matrix metalloproteinase
31
Statin metabolite and CCB show additive
antioxidant effect
Human LDL incubated with O-hydroxy metabolite of
atorvastatin (100 nmol/L), lovastatin (100
nmol/L), and amlodipine (2.5 ?mol/L)
50

40
Inhibition of TBARS formation()
30

20
10
0
Atorvastatin metabolite
AmlodipineLovastatin
AmlodipineAtorvastatinmetabolite
TBARS thiobarbituric acid-reactive
substances P lt 0.0001 vs vehicle treatment
Mason RP et al. Am J Cardiol. 200596(suppl)11F-2
3F.
32
Additive effects of statin CCB on fibrinolytic
balance
N 45 with hypertension, placebo-controlled,
crossover trial
P lt 0.05
0.26
? t-PA(U/mL)

0.17

0.08
Change from baseline
0.5
? PAI-1(U/mL)


9.9
10.2
t-PA / PAI-1 ratio 0.045 0.03 0.06
P lt 0.05 vs placebo P lt 0.01 vs placebo
Fogari R et al. Am J Hypertens. 200417823-7.
33
Beneficial effect of statin ACEI on
endothelial function
N 50 with dyslipidemia, placebo-controlled,
crossover trial
P lt 0.001
7
6.58
6.02
6
4.81
5
4.56
Flow-mediateddilation()
4
3
2
1
0
Baseline 1
Sim PL
Baseline 2
Sim Ram
PL placebo Ram ramipril 10 mg Sim
simvastatin 20 mg
Koh KK et al. Hypertension. 200444180-5.
34
Approaches to CVD prevention
35
Lifestyle changes reduce need for drug therapy
N 3234 with IGT randomized to intensive
lifestyle change, metformin 850 mg 2x/d, or
placebo
  • Lifestyle change goals
  • Weight reduction of 7 initial body weight via
    low-fat, low-calorie diet
  • Moderate-intensity physical activity 150
    min/week

Lifestyle Metformin Placebo
At 3 years

31
32
23
BP-lowering agents required

16
16
12
Lipid-lowering agents required
P lt 0.001 vs other groups
Diabetes Prevention Program Research Group.
Diabetes Care. 200528888-94.
36
New lifestyle guidelines More exercise, fruits
and vegetables
2000 Report 2005 Report
Exercise
30 minutes of moderate physical activity 5-7 days/week 30 minutes of moderate physical activity 5-7 days/week 30 minutes of moderately intense exercise every day 60 min to prevent weight gain
5 servings/day 5 servings/day 9 servings/day

Fruits and vegetables
HHS/USDA. www.healthierus.gov/dietaryguidelines.
37
Exercise reduces CV and all-cause mortality
N 9791, moderate exercise vs little or no
exercise NHANES I Epidemiological Follow-up
Survey (1971-1992)
Favors exercise
Favors no exercise
HR
Normal BP
All-cause death
0.75
0.76
CV death
Prehypertension
All-cause death
0.79
0.79
CV death
Hypertension
All-cause death
0.88
CV death
0.84
1.5
1.0
0.5
0
2.0
Hazard ratio
Fang J et al. Am J Hypertens. 200518751-8.
38
Diet reduces mortality in primary prevention
trials
  • 2002
  • Physicians Health Study(N 20,551)
  • 2003
  • Cardiovascular Health Study(N 5,201)
  • 2002
  • Nurses Health Study(N 84,688)
  • 2003
  • European Prospective Investigation into Cancer
    and NutritionGreek cohort (N 22,043)
  • 2005
  • European Prospective Investigation into Cancer
    and Nutritionelderly cohort (N 74,607)

2004 The Healthy Aging A Longitudinal Study in
Europe (N 2339)
Parikh P et al. J Am Coll Cardiol.
2005451379-87. Trichopoulou A et al. BMJ.
2005330991-7. Knoops KTB et al. JAMA.
20042921433-9.
Blood levels of n-3 fatty acids inversely
related to death Greater adherence associated
with lower mortality
39
Potential cardioprotective mechanisms of dietary
components
  • Omega-3 fatty acids
  • Antiarrhythmic
  • Antithrombogenic
  • Antiinflammatory
  • Antihypertensive
  • Improved endothelial function
  • Folic acid
  • Antioxidant
  • ?NO bioavailability
  • Improved endothelial function

Kris-Etherton PM et al. Circulation.
20021062747-57. Verhaar MC et al. Arterioscler
Thromb Vasc Biol. 2002226-13.
40
Non-pharmacologic interventions and BP reduction
Alcohol reduction
Potassiumsupplement
Exercise
Low salt diet
0
1
2
BP decrease(mm Hg)
3
4
5
Adapted from Messerli FH et al. In Griffin BP et
al, eds.2004. Manual of Cardiovascular Medicine.
2nd ed. Whelton SP et al. Ann Intern Med.
2002136493-503.Cutler JA et al. Am J Clin
Nutr. 199765(suppl)643S-651S. Xin X et al.
Hypertension. 2001381112-7.Whelton PK et al.
JAMA. 19972771624-32.
SBP
DBP
41
Benefit of multifactorial interventions
42
Key findings from recent lipid-lowering trials
IDEAL Benefit of
intensive vs moderate lipid lowering in stable
CAD
ASCOT-LLABenefit in high-risk HTN regardless of
baseline LDL-C
CARDSBenefit in DM
ALLHAT-LLTNeutral effect in HTN with mild
lipid lowering
4D Neutral effect in ESRD
2002 2003 2004 2005
HPS Benefit in CVD and DM
regardless of baseline LDL-C
TNTBenefit of intensive vsmoderate lipid
loweringin stable CAD
PROVE IT-TIMI 22 Early and late benefit of
intensive vs moderate lipid lowering in ACS
A to Z Late benefit of intensive vs moderate
lipid lowering in ACS
Primary prevention
Secondary prevention (ACS)
Secondary prevention (stable CAD)
43
PROVE IT-TIMI 22 Assessment of intensive lipid
lowering in ACS
PRavastatin Or AtorVastatin Evaluation and
Infection TherapyThrombolysis In Myocardial
Infarction 22
Design 4162 patients with ACS randomized to
atorvastatin 80 mg or pravastatin 40
mg Follow-up 2 years Primary outcome All-cause
death, MI, hospitalization for UA,
revascularization, stroke
Cannon CP et al. N Engl J Med. 20043501495-504.
44
PROVE IT-TIMI 22 Early benefit with intensive
lipid lowering
PRavastatin Or AtorVastatin Evaluation and
Infection TherapyThrombolysis In Myocardial
Infarction 22
N 4162 with ACS
30
P 0.005
40 mg Pravastatin
20
80 mg Atorvastatin
Death or major CV event ()
P 0.03 at 4 mos
10
0
3
6
9
12
30
15
18
21
24
27
0
Follow-up (months)
Ray KK and Cannon CP Am J Cardiol.
200596(suppl)54F-60F.Adapted from Cannon CP et
al. N Engl J Med. 20043501495-504.
45
PROVE IT-TIMI 22 Benefit at 30 days
PRavastatin Or AtorVastatin Evaluation and
Infection TherapyThrombolysis In Myocardial
Infarction 22
N 4162 with ACS
Event rates ()
Censoring time
Hazard ratio (95 CI)
Risk reduction ()
Atorvastatin
Pravastatin
30 days 90 days 180 days End of follow-up
17 1.9 2.2 18 6.3 7.7 14 12.2 14.1 16 22.4 26.
3
No ? toxicity
High-doseatorvastatinbetter
Standard-dosepravastatinbetter
Cannon CP et al. N Engl J Med. 20043501495-504.
46
PROVE IT-TIMI 22 Evidence for rapid reduction in
markers of inflammation
PRavastatin Or AtorVastatin Evaluation and
Infection TherapyThrombolysis In Myocardial
Infarction 22
N 4162 with ACS
100
P 0.60
Median CRP (mg/L)
10
Pravastatin(n 1873)
P lt 0.001
P lt 0.001
P lt 0.001
Atorvastatin(n 1872)
1
Randomization
30 days
4 months
End of study
Ridker PM et al. N Engl J Med. 200535220-8.
47
PROVE IT-TIMI 22 Clinical implications
PRavastatin Or AtorVastatin Evaluation and
Infection Therapy-Thrombolysis In Myocardial
Infarction 22
  • In patients with recent ACS, aggressive lipid
    lowering was associated with greater clinical
    benefit vs less aggressive lipid lowering
  • 16 RRR in all-cause death, MI, UA,
    revascularization, stroke
  • Benefit evident at 30 days and may be mediated in
    part by anti-inflammatory effect
  • No relationship between achieved LDL-C level and
    risk of adverse events No excess risk even
    at levels 40 mg/dL

PROVE IT-TIMI 22 supports lower LDL-C goal in
patients with ACS
Cannon CP et al. N Engl J Med. 20043501495-504.
Ray KK et al. Am J Cardiol. 200596(suppl)54F-60F
.Ridker PM et al. N Engl J Med.
200535220-8. Wiviott SD et al. J Am Coll
Cardiol. 2005461411-6.
48
A to Z Early initiation of intensive regimen vs
delayed initiation of less-intensive regimen
Aggrastat to Zocor
Population 4497 patients with ACS Treatments Sim
vastatin 40 mg/d for 1 month, followed by 80
mg/d Placebo for 4 months, followed by
simvastatin 20 mg/d Median follow-up 721
days Primary outcome CV death, nonfatal MI, ACS
readmission, stroke
de Lemos JA et al. JAMA. 20042921307-16.
49
A to Z Treatment effect on LDL-C
Aggrastat to Zocor
N 4497 with ACS
140
124
122
112
111
100
81

77



LDL-C(mg/dL)
68
66
63
62
60
20
0
Baseline
1
4
8
24
Time from randomization (months)
Simvastatin 40/80 mg/d
Placebo/simvastatin 20 mg/d
P lt 0.001 vs placebo/simvastatin 20 mg
de Lemos JA et al. JAMA. 20042921307-16.
50
A to Z Treatment effect on CRP
Aggrastat to Zocor
N 4497 with ACS
21
20.4
20.1
6
5
CRP(mg/L)
4
3
2.5
2.4

2.3

1.8
1.7
2
1.5
1
0
Baseline
1
4
8
Time from randomization (months)
Placebo/simvastatin 20 mg/d
Simvastatin 40/80 mg/d
de Lemos JA et al. JAMA. 20042921307-16.
P lt 0.001 vs placebo/simvastatin 20 mg
51
A to Z Treatment effect on primary outcome
Aggrastat to Zocor
N 4497 with ACS
20
11 RRRHR 0.89 (0.76-1.04) P 0.14
15
Cumulativerate ()
11 RRR
10
27 RRRP 0.02
5
0
4
0
8
12
16
20
24
Time from randomization (months)
Simvastatin 40/80 mg/d
Placebo/simvastatin 20 mg/d
de Lemos JA et al. JAMA. 20042921307-16.
CV death, MI, recurrent ACS hospitalization,
stroke
52
A to Z Treatment effect on primary outcome at
different time periods
Aggrastat to Zocor
N 4497 with ACS
Primary composite outcome rate ()
Simvastatin40/80 mgn 2265
Placebo simvastatin 20 mg n 2232
Favorssimvastatin40/80 mg
Favors placebo simvastatin20 mg
Overall study result
14.4
16.7
Randomization through month 4
8.2
8.1
Months 424
6.8
9.3
0.5
1.0
1.5
Hazard ratio (95 CI)
CV death, MI, recurrent ACS hospitalization,
stroke
de Lemos JA et al. JAMA. 20042921307-16.
53
A to Z Clinical implications
Aggrastat to Zocor
  • In patients with recent ACS, early initiation of
    a moderate/high-dose simvastatin regimen vs
    delayed initiation of a low-dose regimen resulted
    in nonsignificant trend toward reduction in major
    CV events
  • 11 RRR in CV death, nonfatal MI, ACS
    readmission, stroke
  • No difference between the treatment groups was
    observed within the first 4 months
  • Findings are consistent with MIRACL and PROVE
    IT-TIMI 22
  • Early benefits may be due to anti-inflammatory
    effects
  • Late benefits may be due to lipid lowering

de Lemos JA et al. JAMA. 20042921307-16. Ray
KK et al. Am J Cardiol. 200596(suppl)54F-60F.
54
TNT Assessment of intensive lipid lowering on
clinical outcomes
Treating to New Targets
Design 10,001 patients with stable CHD and LDL-C
130-250 mg/dL Treatment Randomized to
atorvastatin 10 mg or 80 mg Follow-up 4.9
years Primary outcome CHD death, MI,
resuscitation after cardiac arrest,
fatal/nonfatal stroke
LaRosa JC et al. N Engl J Med. 20053521425-35.
55
TNT Treatment effects on LDL-C
Treating to New Targets
N 10,001
160
140
120
Atorvastatin 10 mg (n 5006)
100
LDL-C (mg/dL)
80
Atorvastatin 80 mg (n 4995)
60
40
20
0
Screening
Final
60
48
36
24
3
0
12
Months
LaRosa JC et al. N Engl J Med. 20053521425-35.
56
TNT Treatment effects on primary outcome
Treating to New Targets
N 10,001
0.15
Atorvastatin 10 mg (n 5006)
22 Risk reductionHR 0.78 (0.690.89) P lt 0.001
0.10
Major CV events ()
0.05
Atorvastatin 80 mg (n 4995)
0.00
6
5
4
2
1
3
0
Follow-up (years)
CHD death, MI, resuscitation after cardiac
arrest, fatal/nonfatal stroke
LaRosa JC et al. N Engl J Med. 20053521425-35.
57
TNT Incidence of elevated liver or muscle
enzymes
Treating to New Targets
N 10,001
Atorvastatin 80 mg ()(n 4995)
Atorvastatin 10 mg ()(n 5006)
ALT and/or AST gt3xULN
0.2
1.2
CK gt10xULN
0
0
4.8
Myalgia
4.7
Rhabdomyolysis
0.04
0.06
P lt 0.001 vs atorvastatin 10 mg ALT alanine
aminotransferaseAST aspartate
aminotransferaseULN upper limit of normal
LaRosa JC et al. N Engl J Med. 20053521425-35.
58
TNT Clinical implications
Treating to New Targets
  • In patients with stable CHD, aggressive lipid
    lowering was associated with greater clinical
    benefit vs less intensive lipid lowering
  • 22 RRR in CHD death, MI, resuscitation after
    cardiac arrest, and fatal/nonfatal stroke

TNT supports lower LDL-C goal in patients with
stable CHD
LaRosa JC et al. N Engl J Med. 200535225-35.
59
Potential factors contributing to early statin
benefit
  • High baseline risk
  • Intensive LDL-C lowering
  • Rapid anti-inflammatory effect

High risk
Rapid
Intensive
Pepine CJ and Selwyn AP. Vasc Biol Clin Pract.
CME Monograph. UF College of Medicine. 20046(2).
60
HPS and CARDS Benefits of lowering LDL-C in
diabetes
Heart Protection Study and Collaborative
AtoRvastatin Diabetes Study
Event rate ()
Statin better
Placebo better
? LDL-C(mg/dL)
Placebo
Statin
P
HPS
34.8
0.73
lt0.0001 0.0003 0.001
12.6 13.5 9.0
9.4 9.3 5.8
All diabetes
0.67
34.8
Diabetes, no CVD
0.63
46.4
CARDS
0.5
0.7
0.9
1
1.7
Relative risk
HPS Collaborative Group. Lancet.
20033612005-16.Colhoun HM et al. Lancet.
2004364685-96.
Statin vs placebo
61
CARDS Adverse events
Placebo (n1410)
Atorvastatin 10 mg (n1428)
Type of Event
No. of events ( of patients with event)
19 (1.1)
20 (1.1)
Serious adverse event (AE)
122 (9)
145 (10)
Discontinued for AE
0
0
Rhabdomyolysis
1 (0.1)
1 (0.1)
Myopathy
17 (1)
14 (1)
ALT 3 ULN
6 (0.4)
4 (0.3)
AST 3 ULN
Judged by attending clinician to be possibly
associated with study drug ALT alanine
transaminase AST aspartate transaminase ULN
upper limit of normal
Colhoun HM et al. Lancet. 2004364685-96.
62
4D Trial Neutral effect of statin in
hemodialysis patients with diabetes
N 1255 randomized to atorvastatin 20 mg or
placebo for 4 years
Fatal stroke ?103 P 0.04
20
?12
10
0
Change
-10
?8
Baseline LDL-C 121 mg/dL
-20
?18
-30
P 0.03
NS
NS
-40
-50
LDL-C
Nonfatal MI
Coronary
Cerebrovasc
CHD death
events
events
Stroke
Wanner C et al. N Engl J Med. 2005353238-48.
Relative risk reduction
63
Statins reduce all-cause death Meta-analysis of
14 trials

Cholesterol Treatment Trialists Collaboration
Cause of death
Events ()
Treatment(n 45,054)
Control(n 45,002)
Treatment better
Controlbetter
Vascular causes
3.4
0.81
4.4
CHD
0.91
Stroke
0.6
0.6
0.95
Other vascular
0.6
0.7
0.93
Any non-CHD vascular
1.2
1.3
Any vascular
4.7
5.7
0.83
Nonvascular causes
2.4
2.4
Cancer
1.01
0.2
0.3
Respiratory
0.82
0.1
0.1
0.89
Trauma
1.1
1.2
0.87
Other/unknown
3.8
4.0
0.95
Any nonvascular
8.5
9.7
0.88
Any death
1.5
1.0
0.5
Relative risk
CTT Collaborators. Lancet. 20053661267-78.
64
Statin benefit independent of baseline lipids
Meta-analysis of 14 trials
Cholesterol Treatment Trialists Collaboration
Events ()
Groups
Treatment(45,054)
Control(45,002)
Treatment better
Control better
Total-C (mg/dL)
13.5
0.76
16.6
201
0.79
gt201251
13.9
17.4
0.80
gt251
15.2
19.7
LDL-C (mg/dL)
0.76
13.4
16.7
135
14.2
17.6
0.79
gt135174
15.8
0.81
20.4
gt174
HDL-C (mg/dL)
22.7
35
0.78
18.2
14.3
18.2
gt3543
0.79
11.4
14.2
0.79
gt43
TG (mg/dL)
13.4
16.8
0.79
124
13.8
18.0
0.78
gt124177
0.80
15.3
18.8
gt177
0.79
Overall
17.8
14.1
1.5
1.0
0.5
Relative risk
CTT Collaborators. Lancet. 20053661267-78.
CHD death, MI, stroke, coronary revascularization
65
HPS Assessing relation of statin benefit to
baseline LDL-C
Heart Protection Study
Population 20,536 patients with total-C ?135
mg/dL and history of diabetes, treated
hypertension, CAD, stroke, or PAD Treatment Rando
mized to simvastatin 40 mg or placebo Primary
outcome Mortality (for overall analysis) and
fatal or non-fatal vascular events (for
subcategory analyses) Follow-up 5 years
HPS Collaborative Group. Lancet. 20023607-22.
66
HPS Effects on specific major vascular events
Vascular event
Statin (10,269)
Placebo (10,267)
Statin better
Placebo better
Major coronary event
898
1,212
Any stroke
444
585
Any revascularization
1,205
939
0.76 (95 CI, 0.720.81) P lt 0.0001
Any major vascular event
2,033 (19.8)
2,585 (25.2)
0.4
0.6
0.8
1.0
1.2
1.4
Event rate ratio
HPS Collaborative Group. Lancet. 20023607-22.
67
HPS Vascular events by baseline LDL-C levels
Placebo (n10,267)
Statin (n10,269)
Baseline LDL-C (mg/dL)
Statin better
Placebo better
358 (21.0)
282 (16.4)
lt100 (n 3421)
871 (24.7)
668 (18.9)
100 lt130
1356 (26.9)
1083 (21.6)
?130
2585 (25.2)
2033 (19.8)
All patients
24 reduction 2P lt 0.00001
Rate ratio
HPS Collaborative Group. www.hpsinfo.org
68
HPS Statin beneficial irrespective of baseline
lipid level and diabetes status
Heart Protection Study
Event rate ()
Simvastatin n 10,269
Placebo n 10,267
Statin better
Placebo better
LDL-C lt116 mg/dL
15.7
With diabetes
20.9
18.8
No diabetes
22.9
LDL-C 116 mg/dL
With diabetes
23.3
27.9
20.0
No diabetes
26.2
24 reductionP lt 0.0001
All patients
19.8
25.2
0.4
1.0
1.4
0.6
0.8
1.2
Event rate ratio
HPS Collaborative Group. Lancet. 20033612005-16.
69
HPS Incidence of elevated liver or muscle
enzymes
Heart Protection Study
Simvastatin ()(n 10,269)
Placebo () (n 10,267)
Elevated ALT 24xULN 1.35 1.28 gt4xULN
0.42 0.31 Elevated CK 410xULN 0.19 0.13
gt10xULN 0.11 0.06 Myopathy No
rhabdomyolysis 0.05 0.01 Rhabdomyolysis 0.05
0.03
ALT alanine aminotransferase ULN upper limit
of normal
HPS Collaborative Group. Lancet. 20023607-22.
70
Improving time to benefit in clinical outcomes
studies
71
Key findings from recent BP-lowering trials
INVESTCCB ACEIequivalent to ?-blocker
diuretic in hypertension CAD
ASCOT-BPLABenefit of CCB ACEI vs ?-blocker
diureticin high-risk hypertension without CAD
ALLHATBenefit regardless of drug class
VALUEImportanceof promptBP control
2002 2003 2004 2005
CAMELOTEvidence for ? BP goal in hypertension
CAD
?-blocker meta-analysisIncreased risk of stroke
vs other antihypertensives
72
Increased stroke risk for ?-blockers shown in
meta-analysis
N 105,951
RR(95 CI)
Favors ß-blocker
Favors other drug
Stroke
ASCOT-BPLA
1.29 (1.121.49)
0.87 (0.681.12)
CONVINCE
1.58 (0.693.64)
ELSA
0.77 (0.491.23)
HAPPHY
1.14 (0.931.39)
INVEST
1.34 (1.131.58)
LIFE
1.22 (0.831.79)
MRC Old
1.22 (0.991.50)
NORDIL
1.12 (0.961.30)
STOP-2
0.90 (0.481.69)
UKPDS
0.56 (0.211.48)
Yurenev
2.28 (1.313.95)
MRC
1.16 (1.041.30)
Total events
Test for heterogeneity ?2 22.39 (P 0.02)
0.5
0.7
1.0
1.5
2.0
Lindholm LH et al. Lancet. 20053661545-53.
73
Comparison of active treatments on stroke
Blood Pressure Lowering Treatment Trialists
Collaboration meta-analysis
N 158,709
? BP between Rx (mm Hg)
Favorsfirst listed
Favorssecond listed
ACEI vs D/BB Diabetes 2.2/0.3 1.02 No
diabetes 1.4/0.2 1.11 Overall (P homog
.49) 1.08
CCB vs D/BB Diabetes 0.7/0.8 0.94 No
diabetes 1.1/0.4 0.92 Overall (P homog
.84) 0.92
0.5
1.0
2.0
Relative risk
ACEI angiotensin-converting enzyme
inhibitorD/BB diuretic/?-blocker CCB
calcium channel blocker
BPLTTC. Arch Intern Med. 20051651410-9.
74
Comparison of active treatments on CHD
Blood Pressure Lowering Treatment Trialists
Collaboration meta-analysis
N 158,709
? BP between Rx (mm Hg)
Favorsfirst listed
Favorssecond listed
ACEI vs D/BB Diabetes 2.2/0.3 0.83 No
diabetes 1.5/0.2 0.98 Overall (P homog
.33) 0.96
CCB vs D/BB Diabetes 0.7/0.8 1.00 No
diabetes 1.1/0.4 1.01 Overall (P homog
.86) 1.01
ACEI vs CCB Diabetes 1.6/1.2 0.76 No
diabetes 1.3/0.9 0.98 Overall (P homog
.22) 0.83
0.5
1.0
2.0
Relative risk
ACEI angiotensin-converting enzyme
inhibitorD/BB diuretic/?-blocker CCB
calcium channel blocker
BPLTTC. Arch Intern Med. 20051651410-9.
75
VALUE Comparison of CCB and ARB
Valsartan Antihypertensive Long-term Use
Evaluation
Population 15,245 patients with high-risk
hypertension Treatment Amlodipine 510 mg ?
HCTZ 12.525 mgValsartan 80160 mg ? HCTZ
12.525 mg Primary outcome Composite of cardiac
mortality, MI, HF Secondary outcomes MI, HF,
stroke Follow-up 4.2 years
Julius S et al. Lancet. 20043632022-31.
76
VALUE Similar treatment effectson primary
outcome at study end
Valsartan Antihypertensive Long-term Use
Evaluation
N 15,245
14
HR 1.03(95 CI, 0.941.14) P 0.49
12
Main outcome of cardiac disease did not differ
between treatment groups. Unequal reductions in
BP might account for differences.
10
Proportionof patientswith firstevent ()
Valsartan-based regimen (n 7649)
8
6
4
Amlodipine-based regimen (n 7596)
2
0
0
30
18
54
66
6
42
Time (months)
Julius S et al. Lancet. 20043632022-31.
77
VALUE SBP and outcome differencesduring
consecutive time periods
Valsartan Antihypertensive Long-term Use
Evaluation N 15,245
HFhospitalizations
Timeinterval(mos)
Stroke
All-cause death
? SBP(mm Hg)
Favorsvalsartan
Favorsamlodipine
Favorsvalsartan
Favorsamlodipine
Favorsvalsartan
Favorsamlodipine
All study
2.2
03
3.8
36
2.3
612
2.0
1224
1.8
2436
1.6
3648
1.4
Study end
1.7
0.5
1.0
2.0
4.0
0.5
1.0
2.0
4.0
0.5
1.0
2.0
4.0
Odds ratio
Odds ratio
Odds ratio
Julius S et al. Lancet. 20043632022-31.
78
VALUE Clinical implications
Valsartan Antihypertensive Long-term Use
Evaluation
No difference in primary outcome between
treatment groups Unequal reductions in BP might
account for differences between groups in
cause-specific outcomes
Rapid BP control in hypertensive patients at
high CVD risk is essential
Adapted from Julius S et al. Lancet.
20043632022-31.
79
CAMELOT Trial of BP reduction with ACEI or CCB
in CAD patients without HF
Comparison of AMlodipine vs Enalapril to Limit
Occurrences of Thrombosis
Study design Randomized, double-blind,
multicenter, 24-month trial in patients with
angiographically documented CAD, LVEF 40, and
no HF (N 1991) Treatment Amlodipine (10 mg),
enalapril (20 mg), or placebo added to
background therapy with ?-blockers and/or
diuretics Primary outcome Incidence of CV
events for amlodipine vs placebo IVUS
substudy Measurement of atherosclerosis
progression using IVUS (n 274) Outcome Change
in percentage of atheroma volume
Nissen SE et al. JAMA. 20042922217-26.
80
CAMELOT Reduction in primary outcome with
amlodipine and enalapril
Comparison of AMlodipine vs Enalapril to Limit
Occurrences of Thrombosis
0.25
HR (95 CI) A vs P 0.69 (0.540.88) E vs P 0.85
(0.671.07) A vs E 0.81 (0.631.04)
P 0.16
0.20
P 0.003
P 0.1
0.15
Cumulative CV events (proportion)
Placebo
0.10
Enalapril
Amlodipine
0.05
0
0
18
24
6
12
Follow-up (months)
No. at risk No. at risk No. at risk No. at risk No. at risk No. at risk No. at risk No. at risk
Placebo 655 588 558 525 488
Enalapril 673 608 572 553 529
Amlodipine 663 623 599 574 535
Nissen SE et al. JAMA. 20042922217-26.
Incidence of CV events
81
CAMELOT Clinical implications
Comparison of AMlodipine vs Enalapril to Limit
Occurrences of Thrombosis
  • Optimal SBP levels in CAD patients 120 mm Hg
  • Regression of CAD suggested with SBP reduction
    gt10 mm Hg
  • Hemodynamic effects may also modulate clinical
    outcome
  • Increasing evidence to support the following
    strategies Combinations of drugs with
    differing modes of action Lower BP targets in
    special populations

Pepine CJ. JAMA. 20042922271-3.
82
CV pharmacotherapy Impact on newly diagnosed
diabetes
STOP-2
INSIGHT
ALLHAT
INVEST
ALPINE
SCOPE
CHARM
ANBP2
LIFE
HOPE
ALLHAT
CAPPP
STOP-2
VALUE
PEACE
ASCOT
0
10
20
Reduction of new diabetes ()
30
ACEI or ARB
CA ACEI or ARB
100
CA
Pepine CJ and Cooper-DeHoff RM. J Am Coll
Cardiol. 200444509-12.Sever PS et al. Lancet.
20033611149-58.
Randomized active treatment vs control (eg,
placebo, diuretic, ß-blocker ? diuretic)
83
Improving time to benefit in clinical outcomes
studies
84
PROactive Study design
PROspective pioglitAzone Clinical Trial In
macroVascular Events
Objective Assess the effects of pioglitazone
on reducing macrovascular events in type 2
diabetes Design Randomized, double-blind,
placebo-controlled Population N 5238 with
type 2 diabetes and history of macrovascular
disease Treatment Pioglitazone (up to 45 mg)
or placebo Primary outcome Composite of
all-cause mortality, MI, ACS,coronary or
peripheral revascularization, amputation,
stroke Secondary outcomes Individual components
of primary outcome, CV mortality Follow-up 4
years
Dormandy JA et al. Lancet. 20053661279-89. Charb
onnel B et al. Diabetes Care. 2004271647-53.
85
PROactive Reduction in primary outcome
25
10 RRR HR 0.90 (95 CI 0.801.02)P 0.095
20
Placebo(572 events)
Pioglitazone(514 events)
15
Proportionof events()
10
5
0
6
0
12
18
24
30
36
Time from randomization (months)
Number at risk
Pioglitazone
2488
2373
2302
2218
2146
348
Placebo
2530
2413
2317
2215
2122
345
All-cause mortality, MI, ACS, coronary or
peripheral revascularization, amputation,
strokeUnadjusted
Dormandy JA et al. Lancet. 20053661279-89.
86
PROactive Reduction in secondary outcome
25
20
Placebo(358 events)
16 RRR HR 0.84 (95 CI 0.720.98)P 0.027
15
Proportionof events()
10
Pioglitazone(301 events)
5
0
6
0
12
18
24
30
36
Time from randomization (months)
Number at risk
Pioglitazone
2536
2487
2435
2381
2336
396
Placebo
2566
2504
2442
2371
2315
390
All-cause death, MI (excluding silent MI),
stroke Unadjusted
Dormandy JA et al. Lancet. 20053661279-89.
87
PROactive Clinical implications
  • Pioglitazone added to standard antidiabetic and
    CV therapies showed
  • 10 RRR in primary outcome Composite
    all-cause mortality, nonfatal MI (including
    silent MI), stroke, ACS, leg amputation,
    coronary or leg revascularization
  • 16 RRR in secondary outcome All-cause
    mortality, nonfatal MI (excluding silent MI) or
    stroke
  • No difference between groups in HF mortality
  • Continued divergence in survival
    curves Greater benefit with longer treatment
    duration hypothesized

PROactive results support use of PPAR? modulator
in patients with diabetes at high CVD risk May
improve CVD outcomes and decrease need to start
insulin
Dormandy JA et al. Lancet. 20053661279-89.
88
Multifactorial approaches in CVD prevention
89
Potential benefits of multifactorial approaches
Adherence to multiple therapies is more likely
if initiated simultaneously
Early aggressive therapy targeting multiple risk
factors could potentially have a major impact on
CVD prevention
Chapman RH et al. Arch Intern Med.
20051651147-1152. Wald NJ and Law MR. BMJ.
20033261419.
90
ABCs of CVD prevention
A AspirinACE inhibitionA1C control
B BP control/?-blockade
C Cholesterol lowering
D Diet Dont smoke ? Risk of new-onset diabetes
E Exercise
Adapted from Cohen JD. Lancet. 2001357972-3.
91
Steno-2 supports aggressive multifactorial
intervention in type 2 diabetes
  • Objective Target-driven, long-term, intensified
    intervention aimed at multiple risk factors
    compared with conventional therapy
  • N 160 patients with type 2 diabetes and
    microalbuminuria
  • Intensive treatment targets
  • BP lt130/80 mm Hg
  • A1C lt6.5
  • Total-C lt175 mg/dL
  • Triglycerides lt150 mg/dL

Gæde P et al. N Engl J Med. 2003348383-93.
92
Steno-2 Effects of multifactorial intervention
on macrovascular outcomes
60
Conventional (n 80)
53 RRR HR 0.47 (95 CI 0.240.73) P lt 0.01
Longer durationof therapy mayresult in ? benefit
40
Primarycompositeoutcome ()
20
Intensive (n 80)
0
12
36
48
96
24
84
72
60
0
Follow-up (months)
CV death, MI, stroke, revascularization,
amputationUnadjusted Total fat intake lt30,
gt30 min exercise 35x weekly, ACE inhibitor,
aspirin, BP lt130/80 mm Hg, total-C lt175 mg/dL,
TG lt150mg/dL, A1C lt6.5
Gæde P et al. N Engl J Med. 2003348383-93.
93
Majority of Americans do not follow a healthy
lifestyle
2000 Behavioral Risk Factor Surveillance System,
N 153,805
100
77.8
76.7
80
59.9
60
Respondents ()
40
24.0
20
0
Smokers
BMI 25 kg/m2
Consumes fruits/vegetables lt5x/day
Infrequentexercise(lt5x/week)
Reeves MJ and Rafferty AP. Arch Intern Med.
2005165854-7.
94
Only 1 in 3 patients adherent to preventive
therapy after 6 months
N 8406 managed-care enrollees receiving
antihypertensive and lipid-lowering medications
50
44.7
40
35.9
Concomitant antihypertensive andlipid-lowering
therapy ? pill burden and may ? adherence
Patientsadherent to both medications ()
30
20
10
0
3
6
Time from initiation of therapy (months)
Chapman RH et al. Arch Intern Med.
20051651147-52.
95
Combination drugs for treatment of hypertension,
dyslipidemia, and diabetes
Combination product
Condition
  • Antihypertensive/diuretic
  • Benazepril/amlodipine
  • Trandolapril/verapamil

Hypertension
  • Ezetimibe/simvastatin
  • Lovastatin/niacin

Dyslipidemia
  • Metformin/glipizide
  • Metformin/glyburide
  • Pioglitazone/metformin
  • Rosiglitazone/metformin

Diabetes
  • Amlodipine/atorvastatin

Hypertension/dyslipidemia
Numerous combinations
96
Gemini More than 55 of patients achieved both
BP and LDL-C goals
Amlodipine/Atorvastatin Gemini Study N 1220,
14 weeks with amlodipine/atorvastatin single-pill
therapy
90
82.1
65.5
70
57.7
Patients()
50
30
10
0
LDL-C goal(NCEP ATP III)
BP goal(JNC VI)
Both LDL-Cand BP goals
Expert Panel. NCEP ATP III. JAMA.
20012852486-97. JNC VI. Arch Intern Med.
19971572413-46. Blank R et al. J Clin
Hypertens. 20057264-73.
97
More patients at BP goal with fixed-dose
combination vs conventional strategy
N 214 with type 2 diabetes and hypertension, BP
lt130/85 mm Hg
100
80
63
Data support fixed-dose combination therapy in
high-risk patients
56
Subjects()
60
50
40
37
35
40
29
24
20
19
15
20
10
0
2
4
6
8
10
12
Time from randomization (weeks)
Amlodipine/benazepril 5/105/20 mg/d ? HCTZ 12.5
mg/d
Enalapril 1020 mg/d ? HCTZ 12.5 mg/d
Adjunctive HCTZ required in 44 of fixed-dose
combination and 61 of conventional strategy
Bakris GL and Weir MR. J Clin Hypertens.
20035202-9.
98
New paradigm of multiple risk factormanagement
The future of drug therapy belongs to prevention,
which is just now being addressed, and to
intensive management of all cardiovascular risk
factors, in particular, dyslipidemia
Kaplan NM. Hypertension. 200546257-8.
99
ALLHAT Design
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trialand ALLHATLipid-Loweri
ng Trial
N 42,418 stage 1/2 hypertension gt1 CV risk
factor
ALLHAT
Doxazosin28 mg/dn 9061
Chlorthalidone12.525 mg/dn 15,255
Amlodipine2.510 mg/dn 9048
Lisinopril1040 mg/dn 9054
Step 1 titration
Step 2 open-label atenolol 25100 mg/d,
clonidine 0.10.3 mg bid, reserpine 0.050.2 mg/d
Step 3 open-label hydralazine 25100 mg bid
N 10,355 CHD, LDL-C 100 to 129 mg/dL or no
CHD, LDL-C 120 to 189 mg/dL
ALLHAT-LLT
Pravastatin 40 mg/d (n 5170)
Usual care (n 5185)
ALLHAT Collaborative Research Group. JAMA.
20022882981-2997, 2998-3007.
Arm discontinued
100
ALLHAT Primary outcome Fatal coronary disease
or nonfatal MI
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial
N 33,357
20
16
12
Cumulativeevent rate
8
4
0
0
1
2
5
6
7
3
4
Time to event (years)
Chlorthalidone
Amlodipine
Lisinopril
ALLHAT Collaborative Research Group. JAMA.
20022882891-97.
101
ALLHAT-LLT Effects of statin or usual care on
outcomes
N 10,355 with treated hypertension, baseline
LDL-C 120189 mg/dL (no CHD) or LDL-C 100129
mg/dL (CHD)
At 4 yrs, LDL-C ? by 28 (statin) and 11 (usual
care)
All-cause mortality
CHD death nonfatal MI
RR 0.99(95 CI, 0.891.11)
RR 0.91(95 CI, 0.791.04)
Cumulativerate()
Time to death (years)
Time to event (years)
Usual care
Pravastatin
ALLHAT Collaborative Research Group. JAMA.
20022882998-3007.
102
ALLHAT Clinical implications
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial
  • BP-lowering trial
  • Diuretic, ACEI, CCB equivalent in ? CHD death
    and MI
  • Lipid-lowering trial (ALLHAT-LLT)
  • Statin, usual care equivalent in ? all-cause
    mortality
  • Modest differential in on-treatment cholesterol
    levels may have contributed to result

ALLHAT BP results support importance of BP
lowering, regardless of drug class
usedALLHAT-LLT results are consistent with
other statin trials
ALLHAT Collaborative Research Group. JAMA.
20022882981-97, 2998-3007.
103
New paradigms in clinical data supporting
aggressive therapy
  • INternational VErapamil SR/Trandolapril
  • Anglo-Scandinavian Cardiac Outcomes Trial
  • Blood Pressure Lowering Arm

Newer
INVEST Verapamil SR- based
regimen ASCOT-BPLA Amlodipine-
based regimen
Risk factor modification
Older
INVEST Atenolol-based
regimen ASCOT-BPLA Atenolol-
based regimen
Pepine CJ et al. JAMA. 20032902805-16. Dahlöf
B et al. Lancet. 2005366895-906.
Verapamil SR 120480 mg trandolapril 0.58 mg
HCTZ 12.5100 mg Amlodipine 510 mg
perindopril 48 mg Atenolol 25200 mg
trandolapril 0.58 mg HCTZ 12.5100
mg Atenolol 50100 mg bendroflumethiazide
1.252.5 mg potassium
104
INVEST Assessment of combination regimens in
hypertension CAD
INternational VErapamil SR/Trandolapril
Population 22,576 patients ?50 years of age with
hypertension and CAD Treatment Verapamil SR
120480 mg trandolapril 0.5-8 mg HCTZ
12.5100 mg Atenolol 25200 mg trandolapril
0.58 mg HCTZ 12.5100 mg Primary
outcome All-cause death, stroke, MI Secondary
outcomes Individual components of primary
outcome Follow-up 2.7 years
Pepine CJ et al. JAMA. 20032902805-16.
105
INVEST Comparable effects of treatments on BP
INternational VErapamil SR/Trandolapril
N 22,576 with hypertension and CAD
180
Systolic Blood Pressure
160
Level,mm Hg
140
120
110
Diastolic Blood Pressure
100
Level,mm Hg
80
60
Time (months)
CCB strategy
Non-CCB strategy
Pepine CJ et al. JAMA. 20032902805-16.
106
INVEST Comparable effects of treatments on
primary outcome
INternational VErapamil SR/Trandolapril
N 22,576 with hypertension and CAD
All-cause death, stroke, MI
Cumulative
Similar results observed for all-cause
mortality, CV death, CV hospitalization, and BP
control
Time (months)
CCB strategy
Non-CCB strategy
Pepine CJ et al. JAMA. 20032902805-16.
107
INVEST Clinical implications
INternational VErapamil SR/Trandolapril
  • In patients with hypertension and clinically
    stable CAD
  • 70 of both treatment groups achieved BP lt140/90
    mm Hg
  • CCB ACEI was equivalent to ?-blocker diuretic
    in preventing death, MI, or stroke
  • Relative risk reduction of 15 for newly
    diagnosed diabetes in the CCB ACEI treatment
    group

INVEST demonstrates that BP targets can be
achieved in the majority of hypertensive
patients with CAD using a multidrug strategy
Pepine CJ et al. JAMA. 20032902805-16.
108
ASCOT Rationale
  • High prevalence of dyslipidemia in hypertensive
    patients
  • No trial specifically addressing benefits of
    lipid lowering in primary prevention of CHD in
    hypertensive patients not conventionally deemed
    dyslipidemic
  • Less-than-expected CHD prevention using standard
    BP-lowering therapy
  • Insufficient outcome data on newer types of
    BP-lowering agents, especially in specific
    combination treatment regimens
  • Combination risk factors synergistically cause CHD

109
ASCOT Design
Anglo-Scandinavian Cardiac Outcomes Trial
BP 160/100 mm Hg (untreated) BP 140/90 mm Hg
(treated)
Randomized, open-label, blinded outcome
Amlodipine 510 mg perindopril 48 mg
Atenolol 50100 mg bendroflumethiazide
1.252.5 mg
Randomized, double blind
Total-C 250 mg/dL
Atorvastatin 10 mg
Placebo
Sever PS et al. J Hypertens. 2001191139-47.
Plus K supplement if needed
110
ASCOT Patient population risk factor profile
All patients had hypertension plus 3 CHD risk
factors
Hypertension Aged 55 years Male Microalbuminuria/
proteinuria Smoker Family history of CHD Plasma
TCHDL-C 6 Type 2 diabetes Certain ECG
abnormalities LVH Prior cerebrovascular
events Peripheral vascular disease
0
10
20
30
40
50
60
70
80
90
100
Patients with risk factor ()
Sever PS et al. Lancet. 20033611149-58.
LVH left ventricular hypertrophy
111
ASCOT-BPLA Study design
Anglo-Scandinavian Cardiac Outcomes Trial Blood
Pressure Lowering Arm
Design Double-blind, placebo controlled,
randomized Population N 19,257 with
hypertension and 3 other CV risk
factors Treatment Amlodipine 510 mg
perindopril 48 mg prn (n 9639) Atenolol
50100 mg bendroflumethiazide 1.252.5
mg/potassium prn (n 9618) Primary
outcome Nonfatal MI (including silent MI) and
fatal CHD Secondary outcome All-cause
mortality, stroke, nonfatal MI (excluding silent
MI), all coronary events, CV events/procedures,
CV mortality, fatal/nonfatal HF
Dahlöf B et al. Lancet. 2005366895-906.
112
ASCOT-BPLA Reductions in BP over time
Anglo-Scandinavian Cardiac Outcomes Trial Blood
Pressure Lowering Arm
N 19,257
180
160
BP
Systolic BP
137.7 136.1
140
Blood pressure(mm Hg)
Mean difference 2.7, P lt 0.0001
120
Diastolic BP
100
79.2 77.4
80
Mean difference 1.9, P lt 0.0001
60
0
2.0
4.0
Final visit (mean 5.7 SD 0.6, range 4.67.3)
1.0
3.0
5.0
0
Time (years)
Atenolol 50100 mg bendroflumethiazide 1.252.5
mg/potassium prn
Amlodipine 510 mg perindopril 48 mg prn
Dahlöf B et al. Lancet. 2005366895-906.
113
ASCOT-BPLA Reduction in primary outcome
(nonfatal MI and fatal CHD)
Anglo-Scandinavian Cardiac Outcomes Trial Blood
Pressure Lowering Arm
N 19,257
10
8
RRR 10 HR 0.90 (95 CI, 0.791.02) P
0.1052
6
Proportionof events ()
4
Atenolol-based regimen
2
Amlodipine-based regimen
0
1
2
3
4
5
6
0
Time since randomization (years)
Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium Amlodipine 510 mg
perindopril 48 mg
Dahlöf B et al. Lancet. 2005366895-906.
114
ASCOT-BPLA Reduction in fatal and nonfatal
stroke
RRR 23 HR 0.77 (95 CI, 0.660.89) P
0.0003
Proportionof events ()
6
1
2
3
4
5
0
Time (years)
Atenolol-based regimen
Amlodipine-based regimen
Amlodipine 510 mg perindopril 48
mg Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium
Dahlöf B et al. Lancet. 2005366895-906.
115
ASCOT-BPLA Additional reductions with
amlodipine-based regimen
Rate/1000 patient-years
Amlodipine-based(n 9639)
Atenolol-based (n 9618)
lt0.05 lt0.01 lt0.0001 lt0.05 0.001
lt0.001 NS lt0.0001 lt0.05
Secondary endpoints Nonfatal MI (excluding
silent) 7.4 8.5 fatal CHD Total coronary
endpoint 14.6 16.8 Total CV events and
procedures 27.4 32.8 All-cause
mortality 13.9 15.5 CV mortality 4.9 6.5
Fatal/nonfatal stroke 6.2 8.1
Fatal/nonfatal HF 2.5 3.0 Tertiary
endpoints Development of diabetes 11.0 15.9
Development of renal impairment 7.7 9.1
Amlodipine-based better
Atenolol-based better
P
0.50
0.70
1.00
1.45
2.00
Amlodipine 510 mg perindopril 48
mg Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium
Unadjusted hazard ratio
Dahlöf B et al. Lancet. 2005366895-906.
116
ASCOT-BPLA New-onset diabetes
10
RRR 30 HR 0.70 (95 CI, 0.630.78)P lt 0.0001
8
6
Atenolol-based regimen
Proportionof events()
4
Amlodipine-based regimen
2
0
1
2
3
4
5
6
0
Time since randomization (years)
Number at risk
Amlodipine-based regimen(567 events)
9383
9165
8966
8726
7618
9639
Atenolol-based regimen(799 events)
9295
9014
8735
8455
7319
9618
Dahlöf B et al. Lancet. 2005366895-906.
117
ASCOT-LLA Assessing lipid lowering in
hypertensive patients
Anglo-Scandinavian Cardiac Outcomes Trial Lipid
Lowering Arm
Design 10,305 ASCOT patients with mean baseline
LDL-C 133 mg/dL and 3 other risk
factors Treatment Randomized to atorvastatin 10
mg or placebo Primary outcome Nonfatal MI and
fatal CHD Secondary outcomes Total CV
events/procedures, total coronary events,
all-cause mortality, CV mortality, stroke,
HF Follow-up 5 years
Sever PS et al. Lancet. 20033611149-58.
118
ASCOT-LLA Atorvastatin reduces primary outcome
in hypertensive patients

Anglo-Scandinavian Cardiac Outcomes Trial Lipid
Lowering Arm
N 10,305, baseline LDL-C 133 mg/dL
4
Placebo
RRR 36HR 0.64 (95 CI, 0.500.83) P
0.0005
3
Patients ()
2
Atorvastatin
1
0
0
1.0
1.5
3.0
3.5
2.0
2.5
0.5
Follow-up (years)
Nonfatal MI and fatal CHD
Sever PS et al. Lancet. 20033611149-58.
119
ASCOT-LLA Time to benefit post hoc
analysisCardiac events
Anglo-Scandinavian Cardiac Outcomes Trial Lipid
Lowering Arm
Event rate
Atorvastatinbetter
Placebobetter
RRR ()
Censoring time
Atorvastatin
Placebo
30 days 90 days 180 days 1 year 2 years End of
study
83 2.4 14.2 67 5.5 16.6 48 7.5 14.3 45 6.6 12.
0 38 5.9 9.5 36 6.0 9.4
0
0.5
1.0
1.5
2.0
Hazard ratio
Per 1000 patient-years
Sever PS et al. Am J Cardiol. 200596(suppl)39F-4
4F.
120
ASCOT-LLA subanalysis Atorvastatin reduces CV
events in patients with diabetes and hypertension
Anglo-Scandinavian Cardiac Outcomes Trial Lipid
Lowering Arm
N 2532, baseline LDL-C 128 mg/dL
14
Placebo
RRR 23 HR 0.77 (95 CI, 0.610.98) P
0.036
12
10
CV events/procedures,cumulative events ()
8
6
Atorvastatin
4
2
0
0.5
0
1.0
1.5
2.0
2.5
3.0
3.5
Follow-up (years)
Nonfatal MI, CV mortality, UA, stable angina,
arrhythmias, stroke, TIA, PAD, retinal vascular
thrombosis, revascularization
Sever PS et al. Diabetes Care. 2005281151-7.
121
ASCOT Differing effect of statin added to
?-blockerbased or CCB-based therapy
CV events and procedures
NS
P 0.079
P 0.001
3
5
3
1
.
7
3
0
2
9
.
4
2
5
2
7
.
0
Events/1000patient-years
2
0
2
1
.
3
1
5
1
0
5
-

A
t
o
r
v
a
s
t
a
t
i
View by Category
About This Presentation
Title:

New Frontiers in CVD Risk Management: Optimizing Outcomes in Patients with Multiple Cardiovascular Risks

Description:

New Frontiers in CVD Risk Management: Optimizing Outcomes in Patients with Multiple Cardiovascular Risks – PowerPoint PPT presentation

Number of Views:171
Avg rating:3.0/5.0
Slides: 126
Provided by: MEDCON
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: New Frontiers in CVD Risk Management: Optimizing Outcomes in Patients with Multiple Cardiovascular Risks


1
New Frontiers in CVD Risk ManagementOptimizing
Outcomes in Patients with Multiple Cardiovascular
Risks
2
US population at high risk
Hypercholesterolemia
Hypertension
Diabetes
  • 14.6 million diagnosed
  • 6.2 million undiagnosed
  • 65 million
  • 27 million not treated
  • 106.9 million
  • 94 million not treated

Patients with CHD/stroke 18.4 million/y Direct
105.7 billion/y Indirect 93.2 billion/y
Total cost 198.9 billion/y
AHA. Heart Disease and Stroke Statistics2005
Update. Hajjar I and Kotchen TA. JAMA.
2003290199-206. Ford ES et al. Circulation.
20031072185-9.CDC. www.cdc.gov/diabetes/pubs/pd
f/ndfs_2005.pdf.
Total-C 200 mg/dL BP 140/90 mm Hg FBG 126
mg/dL
3
Development and progression of CVD

Age, gender, smoking, inactivity,
obesity, cholesterol, BP, glucose
Risk factors
? Oxidative stress
? Endothelial function? EPCs
Genetic factors
Functional alterations
Structural alterations
Clinical sequelae
EPCs endothelial progenitor cells
Adapted from Pepine CJ. Am J Cardiol.
200188(suppl)5K-9K.
4
Genetics augment effects of environmental risk
factors
ENVIRONMENT
Inactivity Diet Psychosocial Stress
Culture
Obesity
Hypertension
Diabetes
GENES
GENES
Inadequate Medical Care
STROKE / MI
GENES
5
Cardiovascular risk factors, adults 5564 years
Men
19881994
Hypertension
19992002
Obesity
High cholesterol
One or more risk factors
Women
Hypertension
Obesity
High cholesterol
One or more risk factors
0
20
40
60
80
100
Prevalence ()
CDC. www.cdc.gov/nchs/ppt/hus/HUS2005.ppt.
6
Synergistic interaction of traditional multiple
risk factors on CVD risk
SBP (mm Hg)
50
44
110
150
120
160
40
130
170
33
5-year CVD risk per 100 people
140
180
30
24
18
20
12
10
6
3
lt1
0
Reference
TC 270 mg/dL
Smoker
HDL 39 mg/dL
Male
Diabetes
60 yearsof age
Additive risk factors
Jackson R et al. Lancet. 2005365434-41.
TC total cholesterol
7
Obesity decreases life expectancy regardless of
smoking
Framingham Heart Study
Female smokers
Female nonsmokers
1.0
1.0
0.8
0.8

0.6
Proportionalive
0.6
0.4
0.4
0.2
0.2
0.0
0.0
0
10
20
30
40
0
10
20
30
40
Follow-up (years)
Follow-up (years)
Obesity and smoking risks are equivalent
Peeters A et al. Ann Intern Med 200313824-32.
8
Decline in smoking vs rise in obesity A
trade-off?
Smoking rate
0.4
0.35
0.3
0.25
Proportionof population
0.2
0.15
0.1
Obesity rate
0.05
0
1970
1974
1978
1982
1986
1990
1994
1998
2002
Year
Gruber J and Frakes M. J Health Econ. Published
online ahead of print. www.sciencedirect.com.
9
Development and progression of CVD
Risk factors
? Oxidative stress
? Endothelial function? EPCs
Functional alterations
Structural alterations
Clinical sequelae
Adapted from Pepine CJ. Am J Cardiol.
200188(suppl)5K-9K.
EPCs endothelial progenitor cells
10
Traditional CVD risk factors
  • Family history
  • Older age
  • Male gender
  • Smoking
  • Physical inactivity
  • Overweight/obesity
  • Total-C/LDL-C/HDL-C/TG
  • BP
  • Glucose

Adapted from Stampfer MJ et al. Circulation.
2004109(suppl)IV3-IV5.
11
Selected emerging biomarkers
Lipids Lp(a) apoA/apoB Particle size/density
Inflammation CRP SAA IL-6 IL-18
TNF Adhesion mols Lp-PLA2 CD40L CSF
Hemostasis/Thrombosis Homocysteine tPA/PAI-1
TAFI Fibrinogen D-dimer
CSF colony-stimulating factor
MPO myeloperoxidase
Adapted from Stampfer MJ et al. Circulation.
2004109(suppl)IV3-IV5.
TAFI thrombin activatable fibrinolysis inhibitor
12
LDL infiltration triggers inflammatory response
Coronaryartery
Endothelium
LDL
Activation
Accumulation of cholesterol
Uptake
Macrophage
Modification
Retention
Hansson GK. N Engl J Med. 20053521685-95.
13
Role of ox-LDL in macrophage recruitment
Coronaryartery
Endothelium
Migration
Adhesion
Monocyte
Inflammation. tissue damage
Differentiation
Endotoxins,heat-shock proteins, oxidized LDL,
others
Macrophage
Toll-likereceptor
Inflammatory cytokines, chemokines,
proteases,radicals
Hansson GK. N Engl J Med. 20053521685-95.
14
Hypertension increases atherogenic lipoprotein
content of arterial vessel walls
Atherogenic VLDL, VLDL-R,IDL, LDL
BP
Pressure-driven convection
Intima- Enhanced LP penetration media
LP retention
Pressure-induced distension
Stretching
Intima- media
LP lipoprotein
Sposito AC. Eur Heart J Suppl. 20046(suppl
G)G8-G12.
15
AT1 and LOX-1 receptor cross-talk promotes
adhesion molecule expression
Interaction between RAAS and dyslipidemia
Monocyte adhesion
LOX-1
EC
?
?NO
Oxygen
AT1R
?
Angiotensin II LDL Oxidation Cytokines
Platelet Aggregation Monocyte Adhesion
Angiotensin II
?
Growth Factors
?
?
Ox-LDL
Fibroblasts
?
LDL
Smooth Muscle Cells













SRs scavenger receptors
Adapted from Singh BM and Mehta JL. Arch Intern
Med. 20031631296-304.
EC endothelial cell
16
Lipoprotein-associated phospholipase A2 (Lp-PLA2)
Produced by inflammatory cells
  • Hydrolyzes oxidized phospholipids to generate
  • proinflammatory molecules
  • Lysophosphatidylcholine
  • Oxidized fatty acids

Upregulated in atherosclerotic lesions where it
co-localizes with macrophages
Macphee CH et al. Curr Opin Lipidol.
200516442-6.
17
Studies demonstrating association of Lp-PLA2
with incident CHD
Findings
Subjects
Study
RR 1.18 (1.05-1.33) per 1 SD ?
WOSCOPS subgroup LDL-C 174232 mg/dL 580 cases,
1160 controls
Packard et al
HR 1.78 (1.33-2.38)tertile 3 vs tertile 1
General population 608 cases, 740 controls
Ballantyne et al
HR 1.23 (1.02-1.47) per 1 SD ?
General population 97 cases, 837 controls
Koenig et al
HR 1.97 (1.28-3.02)4th vs 1st quartile
General population 418 cases, 1820 controls
Oei et al
Packard CJ et al. N Engl J Med.
20003431148-55.Ballantyne CM et al.
Circulation. 2004109837-42.Koenig W et al.
Circulation. 20041101903-8.Oei H-HS et al.
Circulation. 2005111570-5.
Adjusted relative risk (RR) or hazard ratio (HR)
18
EPC number/function correlates with endothelial
function
N 45 healthy males, mean age 50.3 y, no CVD
3
0
2
0
EPCs(colony-formingunits)
1
0
0
L
o
w
M
i
d
H
i
g
h
Flow-mediated dilation
Hill JM et al. N Engl J Med. 2003348593-600.
EPCs endothelial progenitor cells
19
EPC number has prognostic importance
N 507 males with CAD, mean age 66 y
1.00
Group 3 (high EPC level)
0.98
Group 2 (medium EPC level)
Event- free survival (CV mortality)
0.96
0.94
Group 1 (low EPC level)
0.92
P 0.01
0.90
0
100
200
300
365
0
Follow-up (days)
Werner N et al. N Engl J Med. 2005353999-1007.
EPC endothelial progenitor cell
20
Arterial stiffness Cause and consequence of
atherosclerosis
Endothelial damage mechanical fatigue
?Pulsepressure
?Sympathetic modulation
?Central wave reflection
Atherosclerosis
?Large arterystiffness
Adapted from Dart AM and Kingwell BA. J Am Coll
Cardiol. 200137975-84.
21
Correlation between number of risk factors and
arterial distensibility
N 803, mean age 30 y
7.5
Linear trend P lt 0.0001
? Brachial artery distensibility occurs long
before clinical manifestations of CVD appear
7
Brachial artery distensibility(? / mm Hg)
6.5
6
5.5
0
3
1
4
2
5
Number of CV risk factors
Urbina EM et al. Am J Hypertens. 200518767-71.
Bogalusa Heart Study
22
Peripheral arterial stiffness is associated with
subclinical atherosclerosis
N 256
50
P lt 0.0001 for trend
40
30
Thigh arterial compliance
20
10
0
Q1
Q3
Q2
Q4
MRI resultsQuartile of abdominal aorta wall
thickening
Maximum volume change
X 50
Herrington DM et al. Circulation. 2004110432-7.
Brachial pulse pressure
23
Pleiotropic effects of statins
? Coagulation
? Endothelial progenitor cells
? Platelet activation
? Endothelial function
? Effects on collagen
? NO bioactivity
Statins
? Reactive oxygen species
? MMPs
? AT1 receptor
? VSMC proliferation
? Macrophages
? Inflammation
? Immunomodulation
? Endothelin
Liao JK. Am J Cardiol. 200596(suppl 1)24F-33F.
MMPs matrix metalloproteinases
24
High-dose statin treatment reduces Ox-LDL markers
MIRACL study subgroup analysis, N 2341 with
ACS, atorvastatin 80 mg for 16 weeks
Mean
95 CI
ApoB-100
Atorvastatin
33.0 34.2, 31.8
Placebo
5.8 4.6, 7.0
Total apoB-OxPL
Atorvastatin
29.7 31.5, 28.0
Placebo
0.2 2.3, 1.9
Total apoB-IC IgG
Atorvastatin
29.5 31.9, 27.0
Placebo
2.1 1.1, 5.4
Total apoB-IC IgM
Atorvastatin
25.7 28.1, 23.3
Placebo
13.2 9.3, 17.3
40
20
0
20
40
change
OxPL oxidized phospholipids IC-IgG, -IgM
immune complexes with IgG and IgM,
respectively Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering
Tsimikas S et al. Circulation. 20041101406-12.
25
Statin treatment reduces Lp-PLA2
100
87.1
73.5
80
62.2
60
Plasma Lp-PLA2 activity(nmol x mL-1 x min-1)
42.3
40
20
0
Type IIA dyslipidemia (n 55)
Type IIB dyslipidemia(n 21)
Atorvastatin 20 mg, 4 mos
Baseline
Tsimihodimos V et al. Arterioscler Thromb Vasc
Biol. 200222306-11.
P lt 0.001 vs baseline
26
Statins increase circulating EPCs
N 15 with CAD treated with atorvastatin 40 mg
for 4 weeks
700

600

500
  • Postulated mechanism
  • Activation of
  • PI3-K/Akt pathway
  • Endothelial NO synthase

EPCs(cells/mm2)
400

300
200
100
n 13
n 12
n 14
n 12
n 15
0
0
7
14
21
28
Treatment (days)
Vasa M et al. Circulation. 20011032885-90. Liao
JK. Am J Cardiol. 200596(suppl)24F-33F.
P lt 0.05 vs baseline
27
Intensive lipid lowering improves arterial
compliance
N 22 with ISH treated with atorvastatin 80 mg
for 3 months
P 0.03
0.5
Systemic arterial compliance (mL/mm Hg)
0.4
0.3
0.0
Placebo
Atorvastatin
Ferrier KE et al. J Am Coll Cardiol.
2002391020-5.
28
Comparative effects of statin and ezetimibe on
EPCs and endogenous antioxidant system
N 20 with HF treated with simvastatin 10 mg or
ezetimibe 10 mg for 4 weeks
Extracellular superoxide dismutase
EPCs
P lt 0.05
NS
P lt 0.05
NS
160
450
120
Number per high power field
Endothelium-bound ecSOD activity
300
80
(U x mL-1 x min-1)
150
40
0
0
Pre
Post
Pre
Post
Pre
Pre
Post
Post
Statin
Ezetimibe
Statin
Ezetimibe
Group
Pre baseline Post 4 weeks
Landmesser U et al. Circulation. 20051112356-63.
29
Neuroprotection with statins in stroke model
Occlusion of middle cerebral artery in rats
Post-treated with statin after occlusion
Pre-treated with statin before occlusion
Vehicle
Simvastatin
24 hrs
24 hrs
48 hrs
48 hrs
Statin effect accompanied by eNOS upregulation in
cerebral blood vessels
Sironi L et al. Arterioscler Thromb Vasc Biol.
200323322-7.
Ischemic areas indicated by arrows
30
Pleiotropic effects of BP-lowering agents
ACEIs/ARBs
CCBs
? Fibrinolysis
? NO
? Mononuclear cell migration
? MMP activity
? Collagen matrix formation
BP-loweringagents
? Endothelial function
? Cholesterol depositionin membrane
AHTNagents
? Plaque stability
? Arterial compliance
Both
? Platelet aggregation
? Oxidative stress
? Inflammation
? VSMC proliferation
Lonn E et al. Eur Heart J Suppl. 20035(suppl
A)A43-A8.Wassman S and Nickenig G. Eur Heart J
Suppl. 20046(suppl H)H3-H9. Mason RP et al.
Arterioscler Thromb Vasc Biol. 2003232155-63.
MMP matrix metalloproteinase
31
Statin metabolite and CCB show additive
antioxidant effect
Human LDL incubated with O-hydroxy metabolite of
atorvastatin (100 nmol/L), lovastatin (100
nmol/L), and amlodipine (2.5 ?mol/L)
50

40
Inhibition of TBARS formation()
30

20
10
0
Atorvastatin metabolite
AmlodipineLovastatin
AmlodipineAtorvastatinmetabolite
TBARS thiobarbituric acid-reactive
substances P lt 0.0001 vs vehicle treatment
Mason RP et al. Am J Cardiol. 200596(suppl)11F-2
3F.
32
Additive effects of statin CCB on fibrinolytic
balance
N 45 with hypertension, placebo-controlled,
crossover trial
P lt 0.05
0.26
? t-PA(U/mL)

0.17

0.08
Change from baseline
0.5
? PAI-1(U/mL)


9.9
10.2
t-PA / PAI-1 ratio 0.045 0.03 0.06
P lt 0.05 vs placebo P lt 0.01 vs placebo
Fogari R et al. Am J Hypertens. 200417823-7.
33
Beneficial effect of statin ACEI on
endothelial function
N 50 with dyslipidemia, placebo-controlled,
crossover trial
P lt 0.001
7
6.58
6.02
6
4.81
5
4.56
Flow-mediateddilation()
4
3
2
1
0
Baseline 1
Sim PL
Baseline 2
Sim Ram
PL placebo Ram ramipril 10 mg Sim
simvastatin 20 mg
Koh KK et al. Hypertension. 200444180-5.
34
Approaches to CVD prevention
35
Lifestyle changes reduce need for drug therapy
N 3234 with IGT randomized to intensive
lifestyle change, metformin 850 mg 2x/d, or
placebo
  • Lifestyle change goals
  • Weight reduction of 7 initial body weight via
    low-fat, low-calorie diet
  • Moderate-intensity physical activity 150
    min/week

Lifestyle Metformin Placebo
At 3 years

31
32
23
BP-lowering agents required

16
16
12
Lipid-lowering agents required
P lt 0.001 vs other groups
Diabetes Prevention Program Research Group.
Diabetes Care. 200528888-94.
36
New lifestyle guidelines More exercise, fruits
and vegetables
2000 Report 2005 Report
Exercise
30 minutes of moderate physical activity 5-7 days/week 30 minutes of moderate physical activity 5-7 days/week 30 minutes of moderately intense exercise every day 60 min to prevent weight gain
5 servings/day 5 servings/day 9 servings/day

Fruits and vegetables
HHS/USDA. www.healthierus.gov/dietaryguidelines.
37
Exercise reduces CV and all-cause mortality
N 9791, moderate exercise vs little or no
exercise NHANES I Epidemiological Follow-up
Survey (1971-1992)
Favors exercise
Favors no exercise
HR
Normal BP
All-cause death
0.75
0.76
CV death
Prehypertension
All-cause death
0.79
0.79
CV death
Hypertension
All-cause death
0.88
CV death
0.84
1.5
1.0
0.5
0
2.0
Hazard ratio
Fang J et al. Am J Hypertens. 200518751-8.
38
Diet reduces mortality in primary prevention
trials
  • 2002
  • Physicians Health Study(N 20,551)
  • 2003
  • Cardiovascular Health Study(N 5,201)
  • 2002
  • Nurses Health Study(N 84,688)
  • 2003
  • European Prospective Investigation into Cancer
    and NutritionGreek cohort (N 22,043)
  • 2005
  • European Prospective Investigation into Cancer
    and Nutritionelderly cohort (N 74,607)

2004 The Healthy Aging A Longitudinal Study in
Europe (N 2339)
Parikh P et al. J Am Coll Cardiol.
2005451379-87. Trichopoulou A et al. BMJ.
2005330991-7. Knoops KTB et al. JAMA.
20042921433-9.
Blood levels of n-3 fatty acids inversely
related to death Greater adherence associated
with lower mortality
39
Potential cardioprotective mechanisms of dietary
components
  • Omega-3 fatty acids
  • Antiarrhythmic
  • Antithrombogenic
  • Antiinflammatory
  • Antihypertensive
  • Improved endothelial function
  • Folic acid
  • Antioxidant
  • ?NO bioavailability
  • Improved endothelial function

Kris-Etherton PM et al. Circulation.
20021062747-57. Verhaar MC et al. Arterioscler
Thromb Vasc Biol. 2002226-13.
40
Non-pharmacologic interventions and BP reduction
Alcohol reduction
Potassiumsupplement
Exercise
Low salt diet
0
1
2
BP decrease(mm Hg)
3
4
5
Adapted from Messerli FH et al. In Griffin BP et
al, eds.2004. Manual of Cardiovascular Medicine.
2nd ed. Whelton SP et al. Ann Intern Med.
2002136493-503.Cutler JA et al. Am J Clin
Nutr. 199765(suppl)643S-651S. Xin X et al.
Hypertension. 2001381112-7.Whelton PK et al.
JAMA. 19972771624-32.
SBP
DBP
41
Benefit of multifactorial interventions
42
Key findings from recent lipid-lowering trials
IDEAL Benefit of
intensive vs moderate lipid lowering in stable
CAD
ASCOT-LLABenefit in high-risk HTN regardless of
baseline LDL-C
CARDSBenefit in DM
ALLHAT-LLTNeutral effect in HTN with mild
lipid lowering
4D Neutral effect in ESRD
2002 2003 2004 2005
HPS Benefit in CVD and DM
regardless of baseline LDL-C
TNTBenefit of intensive vsmoderate lipid
loweringin stable CAD
PROVE IT-TIMI 22 Early and late benefit of
intensive vs moderate lipid lowering in ACS
A to Z Late benefit of intensive vs moderate
lipid lowering in ACS
Primary prevention
Secondary prevention (ACS)
Secondary prevention (stable CAD)
43
PROVE IT-TIMI 22 Assessment of intensive lipid
lowering in ACS
PRavastatin Or AtorVastatin Evaluation and
Infection TherapyThrombolysis In Myocardial
Infarction 22
Design 4162 patients with ACS randomized to
atorvastatin 80 mg or pravastatin 40
mg Follow-up 2 years Primary outcome All-cause
death, MI, hospitalization for UA,
revascularization, stroke
Cannon CP et al. N Engl J Med. 20043501495-504.
44
PROVE IT-TIMI 22 Early benefit with intensive
lipid lowering
PRavastatin Or AtorVastatin Evaluation and
Infection TherapyThrombolysis In Myocardial
Infarction 22
N 4162 with ACS
30
P 0.005
40 mg Pravastatin
20
80 mg Atorvastatin
Death or major CV event ()
P 0.03 at 4 mos
10
0
3
6
9
12
30
15
18
21
24
27
0
Follow-up (months)
Ray KK and Cannon CP Am J Cardiol.
200596(suppl)54F-60F.Adapted from Cannon CP et
al. N Engl J Med. 20043501495-504.
45
PROVE IT-TIMI 22 Benefit at 30 days
PRavastatin Or AtorVastatin Evaluation and
Infection TherapyThrombolysis In Myocardial
Infarction 22
N 4162 with ACS
Event rates ()
Censoring time
Hazard ratio (95 CI)
Risk reduction ()
Atorvastatin
Pravastatin
30 days 90 days 180 days End of follow-up
17 1.9 2.2 18 6.3 7.7 14 12.2 14.1 16 22.4 26.
3
No ? toxicity
High-doseatorvastatinbetter
Standard-dosepravastatinbetter
Cannon CP et al. N Engl J Med. 20043501495-504.
46
PROVE IT-TIMI 22 Evidence for rapid reduction in
markers of inflammation
PRavastatin Or AtorVastatin Evaluation and
Infection TherapyThrombolysis In Myocardial
Infarction 22
N 4162 with ACS
100
P 0.60
Median CRP (mg/L)
10
Pravastatin(n 1873)
P lt 0.001
P lt 0.001
P lt 0.001
Atorvastatin(n 1872)
1
Randomization
30 days
4 months
End of study
Ridker PM et al. N Engl J Med. 200535220-8.
47
PROVE IT-TIMI 22 Clinical implications
PRavastatin Or AtorVastatin Evaluation and
Infection Therapy-Thrombolysis In Myocardial
Infarction 22
  • In patients with recent ACS, aggressive lipid
    lowering was associated with greater clinical
    benefit vs less aggressive lipid lowering
  • 16 RRR in all-cause death, MI, UA,
    revascularization, stroke
  • Benefit evident at 30 days and may be mediated in
    part by anti-inflammatory effect
  • No relationship between achieved LDL-C level and
    risk of adverse events No excess risk even
    at levels 40 mg/dL

PROVE IT-TIMI 22 supports lower LDL-C goal in
patients with ACS
Cannon CP et al. N Engl J Med. 20043501495-504.
Ray KK et al. Am J Cardiol. 200596(suppl)54F-60F
.Ridker PM et al. N Engl J Med.
200535220-8. Wiviott SD et al. J Am Coll
Cardiol. 2005461411-6.
48
A to Z Early initiation of intensive regimen vs
delayed initiation of less-intensive regimen
Aggrastat to Zocor
Population 4497 patients with ACS Treatments Sim
vastatin 40 mg/d for 1 month, followed by 80
mg/d Placebo for 4 months, followed by
simvastatin 20 mg/d Median follow-up 721
days Primary outcome CV death, nonfatal MI, ACS
readmission, stroke
de Lemos JA et al. JAMA. 20042921307-16.
49
A to Z Treatment effect on LDL-C
Aggrastat to Zocor
N 4497 with ACS
140
124
122
112
111
100
81

77



LDL-C(mg/dL)
68
66
63
62
60
20
0
Baseline
1
4
8
24
Time from randomization (months)
Simvastatin 40/80 mg/d
Placebo/simvastatin 20 mg/d
P lt 0.001 vs placebo/simvastatin 20 mg
de Lemos JA et al. JAMA. 20042921307-16.
50
A to Z Treatment effect on CRP
Aggrastat to Zocor
N 4497 with ACS
21
20.4
20.1
6
5
CRP(mg/L)
4
3
2.5
2.4

2.3

1.8
1.7
2
1.5
1
0
Baseline
1
4
8
Time from randomization (months)
Placebo/simvastatin 20 mg/d
Simvastatin 40/80 mg/d
de Lemos JA et al. JAMA. 20042921307-16.
P lt 0.001 vs placebo/simvastatin 20 mg
51
A to Z Treatment effect on primary outcome
Aggrastat to Zocor
N 4497 with ACS
20
11 RRRHR 0.89 (0.76-1.04) P 0.14
15
Cumulativerate ()
11 RRR
10
27 RRRP 0.02
5
0
4
0
8
12
16
20
24
Time from randomization (months)
Simvastatin 40/80 mg/d
Placebo/simvastatin 20 mg/d
de Lemos JA et al. JAMA. 20042921307-16.
CV death, MI, recurrent ACS hospitalization,
stroke
52
A to Z Treatment effect on primary outcome at
different time periods
Aggrastat to Zocor
N 4497 with ACS
Primary composite outcome rate ()
Simvastatin40/80 mgn 2265
Placebo simvastatin 20 mg n 2232
Favorssimvastatin40/80 mg
Favors placebo simvastatin20 mg
Overall study result
14.4
16.7
Randomization through month 4
8.2
8.1
Months 424
6.8
9.3
0.5
1.0
1.5
Hazard ratio (95 CI)
CV death, MI, recurrent ACS hospitalization,
stroke
de Lemos JA et al. JAMA. 20042921307-16.
53
A to Z Clinical implications
Aggrastat to Zocor
  • In patients with recent ACS, early initiation of
    a moderate/high-dose simvastatin regimen vs
    delayed initiation of a low-dose regimen resulted
    in nonsignificant trend toward reduction in major
    CV events
  • 11 RRR in CV death, nonfatal MI, ACS
    readmission, stroke
  • No difference between the treatment groups was
    observed within the first 4 months
  • Findings are consistent with MIRACL and PROVE
    IT-TIMI 22
  • Early benefits may be due to anti-inflammatory
    effects
  • Late benefits may be due to lipid lowering

de Lemos JA et al. JAMA. 20042921307-16. Ray
KK et al. Am J Cardiol. 200596(suppl)54F-60F.
54
TNT Assessment of intensive lipid lowering on
clinical outcomes
Treating to New Targets
Design 10,001 patients with stable CHD and LDL-C
130-250 mg/dL Treatment Randomized to
atorvastatin 10 mg or 80 mg Follow-up 4.9
years Primary outcome CHD death, MI,
resuscitation after cardiac arrest,
fatal/nonfatal stroke
LaRosa JC et al. N Engl J Med. 20053521425-35.
55
TNT Treatment effects on LDL-C
Treating to New Targets
N 10,001
160
140
120
Atorvastatin 10 mg (n 5006)
100
LDL-C (mg/dL)
80
Atorvastatin 80 mg (n 4995)
60
40
20
0
Screening
Final
60
48
36
24
3
0
12
Months
LaRosa JC et al. N Engl J Med. 20053521425-35.
56
TNT Treatment effects on primary outcome
Treating to New Targets
N 10,001
0.15
Atorvastatin 10 mg (n 5006)
22 Risk reductionHR 0.78 (0.690.89) P lt 0.001
0.10
Major CV events ()
0.05
Atorvastatin 80 mg (n 4995)
0.00
6
5
4
2
1
3
0
Follow-up (years)
CHD death, MI, resuscitation after cardiac
arrest, fatal/nonfatal stroke
LaRosa JC et al. N Engl J Med. 20053521425-35.
57
TNT Incidence of elevated liver or muscle
enzymes
Treating to New Targets
N 10,001
Atorvastatin 80 mg ()(n 4995)
Atorvastatin 10 mg ()(n 5006)
ALT and/or AST gt3xULN
0.2
1.2
CK gt10xULN
0
0
4.8
Myalgia
4.7
Rhabdomyolysis
0.04
0.06
P lt 0.001 vs atorvastatin 10 mg ALT alanine
aminotransferaseAST aspartate
aminotransferaseULN upper limit of normal
LaRosa JC et al. N Engl J Med. 20053521425-35.
58
TNT Clinical implications
Treating to New Targets
  • In patients with stable CHD, aggressive lipid
    lowering was associated with greater clinical
    benefit vs less intensive lipid lowering
  • 22 RRR in CHD death, MI, resuscitation after
    cardiac arrest, and fatal/nonfatal stroke

TNT supports lower LDL-C goal in patients with
stable CHD
LaRosa JC et al. N Engl J Med. 200535225-35.
59
Potential factors contributing to early statin
benefit
  • High baseline risk
  • Intensive LDL-C lowering
  • Rapid anti-inflammatory effect

High risk
Rapid
Intensive
Pepine CJ and Selwyn AP. Vasc Biol Clin Pract.
CME Monograph. UF College of Medicine. 20046(2).
60
HPS and CARDS Benefits of lowering LDL-C in
diabetes
Heart Protection Study and Collaborative
AtoRvastatin Diabetes Study
Event rate ()
Statin better
Placebo better
? LDL-C(mg/dL)
Placebo
Statin
P
HPS
34.8
0.73
lt0.0001 0.0003 0.001
12.6 13.5 9.0
9.4 9.3 5.8
All diabetes
0.67
34.8
Diabetes, no CVD
0.63
46.4
CARDS
0.5
0.7
0.9
1
1.7
Relative risk
HPS Collaborative Group. Lancet.
20033612005-16.Colhoun HM et al. Lancet.
2004364685-96.
Statin vs placebo
61
CARDS Adverse events
Placebo (n1410)
Atorvastatin 10 mg (n1428)
Type of Event
No. of events ( of patients with event)
19 (1.1)
20 (1.1)
Serious adverse event (AE)
122 (9)
145 (10)
Discontinued for AE
0
0
Rhabdomyolysis
1 (0.1)
1 (0.1)
Myopathy
17 (1)
14 (1)
ALT 3 ULN
6 (0.4)
4 (0.3)
AST 3 ULN
Judged by attending clinician to be possibly
associated with study drug ALT alanine
transaminase AST aspartate transaminase ULN
upper limit of normal
Colhoun HM et al. Lancet. 2004364685-96.
62
4D Trial Neutral effect of statin in
hemodialysis patients with diabetes
N 1255 randomized to atorvastatin 20 mg or
placebo for 4 years
Fatal stroke ?103 P 0.04
20
?12
10
0
Change
-10
?8
Baseline LDL-C 121 mg/dL
-20
?18
-30
P 0.03
NS
NS
-40
-50
LDL-C
Nonfatal MI
Coronary
Cerebrovasc
CHD death
events
events
Stroke
Wanner C et al. N Engl J Med. 2005353238-48.
Relative risk reduction
63
Statins reduce all-cause death Meta-analysis of
14 trials

Cholesterol Treatment Trialists Collaboration
Cause of death
Events ()
Treatment(n 45,054)
Control(n 45,002)
Treatment better
Controlbetter
Vascular causes
3.4
0.81
4.4
CHD
0.91
Stroke
0.6
0.6
0.95
Other vascular
0.6
0.7
0.93
Any non-CHD vascular
1.2
1.3
Any vascular
4.7
5.7
0.83
Nonvascular causes
2.4
2.4
Cancer
1.01
0.2
0.3
Respiratory
0.82
0.1
0.1
0.89
Trauma
1.1
1.2
0.87
Other/unknown
3.8
4.0
0.95
Any nonvascular
8.5
9.7
0.88
Any death
1.5
1.0
0.5
Relative risk
CTT Collaborators. Lancet. 20053661267-78.
64
Statin benefit independent of baseline lipids
Meta-analysis of 14 trials
Cholesterol Treatment Trialists Collaboration
Events ()
Groups
Treatment(45,054)
Control(45,002)
Treatment better
Control better
Total-C (mg/dL)
13.5
0.76
16.6
201
0.79
gt201251
13.9
17.4
0.80
gt251
15.2
19.7
LDL-C (mg/dL)
0.76
13.4
16.7
135
14.2
17.6
0.79
gt135174
15.8
0.81
20.4
gt174
HDL-C (mg/dL)
22.7
35
0.78
18.2
14.3
18.2
gt3543
0.79
11.4
14.2
0.79
gt43
TG (mg/dL)
13.4
16.8
0.79
124
13.8
18.0
0.78
gt124177
0.80
15.3
18.8
gt177
0.79
Overall
17.8
14.1
1.5
1.0
0.5
Relative risk
CTT Collaborators. Lancet. 20053661267-78.
CHD death, MI, stroke, coronary revascularization
65
HPS Assessing relation of statin benefit to
baseline LDL-C
Heart Protection Study
Population 20,536 patients with total-C ?135
mg/dL and history of diabetes, treated
hypertension, CAD, stroke, or PAD Treatment Rando
mized to simvastatin 40 mg or placebo Primary
outcome Mortality (for overall analysis) and
fatal or non-fatal vascular events (for
subcategory analyses) Follow-up 5 years
HPS Collaborative Group. Lancet. 20023607-22.
66
HPS Effects on specific major vascular events
Vascular event
Statin (10,269)
Placebo (10,267)
Statin better
Placebo better
Major coronary event
898
1,212
Any stroke
444
585
Any revascularization
1,205
939
0.76 (95 CI, 0.720.81) P lt 0.0001
Any major vascular event
2,033 (19.8)
2,585 (25.2)
0.4
0.6
0.8
1.0
1.2
1.4
Event rate ratio
HPS Collaborative Group. Lancet. 20023607-22.
67
HPS Vascular events by baseline LDL-C levels
Placebo (n10,267)
Statin (n10,269)
Baseline LDL-C (mg/dL)
Statin better
Placebo better
358 (21.0)
282 (16.4)
lt100 (n 3421)
871 (24.7)
668 (18.9)
100 lt130
1356 (26.9)
1083 (21.6)
?130
2585 (25.2)
2033 (19.8)
All patients
24 reduction 2P lt 0.00001
Rate ratio
HPS Collaborative Group. www.hpsinfo.org
68
HPS Statin beneficial irrespective of baseline
lipid level and diabetes status
Heart Protection Study
Event rate ()
Simvastatin n 10,269
Placebo n 10,267
Statin better
Placebo better
LDL-C lt116 mg/dL
15.7
With diabetes
20.9
18.8
No diabetes
22.9
LDL-C 116 mg/dL
With diabetes
23.3
27.9
20.0
No diabetes
26.2
24 reductionP lt 0.0001
All patients
19.8
25.2
0.4
1.0
1.4
0.6
0.8
1.2
Event rate ratio
HPS Collaborative Group. Lancet. 20033612005-16.
69
HPS Incidence of elevated liver or muscle
enzymes
Heart Protection Study
Simvastatin ()(n 10,269)
Placebo () (n 10,267)
Elevated ALT 24xULN 1.35 1.28 gt4xULN
0.42 0.31 Elevated CK 410xULN 0.19 0.13
gt10xULN 0.11 0.06 Myopathy No
rhabdomyolysis 0.05 0.01 Rhabdomyolysis 0.05
0.03
ALT alanine aminotransferase ULN upper limit
of normal
HPS Collaborative Group. Lancet. 20023607-22.
70
Improving time to benefit in clinical outcomes
studies
71
Key findings from recent BP-lowering trials
INVESTCCB ACEIequivalent to ?-blocker
diuretic in hypertension CAD
ASCOT-BPLABenefit of CCB ACEI vs ?-blocker
diureticin high-risk hypertension without CAD
ALLHATBenefit regardless of drug class
VALUEImportanceof promptBP control
2002 2003 2004 2005
CAMELOTEvidence for ? BP goal in hypertension
CAD
?-blocker meta-analysisIncreased risk of stroke
vs other antihypertensives
72
Increased stroke risk for ?-blockers shown in
meta-analysis
N 105,951
RR(95 CI)
Favors ß-blocker
Favors other drug
Stroke
ASCOT-BPLA
1.29 (1.121.49)
0.87 (0.681.12)
CONVINCE
1.58 (0.693.64)
ELSA
0.77 (0.491.23)
HAPPHY
1.14 (0.931.39)
INVEST
1.34 (1.131.58)
LIFE
1.22 (0.831.79)
MRC Old
1.22 (0.991.50)
NORDIL
1.12 (0.961.30)
STOP-2
0.90 (0.481.69)
UKPDS
0.56 (0.211.48)
Yurenev
2.28 (1.313.95)
MRC
1.16 (1.041.30)
Total events
Test for heterogeneity ?2 22.39 (P 0.02)
0.5
0.7
1.0
1.5
2.0
Lindholm LH et al. Lancet. 20053661545-53.
73
Comparison of active treatments on stroke
Blood Pressure Lowering Treatment Trialists
Collaboration meta-analysis
N 158,709
? BP between Rx (mm Hg)
Favorsfirst listed
Favorssecond listed
ACEI vs D/BB Diabetes 2.2/0.3 1.02 No
diabetes 1.4/0.2 1.11 Overall (P homog
.49) 1.08
CCB vs D/BB Diabetes 0.7/0.8 0.94 No
diabetes 1.1/0.4 0.92 Overall (P homog
.84) 0.92
0.5
1.0
2.0
Relative risk
ACEI angiotensin-converting enzyme
inhibitorD/BB diuretic/?-blocker CCB
calcium channel blocker
BPLTTC. Arch Intern Med. 20051651410-9.
74
Comparison of active treatments on CHD
Blood Pressure Lowering Treatment Trialists
Collaboration meta-analysis
N 158,709
? BP between Rx (mm Hg)
Favorsfirst listed
Favorssecond listed
ACEI vs D/BB Diabetes 2.2/0.3 0.83 No
diabetes 1.5/0.2 0.98 Overall (P homog
.33) 0.96
CCB vs D/BB Diabetes 0.7/0.8 1.00 No
diabetes 1.1/0.4 1.01 Overall (P homog
.86) 1.01
ACEI vs CCB Diabetes 1.6/1.2 0.76 No
diabetes 1.3/0.9 0.98 Overall (P homog
.22) 0.83
0.5
1.0
2.0
Relative risk
ACEI angiotensin-converting enzyme
inhibitorD/BB diuretic/?-blocker CCB
calcium channel blocker
BPLTTC. Arch Intern Med. 20051651410-9.
75
VALUE Comparison of CCB and ARB
Valsartan Antihypertensive Long-term Use
Evaluation
Population 15,245 patients with high-risk
hypertension Treatment Amlodipine 510 mg ?
HCTZ 12.525 mgValsartan 80160 mg ? HCTZ
12.525 mg Primary outcome Composite of cardiac
mortality, MI, HF Secondary outcomes MI, HF,
stroke Follow-up 4.2 years
Julius S et al. Lancet. 20043632022-31.
76
VALUE Similar treatment effectson primary
outcome at study end
Valsartan Antihypertensive Long-term Use
Evaluation
N 15,245
14
HR 1.03(95 CI, 0.941.14) P 0.49
12
Main outcome of cardiac disease did not differ
between treatment groups. Unequal reductions in
BP might account for differences.
10
Proportionof patientswith firstevent ()
Valsartan-based regimen (n 7649)
8
6
4
Amlodipine-based regimen (n 7596)
2
0
0
30
18
54
66
6
42
Time (months)
Julius S et al. Lancet. 20043632022-31.
77
VALUE SBP and outcome differencesduring
consecutive time periods
Valsartan Antihypertensive Long-term Use
Evaluation N 15,245
HFhospitalizations
Timeinterval(mos)
Stroke
All-cause death
? SBP(mm Hg)
Favorsvalsartan
Favorsamlodipine
Favorsvalsartan
Favorsamlodipine
Favorsvalsartan
Favorsamlodipine
All study
2.2
03
3.8
36
2.3
612
2.0
1224
1.8
2436
1.6
3648
1.4
Study end
1.7
0.5
1.0
2.0
4.0
0.5
1.0
2.0
4.0
0.5
1.0
2.0
4.0
Odds ratio
Odds ratio
Odds ratio
Julius S et al. Lancet. 20043632022-31.
78
VALUE Clinical implications
Valsartan Antihypertensive Long-term Use
Evaluation
No difference in primary outcome between
treatment groups Unequal reductions in BP might
account for differences between groups in
cause-specific outcomes
Rapid BP control in hypertensive patients at
high CVD risk is essential
Adapted from Julius S et al. Lancet.
20043632022-31.
79
CAMELOT Trial of BP reduction with ACEI or CCB
in CAD patients without HF
Comparison of AMlodipine vs Enalapril to Limit
Occurrences of Thrombosis
Study design Randomized, double-blind,
multicenter, 24-month trial in patients with
angiographically documented CAD, LVEF 40, and
no HF (N 1991) Treatment Amlodipine (10 mg),
enalapril (20 mg), or placebo added to
background therapy with ?-blockers and/or
diuretics Primary outcome Incidence of CV
events for amlodipine vs placebo IVUS
substudy Measurement of atherosclerosis
progression using IVUS (n 274) Outcome Change
in percentage of atheroma volume
Nissen SE et al. JAMA. 20042922217-26.
80
CAMELOT Reduction in primary outcome with
amlodipine and enalapril
Comparison of AMlodipine vs Enalapril to Limit
Occurrences of Thrombosis
0.25
HR (95 CI) A vs P 0.69 (0.540.88) E vs P 0.85
(0.671.07) A vs E 0.81 (0.631.04)
P 0.16
0.20
P 0.003
P 0.1
0.15
Cumulative CV events (proportion)
Placebo
0.10
Enalapril
Amlodipine
0.05
0
0
18
24
6
12
Follow-up (months)
No. at risk No. at risk No. at risk No. at risk No. at risk No. at risk No. at risk No. at risk
Placebo 655 588 558 525 488
Enalapril 673 608 572 553 529
Amlodipine 663 623 599 574 535
Nissen SE et al. JAMA. 20042922217-26.
Incidence of CV events
81
CAMELOT Clinical implications
Comparison of AMlodipine vs Enalapril to Limit
Occurrences of Thrombosis
  • Optimal SBP levels in CAD patients 120 mm Hg
  • Regression of CAD suggested with SBP reduction
    gt10 mm Hg
  • Hemodynamic effects may also modulate clinical
    outcome
  • Increasing evidence to support the following
    strategies Combinations of drugs with
    differing modes of action Lower BP targets in
    special populations

Pepine CJ. JAMA. 20042922271-3.
82
CV pharmacotherapy Impact on newly diagnosed
diabetes
STOP-2
INSIGHT
ALLHAT
INVEST
ALPINE
SCOPE
CHARM
ANBP2
LIFE
HOPE
ALLHAT
CAPPP
STOP-2
VALUE
PEACE
ASCOT
0
10
20
Reduction of new diabetes ()
30
ACEI or ARB
CA ACEI or ARB
100
CA
Pepine CJ and Cooper-DeHoff RM. J Am Coll
Cardiol. 200444509-12.Sever PS et al. Lancet.
20033611149-58.
Randomized active treatment vs control (eg,
placebo, diuretic, ß-blocker ? diuretic)
83
Improving time to benefit in clinical outcomes
studies
84
PROactive Study design
PROspective pioglitAzone Clinical Trial In
macroVascular Events
Objective Assess the effects of pioglitazone
on reducing macrovascular events in type 2
diabetes Design Randomized, double-blind,
placebo-controlled Population N 5238 with
type 2 diabetes and history of macrovascular
disease Treatment Pioglitazone (up to 45 mg)
or placebo Primary outcome Composite of
all-cause mortality, MI, ACS,coronary or
peripheral revascularization, amputation,
stroke Secondary outcomes Individual components
of primary outcome, CV mortality Follow-up 4
years
Dormandy JA et al. Lancet. 20053661279-89. Charb
onnel B et al. Diabetes Care. 2004271647-53.
85
PROactive Reduction in primary outcome
25
10 RRR HR 0.90 (95 CI 0.801.02)P 0.095
20
Placebo(572 events)
Pioglitazone(514 events)
15
Proportionof events()
10
5
0
6
0
12
18
24
30
36
Time from randomization (months)
Number at risk
Pioglitazone
2488
2373
2302
2218
2146
348
Placebo
2530
2413
2317
2215
2122
345
All-cause mortality, MI, ACS, coronary or
peripheral revascularization, amputation,
strokeUnadjusted
Dormandy JA et al. Lancet. 20053661279-89.
86
PROactive Reduction in secondary outcome
25
20
Placebo(358 events)
16 RRR HR 0.84 (95 CI 0.720.98)P 0.027
15
Proportionof events()
10
Pioglitazone(301 events)
5
0
6
0
12
18
24
30
36
Time from randomization (months)
Number at risk
Pioglitazone
2536
2487
2435
2381
2336
396
Placebo
2566
2504
2442
2371
2315
390
All-cause death, MI (excluding silent MI),
stroke Unadjusted
Dormandy JA et al. Lancet. 20053661279-89.
87
PROactive Clinical implications
  • Pioglitazone added to standard antidiabetic and
    CV therapies showed
  • 10 RRR in primary outcome Composite
    all-cause mortality, nonfatal MI (including
    silent MI), stroke, ACS, leg amputation,
    coronary or leg revascularization
  • 16 RRR in secondary outcome All-cause
    mortality, nonfatal MI (excluding silent MI) or
    stroke
  • No difference between groups in HF mortality
  • Continued divergence in survival
    curves Greater benefit with longer treatment
    duration hypothesized

PROactive results support use of PPAR? modulator
in patients with diabetes at high CVD risk May
improve CVD outcomes and decrease need to start
insulin
Dormandy JA et al. Lancet. 20053661279-89.
88
Multifactorial approaches in CVD prevention
89
Potential benefits of multifactorial approaches
Adherence to multiple therapies is more likely
if initiated simultaneously
Early aggressive therapy targeting multiple risk
factors could potentially have a major impact on
CVD prevention
Chapman RH et al. Arch Intern Med.
20051651147-1152. Wald NJ and Law MR. BMJ.
20033261419.
90
ABCs of CVD prevention
A AspirinACE inhibitionA1C control
B BP control/?-blockade
C Cholesterol lowering
D Diet Dont smoke ? Risk of new-onset diabetes
E Exercise
Adapted from Cohen JD. Lancet. 2001357972-3.
91
Steno-2 supports aggressive multifactorial
intervention in type 2 diabetes
  • Objective Target-driven, long-term, intensified
    intervention aimed at multiple risk factors
    compared with conventional therapy
  • N 160 patients with type 2 diabetes and
    microalbuminuria
  • Intensive treatment targets
  • BP lt130/80 mm Hg
  • A1C lt6.5
  • Total-C lt175 mg/dL
  • Triglycerides lt150 mg/dL

Gæde P et al. N Engl J Med. 2003348383-93.
92
Steno-2 Effects of multifactorial intervention
on macrovascular outcomes
60
Conventional (n 80)
53 RRR HR 0.47 (95 CI 0.240.73) P lt 0.01
Longer durationof therapy mayresult in ? benefit
40
Primarycompositeoutcome ()
20
Intensive (n 80)
0
12
36
48
96
24
84
72
60
0
Follow-up (months)
CV death, MI, stroke, revascularization,
amputationUnadjusted Total fat intake lt30,
gt30 min exercise 35x weekly, ACE inhibitor,
aspirin, BP lt130/80 mm Hg, total-C lt175 mg/dL,
TG lt150mg/dL, A1C lt6.5
Gæde P et al. N Engl J Med. 2003348383-93.
93
Majority of Americans do not follow a healthy
lifestyle
2000 Behavioral Risk Factor Surveillance System,
N 153,805
100
77.8
76.7
80
59.9
60
Respondents ()
40
24.0
20
0
Smokers
BMI 25 kg/m2
Consumes fruits/vegetables lt5x/day
Infrequentexercise(lt5x/week)
Reeves MJ and Rafferty AP. Arch Intern Med.
2005165854-7.
94
Only 1 in 3 patients adherent to preventive
therapy after 6 months
N 8406 managed-care enrollees receiving
antihypertensive and lipid-lowering medications
50
44.7
40
35.9
Concomitant antihypertensive andlipid-lowering
therapy ? pill burden and may ? adherence
Patientsadherent to both medications ()
30
20
10
0
3
6
Time from initiation of therapy (months)
Chapman RH et al. Arch Intern Med.
20051651147-52.
95
Combination drugs for treatment of hypertension,
dyslipidemia, and diabetes
Combination product
Condition
  • Antihypertensive/diuretic
  • Benazepril/amlodipine
  • Trandolapril/verapamil

Hypertension
  • Ezetimibe/simvastatin
  • Lovastatin/niacin

Dyslipidemia
  • Metformin/glipizide
  • Metformin/glyburide
  • Pioglitazone/metformin
  • Rosiglitazone/metformin

Diabetes
  • Amlodipine/atorvastatin

Hypertension/dyslipidemia
Numerous combinations
96
Gemini More than 55 of patients achieved both
BP and LDL-C goals
Amlodipine/Atorvastatin Gemini Study N 1220,
14 weeks with amlodipine/atorvastatin single-pill
therapy
90
82.1
65.5
70
57.7
Patients()
50
30
10
0
LDL-C goal(NCEP ATP III)
BP goal(JNC VI)
Both LDL-Cand BP goals
Expert Panel. NCEP ATP III. JAMA.
20012852486-97. JNC VI. Arch Intern Med.
19971572413-46. Blank R et al. J Clin
Hypertens. 20057264-73.
97
More patients at BP goal with fixed-dose
combination vs conventional strategy
N 214 with type 2 diabetes and hypertension, BP
lt130/85 mm Hg
100
80
63
Data support fixed-dose combination therapy in
high-risk patients
56
Subjects()
60
50
40
37
35
40
29
24
20
19
15
20
10
0
2
4
6
8
10
12
Time from randomization (weeks)
Amlodipine/benazepril 5/105/20 mg/d ? HCTZ 12.5
mg/d
Enalapril 1020 mg/d ? HCTZ 12.5 mg/d
Adjunctive HCTZ required in 44 of fixed-dose
combination and 61 of conventional strategy
Bakris GL and Weir MR. J Clin Hypertens.
20035202-9.
98
New paradigm of multiple risk factormanagement
The future of drug therapy belongs to prevention,
which is just now being addressed, and to
intensive management of all cardiovascular risk
factors, in particular, dyslipidemia
Kaplan NM. Hypertension. 200546257-8.
99
ALLHAT Design
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trialand ALLHATLipid-Loweri
ng Trial
N 42,418 stage 1/2 hypertension gt1 CV risk
factor
ALLHAT
Doxazosin28 mg/dn 9061
Chlorthalidone12.525 mg/dn 15,255
Amlodipine2.510 mg/dn 9048
Lisinopril1040 mg/dn 9054
Step 1 titration
Step 2 open-label atenolol 25100 mg/d,
clonidine 0.10.3 mg bid, reserpine 0.050.2 mg/d
Step 3 open-label hydralazine 25100 mg bid
N 10,355 CHD, LDL-C 100 to 129 mg/dL or no
CHD, LDL-C 120 to 189 mg/dL
ALLHAT-LLT
Pravastatin 40 mg/d (n 5170)
Usual care (n 5185)
ALLHAT Collaborative Research Group. JAMA.
20022882981-2997, 2998-3007.
Arm discontinued
100
ALLHAT Primary outcome Fatal coronary disease
or nonfatal MI
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial
N 33,357
20
16
12
Cumulativeevent rate
8
4
0
0
1
2
5
6
7
3
4
Time to event (years)
Chlorthalidone
Amlodipine
Lisinopril
ALLHAT Collaborative Research Group. JAMA.
20022882891-97.
101
ALLHAT-LLT Effects of statin or usual care on
outcomes
N 10,355 with treated hypertension, baseline
LDL-C 120189 mg/dL (no CHD) or LDL-C 100129
mg/dL (CHD)
At 4 yrs, LDL-C ? by 28 (statin) and 11 (usual
care)
All-cause mortality
CHD death nonfatal MI
RR 0.99(95 CI, 0.891.11)
RR 0.91(95 CI, 0.791.04)
Cumulativerate()
Time to death (years)
Time to event (years)
Usual care
Pravastatin
ALLHAT Collaborative Research Group. JAMA.
20022882998-3007.
102
ALLHAT Clinical implications
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial
  • BP-lowering trial
  • Diuretic, ACEI, CCB equivalent in ? CHD death
    and MI
  • Lipid-lowering trial (ALLHAT-LLT)
  • Statin, usual care equivalent in ? all-cause
    mortality
  • Modest differential in on-treatment cholesterol
    levels may have contributed to result

ALLHAT BP results support importance of BP
lowering, regardless of drug class
usedALLHAT-LLT results are consistent with
other statin trials
ALLHAT Collaborative Research Group. JAMA.
20022882981-97, 2998-3007.
103
New paradigms in clinical data supporting
aggressive therapy
  • INternational VErapamil SR/Trandolapril
  • Anglo-Scandinavian Cardiac Outcomes Trial
  • Blood Pressure Lowering Arm

Newer
INVEST Verapamil SR- based
regimen ASCOT-BPLA Amlodipine-
based regimen
Risk factor modification
Older
INVEST Atenolol-based
regimen ASCOT-BPLA Atenolol-
based regimen
Pepine CJ et al. JAMA. 20032902805-16. Dahlöf
B et al. Lancet. 2005366895-906.
Verapamil SR 120480 mg trandolapril 0.58 mg
HCTZ 12.5100 mg Amlodipine 510 mg
perindopril 48 mg Atenolol 25200 mg
trandolapril 0.58 mg HCTZ 12.5100
mg Atenolol 50100 mg bendroflumethiazide
1.252.5 mg potassium
104
INVEST Assessment of combination regimens in
hypertension CAD
INternational VErapamil SR/Trandolapril
Population 22,576 patients ?50 years of age with
hypertension and CAD Treatment Verapamil SR
120480 mg trandolapril 0.5-8 mg HCTZ
12.5100 mg Atenolol 25200 mg trandolapril
0.58 mg HCTZ 12.5100 mg Primary
outcome All-cause death, stroke, MI Secondary
outcomes Individual components of primary
outcome Follow-up 2.7 years
Pepine CJ et al. JAMA. 20032902805-16.
105
INVEST Comparable effects of treatments on BP
INternational VErapamil SR/Trandolapril
N 22,576 with hypertension and CAD
180
Systolic Blood Pressure
160
Level,mm Hg
140
120
110
Diastolic Blood Pressure
100
Level,mm Hg
80
60
Time (months)
CCB strategy
Non-CCB strategy
Pepine CJ et al. JAMA. 20032902805-16.
106
INVEST Comparable effects of treatments on
primary outcome
INternational VErapamil SR/Trandolapril
N 22,576 with hypertension and CAD
All-cause death, stroke, MI
Cumulative
Similar results observed for all-cause
mortality, CV death, CV hospitalization, and BP
control
Time (months)
CCB strategy
Non-CCB strategy
Pepine CJ et al. JAMA. 20032902805-16.
107
INVEST Clinical implications
INternational VErapamil SR/Trandolapril
  • In patients with hypertension and clinically
    stable CAD
  • 70 of both treatment groups achieved BP lt140/90
    mm Hg
  • CCB ACEI was equivalent to ?-blocker diuretic
    in preventing death, MI, or stroke
  • Relative risk reduction of 15 for newly
    diagnosed diabetes in the CCB ACEI treatment
    group

INVEST demonstrates that BP targets can be
achieved in the majority of hypertensive
patients with CAD using a multidrug strategy
Pepine CJ et al. JAMA. 20032902805-16.
108
ASCOT Rationale
  • High prevalence of dyslipidemia in hypertensive
    patients
  • No trial specifically addressing benefits of
    lipid lowering in primary prevention of CHD in
    hypertensive patients not conventionally deemed
    dyslipidemic
  • Less-than-expected CHD prevention using standard
    BP-lowering therapy
  • Insufficient outcome data on newer types of
    BP-lowering agents, especially in specific
    combination treatment regimens
  • Combination risk factors synergistically cause CHD

109
ASCOT Design
Anglo-Scandinavian Cardiac Outcomes Trial
BP 160/100 mm Hg (untreated) BP 140/90 mm Hg
(treated)
Randomized, open-label, blinded outcome
Amlodipine 510 mg perindopril 48 mg
Atenolol 50100 mg bendroflumethiazide
1.252.5 mg
Randomized, double blind
Total-C 250 mg/dL
Atorvastatin 10 mg
Placebo
Sever PS et al. J Hypertens. 2001191139-47.
Plus K supplement if needed
110
ASCOT Patient population risk factor profile
All patients had hypertension plus 3 CHD risk
factors
Hypertension Aged 55 years Male Microalbuminuria/
proteinuria Smoker Family history of CHD Plasma
TCHDL-C 6 Type 2 diabetes Certain ECG
abnormalities LVH Prior cerebrovascular
events Peripheral vascular disease
0
10
20
30
40
50
60
70
80
90
100
Patients with risk factor ()
Sever PS et al. Lancet. 20033611149-58.
LVH left ventricular hypertrophy
111
ASCOT-BPLA Study design
Anglo-Scandinavian Cardiac Outcomes Trial Blood
Pressure Lowering Arm
Design Double-blind, placebo controlled,
randomized Population N 19,257 with
hypertension and 3 other CV risk
factors Treatment Amlodipine 510 mg
perindopril 48 mg prn (n 9639) Atenolol
50100 mg bendroflumethiazide 1.252.5
mg/potassium prn (n 9618) Primary
outcome Nonfatal MI (including silent MI) and
fatal CHD Secondary outcome All-cause
mortality, stroke, nonfatal MI (excluding silent
MI), all coronary events, CV events/procedures,
CV mortality, fatal/nonfatal HF
Dahlöf B et al. Lancet. 2005366895-906.
112
ASCOT-BPLA Reductions in BP over time
Anglo-Scandinavian Cardiac Outcomes Trial Blood
Pressure Lowering Arm
N 19,257
180
160
BP
Systolic BP
137.7 136.1
140
Blood pressure(mm Hg)
Mean difference 2.7, P lt 0.0001
120
Diastolic BP
100
79.2 77.4
80
Mean difference 1.9, P lt 0.0001
60
0
2.0
4.0
Final visit (mean 5.7 SD 0.6, range 4.67.3)
1.0
3.0
5.0
0
Time (years)
Atenolol 50100 mg bendroflumethiazide 1.252.5
mg/potassium prn
Amlodipine 510 mg perindopril 48 mg prn
Dahlöf B et al. Lancet. 2005366895-906.
113
ASCOT-BPLA Reduction in primary outcome
(nonfatal MI and fatal CHD)
Anglo-Scandinavian Cardiac Outcomes Trial Blood
Pressure Lowering Arm
N 19,257
10
8
RRR 10 HR 0.90 (95 CI, 0.791.02) P
0.1052
6
Proportionof events ()
4
Atenolol-based regimen
2
Amlodipine-based regimen
0
1
2
3
4
5
6
0
Time since randomization (years)
Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium Amlodipine 510 mg
perindopril 48 mg
Dahlöf B et al. Lancet. 2005366895-906.
114
ASCOT-BPLA Reduction in fatal and nonfatal
stroke
RRR 23 HR 0.77 (95 CI, 0.660.89) P
0.0003
Proportionof events ()
6
1
2
3
4
5
0
Time (years)
Atenolol-based regimen
Amlodipine-based regimen
Amlodipine 510 mg perindopril 48
mg Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium
Dahlöf B et al. Lancet. 2005366895-906.
115
ASCOT-BPLA Additional reductions with
amlodipine-based regimen
Rate/1000 patient-years
Amlodipine-based(n 9639)
Atenolol-based (n 9618)
lt0.05 lt0.01 lt0.0001 lt0.05 0.001
lt0.001 NS lt0.0001 lt0.05
Secondary endpoints Nonfatal MI (excluding
silent) 7.4 8.5 fatal CHD Total coronary
endpoint 14.6 16.8 Total CV events and
procedures 27.4 32.8 All-cause
mortality 13.9 15.5 CV mortality 4.9 6.5
Fatal/nonfatal stroke 6.2 8.1
Fatal/nonfatal HF 2.5 3.0 Tertiary
endpoints Development of diabetes 11.0 15.9
Development of renal impairment 7.7 9.1
Amlodipine-based better
Atenolol-based better
P
0.50
0.70
1.00
1.45
2.00
Amlodipine 510 mg perindopril 48
mg Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium
Unadjusted hazard ratio
Dahlöf B et al. Lancet. 2005366895-906.
116
ASCOT-BPLA New-onset diabetes
10
RRR 30 HR 0.70 (95 CI, 0.630.78)P lt 0.0001
8
6
Atenolol-based regimen
Proportionof events()
4
Amlodipine-based regimen
2
0
1
2
3
4
5
6
0
Time since randomization (years)
Number at risk
Amlodipine-based regimen(567 events)
9383
9165
8966
8726
7618
9639
Atenolol-based regimen(799 events)
9295
9014
8735
8455
7319
9618
Dahlöf B et al. Lancet. 2005366895-906.
117
ASCOT-LLA Assessing lipid lowering in
hypertensive patients
Anglo-Scandinavian Cardiac Outcomes Trial Lipid
Lowering Arm
Design 10,305 ASCOT patients with mean baseline
LDL-C 133 mg/dL and 3 other risk
factors Treatment Randomized to atorvastatin 10
mg or placebo Primary outcome Nonfatal MI and
fatal CHD Secondary outcomes Total CV
events/procedures, total coronary events,
all-cause mortality, CV mortality, stroke,
HF Follow-up 5 years
Sever PS et al. Lancet. 20033611149-58.
118
ASCOT-LLA Atorvastatin reduces primary outcome
in hypertensive patients

Anglo-Scandinavian Cardiac Outcomes Trial Lipid
Lowering Arm
N 10,305, baseline LDL-C 133 mg/dL
4
Placebo
RRR 36HR 0.64 (95 CI, 0.500.83) P
0.0005
3
Patients ()
2
Atorvastatin
1
0
0
1.0
1.5
3.0
3.5
2.0
2.5
0.5
Follow-up (years)
Nonfatal MI and fatal CHD
Sever PS et al. Lancet. 20033611149-58.
119
ASCOT-LLA Time to benefit post hoc
analysisCardiac events
Anglo-Scandinavian Cardiac Outcomes Trial Lipid
Lowering Arm
Event rate
Atorvastatinbetter
Placebobetter
RRR ()
Censoring time
Atorvastatin
Placebo
30 days 90 days 180 days 1 year 2 years End of
study
83 2.4 14.2 67 5.5 16.6 48 7.5 14.3 45 6.6 12.
0 38 5.9 9.5 36 6.0 9.4
0
0.5
1.0
1.5
2.0
Hazard ratio
Per 1000 patient-years
Sever PS et al. Am J Cardiol. 200596(suppl)39F-4
4F.
120
ASCOT-LLA subanalysis Atorvastatin reduces CV
events in patients with diabetes and hypertension
Anglo-Scandinavian Cardiac Outcomes Trial Lipid
Lowering Arm
N 2532, baseline LDL-C 128 mg/dL
14
Placebo
RRR 23 HR 0.77 (95 CI, 0.610.98) P
0.036
12
10
CV events/procedures,cumulative events ()
8
6
Atorvastatin
4
2
0
0.5
0
1.0
1.5
2.0
2.5
3.0
3.5
Follow-up (years)
Nonfatal MI, CV mortality, UA, stable angina,
arrhythmias, stroke, TIA, PAD, retinal vascular
thrombosis, revascularization
Sever PS et al. Diabetes Care. 2005281151-7.
121
ASCOT Differing effect of statin added to
?-blockerbased or CCB-based therapy
CV events and procedures
NS
P 0.079
P 0.001
3
5
3
1
.
7
3
0
2
9
.
4
2
5
2
7
.
0
Events/1000patient-years
2
0
2
1
.
3
1
5
1
0
5
-

A
t
o
r
v
a
s
t
a
t
i
About PowerShow.com