??e? ??s? t? p???f??

1
??e? ??s? t? p???f??µa?? st?? ?pe?tas??? as?e???

• ??d??a? ??tta??? MD

2
?p?d?µ??????a

• ? ?a?d?a??e?a?? ??s?? (???) e??a? ? ????a a?t?a
  ???t?t?ta? pa???sµ??? se a?apt??µ??e? ?a?
  a?apt?ss?µe?e? ???e?1
• ? ep?ß????s? t?? ??? p???a?e?ta? ap? t??
  ?p??tas?,t?? ?pe???p?da?µ?a ?a? t??? ???p???
  pa?????te? ???d???? 2
• ? ?p??tas? s???? s???p???e? µe ?pe???p?da?µ?a
  ?a? ???p??? pa?????te? ???d????3,4
• CVR e??s??eta? ?ta? ? ?p??tas? s???p???e? a??µa
  ?a? µe ?p?e? ? µ?t??e? a???se?? st??? ??????
  pa?????te? ???d????4

1. World Health Organization. The World Health
Report 2003 Shaping the Future. 2003 2. Yusuf
et al. Circulation. 20011042746-2753 3. NHANES
III Phase 2 Morning Fasting Subset. 2000 Census
Data 4. De Backer et al. Eur J Cardiovasc Prev
Rehabil. 200310(suppl)S1-S78.
3
?a???sµ?a ???t?t?ta 2002
CVD
Malignant neoplasms
Injuries
Respiratory infections
COPD and asthma
HIV/AIDS
Perinatal conditions
Digestive diseases
Diarrhoeal diseases
Tuberculosis
Childhood diseases
Malaria
Diabetes
Mortality (millions)
World Health Organization. The World Health
Report 2003 Shaping the Future. 2003.
4
??????S?pa?????ta? ???d???? ??a ?a?d?a??e?a??
???t?t?ta
?e??fe???? a?t????p??e?a
Stefa??a?a ??s??
???
?a?d?a?? ??ep???e?a
Biennial age-adjusted rate per 1000
Men
Women
Women
Women
Women
Men
Men
Men
Risk of CV events by hypertensive status in
subjects aged 35 to 64 years, Framingham study,
36-year follow-up.
5
?a?????te? ???d???? ?a? ???t?t?ta
Blood pressure
Tobacco
Developing countries
Underweight
Alcohol
Developed countries
Cholesterol
Unsafe sex
Overweight
Unsafe water, sanitation, hygiene
Low fruit and vegetable intake
Indoor smoke from solid fuels
Physical inactivity
Percentage of Mortality Attributable to Risk
Factors
Based on The World Health Report 2003. Yach et
al. JAMA. 20042912616-2622.
6
?p?pt?s? ?p??tas??
Germany1
Finland1
Spain1
England1
Sweden1
Italy1
Japan2
Egypt3

South Korea3
United States1
Canada1
Taiwan3
0
10
20
30
40
50
60
70
Prevalence ()
Defined as systolic/diastolic blood pressure
?140/90, (?160/95 for Taiwan) or receiving
treatment. South Korea is defined as men, aged
30-59. 1. Wolf-Maier et al. JAMA.
20032892363-2369 2. Data on file. Pfizer Inc,
New York, NY3. WHO Collaborating Centre on
Surveillance of Cardiovascular Disease Web site.
Available at www.cvdinfobase.ca. Accessed
February 22, 2005.
7
Worldwide Age-Adjusted Prevalence of
Hypercholesterolaemia
Men
Women
?6.5 mmol/L
?6.5 mmol/L or treatment
?6.2 mmol/L
?5.0 mmol/L
SWI-TIC
GER-BRE
SWI-VAF
SWI-TIC
GER-BRE
SWI-VAF
SWE-NSW
BEL-CHA
YUG-NOS
CZE-CZE
CZE-CZE
YUG-NOS
FRA-STR
SWE-NSW
ICE-ICE
UNK-GLA
UNK-GLA
LTU-KAU
DEN-GLO
ICE-ICE
BEL-GHE
BEL-GHE
BEL-CHA
FRA-STR
UNK-BEL
ITA-BRI
FRA-LIL
FRA-LIL
FRA-TOU
CAN-HAL
ITA-BRI
DEN-GLO
LTU-KAU
UNK-BEL
GER-EGE
FRA-TOU
ITA-FRI
GER-EGE
AUS-NAW
POL-WAR
CAN-HAL
AUS-NEW
POL-WAR
ITA-FRI
SWE-GOT
POL-TAR
SPA-CAT
SPA-CAT
AUS-PER
SWE-GOT
POL-TAR
AUS-PER
RUS-NOI
RUS-MOC
RUS-MOI
RUS-MOI
USA-STA
RUS-NOI
RUS-MOC
RUS-NOC
RUS-NOC
USA-STA
CHN-BEI
CHN-BEI
0
20
40
60
80
100
0
20
40
60
80
100
Prevalence () Hypercholesterolaemia
Prevalence () Hypercholesterolaemia
Tolonen et al. Int J Epidemiol. 200534181-192.
8
MONICA S????t?ta a???µ???? ?? TChol se 38
p????sµ???
Men
Women
Average Prevalence ()
BP 130/80 mm Hg TC 5 mmol/L
BP 140/90 mm Hg TC 5 mmol/L
BP 140/90 mm HgTC 5.5 mmol/L
BP 160/95 mm HgTC 6.5 mmol/L
Tunstall-Pedoe et al. ESC. 2004
9
S???pa??? ??s?? se ?pe?tas????? ?s?e?e??

• ?s?a?µ??? ?a?d??p??e?a (IHD) 20-30
• S?µf???t??? ?a?d. a?ep???e?a (CHF) 10-20
• ??s??p?da?µ?a 25-35
• S. ??aß?t?? 10-15
• ?????µ?e? 10-15
• ?pe?t??f?a t?? ??. ?????a?
  10-40
• ?ef???? ß??ß? 3 - 5
• ?s?µa 5 -10
• ?e??fe???? a?t????p??e?a 10-15
• ????? ???? ??s? (a?ep?p?e?t?) 20
  

Am J Med 1996 101 (Suppl 4A) 50S - 55S
10
Trends in Awareness, Treatment, and Control of
Hypertension in the US
100
90
1976-1980
80
73
1988-1991
68
70
1991-1994
55
54
60
51
Percentage of Population
50
40
31
29
27
30
20
10
10
0
???µe???
Te?ape?µ????
???µ?sµ????
Data represent percentage of adults 18 to 74
years of age who have systolic blood
pressure?140 mm Hg, diastolic blood pressure ?90
mm Hg, or are taking antihypertensive
medication.Systolic blood pressure lt140 mm Hg
and diastolic blood pressure lt90 mm Hg. Adapted
from JNC VI. Arch Intern Med. 19971572413-2446.
11
EUROASPIRE II ???? ?? µ?s?? st? st??? ?e?ape?a?
??
Percentage of Patients Who Reached Goal at
Interview Among Those Using BP-Lowering Medication
Hungary
Czech Republic
Belgium
Spain
Greece
Poland
Ireland
Finland
Italy
The Netherlands
United Kingdom
France
Slovenia
Sweden
Germany
Total
0
20
40
60
80
At Goal
BP lt140/90 mm Hg. Weighted average of total
population. EUROASPIRE II Study Group. Eur Heart
J. 200122554-572.
12
Relation Between CHD Events and LDL-C Outcomes in
Statin Trials
30
4S-PI
HPS-Pl
25
2 Prevention
4S-Rx
HPS-Rx
20
with CHD event
15
LIPID-Rx
LIPID-PI
CARE-Rx
CARE-PI
1 Prevention
10
HPS-Pl
w/revascstroke CHD only
AFCAPS-PI
HPS-Rx
5
WOSCOPS-PI
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
70
PIplacebo Rxtreatment
Mean LDL-C level at follow-up (mg/dL)
HPS enrolled high-risk primary- and
secondary-prevention patients.
HPS. Lancet. 20023607. Downs. JAMA.
19982791615. LIPID. N Engl J Med.
19983391349. Sacks. N Engl J Med.
19963351001. 4S. Lancet. 19953451274.
Shepherd. N Engl J Med. 19953331301.
13
?????? as?e?e?? de? ep?t???????? t?? st??? t??
LDL-C
100
90
Diet/exercise ()
80
Drug therapy ()
70
70
59
60
Percent of Patients Achieving Goal
50
40
40
30
21
18
20
8
10
0
Low Risk
High Risk
CHD

282
861
361
1924
108
1352
n
Included statins (fluvastatin, lovastatin,
pravastatin, simvastatin), gemfibrozil, bile acid
sequestrants, niacin, psyllium fiber, or
combination drug therapy
Pearson TA, et al. Arch Intern Med.
2000160459-467.
14
?p?te??? st???? se as?e?e?? ?p? ?e?ape?a
L-TAP (1996-1997)
80
72.8
NHANES III (1988-1994)
68
70
60
50
37
Patients () at Goal
40
30.2
30
18
16.6
20
10
0
CHD
High Risk
Low Risk
Jacobson TA et al. Arch Intern Med.
20001601361-1369. Pearson TA et al. Arch Intern
Med. 2000160459-467.
15
EUROASPIRE II Only Half of Patients With CHD
Achieved Total Cholesterol Goals
Percentage of Patients Who Reached Goal at
Interview Among Those Using Lipid-Lowering
Medication
Finland
The Netherlands
Sweden
Ireland
United Kingdom
Spain
Italy
Poland
Hungary
France
Greece
Slovenia
Germany
Belgium
Czech Republic
Total
0
20
40
60
80
At Goal
TC lt190 mg/dL (lt5 mmol/L). Weighted average of
total population. EUROASPIRE II Study Group. Eur
Heart J. 200122554-572.
16
? p?e????t?ta t?? ?pe?tas???? ??e? LDL-C 100mg/dl
33.7
26.8
Patients ()
17.4
14.3
7.7
lt100 mg/dL)
100 lt130 mg/dL)
160 lt190 mg/dL)
?190 mg/dL)
130 lt160 mg/dL)
Frequency of Hypertensive Patients by LDL-C Levels
Adapted by Pfizer Inc, New York, NY, from the
NHANES III Phase 2 Morning Fasting Subset. 2000
Census Data. (Unweighted N7697 weighted
sample200,948,641).
17
S???pa??? ?p??tas?? ?a? ?pe???p?da?µ?a? a????e?
t?? ???d??? a??pt???? ?a?at?f??a? CVD
??s??p?da?µ?a / ?p??tas?
?p??tas?
??s??p?da?µ?a
TC 271 mg/dL)
SBP 180 mm Hg
TC 271 mg/dL) SBP 180 mm Hg
Adapted from De Backer et al. Eur J Cardiovasc
Prev Rehabil. 200310(suppl 1)S1-S78.
18
S??d?asµ?? S?? ??p?d??? st?? ?a?d?a??e?a??
???t?t?ta MRFIT
n316,099
23
21
18
17
12
17
Deaths/10,000Patient-Years
13
11
14
8
12
10
9
8
8
6
6
5
6
gt245
6
6
142
221-244
4
132-141
3
203-220
SBP quintile (mm Hg)
3
125-131
182-202
118-124
Cholesterol quintile mg/dL
lt182
lt118
Neaton et al, for the Multiple Risk Factor
Intervention Trial Research Group. Arch Intern
Med. 199215256-64.
19
Number of People With Diabetes in the Adult
Population Worldwide for 2000 and 2010
World
2000 151 million
2010 221 million
Increase 46
84.5 m
26.5 m
14.2 m
132.3 m
32.9 m
17.5 m
?57
?24
?23
9.4 m
14.1 m
15.6 m
1.0 m
?50
22.5 m
1.3 m
?44
?33
Amos et al. Diabet Med. 199714S1-S85 Zimmet et
al. Nature. 2001414782-787.
20
Impact of Diabetes and Increasing Risk Factors on
CV Death Rate MRFIT
140
120
No diabetes Diabetes
100
80
Age-Adjusted Cardiovascular Death Rate per
10,000 Person-Years
60
40
20
0
0
1
2
3
Number of Risk Factors
Increased systolic BP, elevated TC,
smoking. Jamerson. Am J Hypertens.
20001368S-73S.
21
??a st?at?????

• ?? t?????se? e???pa???? ?a? pa???sµ?e? ?d???e?
  a?a????????? t?? e?t?µ?s? t?? s???????? ?a?d?a???
  ???d????1-3
• ??a??s?µa ??????? e??a?e?a p??ß?e??? s????????
  ???d????2,4,5
• ?e?a??te?? µe??s? ???d???? µp??e? ?a ep?te???e?
  st??e???ta? st? s??????? ???d??? ?a? st???
  ?e????st??? ?a?d?a??e?a???? pa?????te? ???d????6

1. World Health Organization, International
Society of Hypertension Writing Group. J
Hypertens. 2003211983-1992 2. De Backer et al.
Eur Heart J. 2003241601-1610 3. European
Society of Hypertension Guidelines Committee. J
Hypertens. 2003211011-1053 4. Volpe et al. Am
J Hypertens. 2004171068-1074 5. Expert Panel
on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA.
20012852486-2497 6. Emberson et al. Eur Heart
J. 200425484-491.
22
Current Guidelines Recognize the Relationship
Among Risk Factors

• The European Joint Task Force guidelines1 lower
  BP and lipid goals for patients at high total CV
  risk or with diabetes, CVD
• The ESH/ESC2 guidelines SBP/DBP and other risk
  factors, such as diabetes, contributors to a
  patients risk stratification and subsequent
  prognosis
• The WHO/ISH guidelines3 comprehensive
  risk-factor assessment for patients

1. De Backer et al. Eur Heart J.
2003241601-1610 2. European Society of
Hypertension Guidelines Committee. J Hypertens.
2003211011-1053 3. World Health Organization,
International Society of Hypertension Writing
Group. J Hypertens. 2003211983-1992.
23
??????? e??a?e?a e?t?µ?s?? ???d????

• European SCORE Project
• Framingham Risk Score
• PROCAM Score

Volpe et al. Am J Hypertens. 2004171068-1074.
24
SCORE 10-Year Risk of Fatal CVD in High-Risk
Regions
Chart should be used in all European countries
excluding those considered low-risk (Belgium,
France, Greece, Italy, Luxembourg, Spain,
Switzerland, Portugal)
De Backer et al. Eur Heart J. 2003241601-1610.
25
SCORE 10-Year Risk of Fatal CVD in Low-Risk
Regions
DeBacker et al. Eur Heart J. 2003241601-1610.
26
ATP III Framingham Point ScoresEstimate of
10-Year Risk for Women
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
27
ATP III Framingham Point ScoresEstimate of
10-Year Risk for Men
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
28
?a????????a ep?d?as? µ?t???? µe??se?? pa?a???t??
???d????
Emberson et al. Eur Heart J. 200425484-491.
29
????????s? d?af??et???? st?at?????? ??a
?a?d?a??e?a?? p?????? st? µe??s? t??
?a?d?a??e?a??? ???d????
Treatment Based on Overall Absolute Risk(ASA,
statin, ACEI, ß-blocker, diuretic)
Treatment Based on BP(ß-blocker, diuretic)
Treatment Based on TC (statin)
Predicted Reduction in Major CVD ()
Treatment thresholds
Adapted from Emberson et al. Eur Heart J.
200425484-491.
30

• Overall risk reduction is the goal (it) is
  best achieved by establishing global risk status,
  identifying modifiable components of that risk
  and then, in league with the patient, initiating
  the most efficient and least intrusive
  therapeutic strategy.

Volpe et al. Am J Hypertens. 2004171068-1074.
31
????????? ß?s? ??a s??????? a?t?µet?p?s? t??
?a?d?a??e?a???

• Atherosclerosis is a progressive disease1
• Risk factors in concert contribute to the
  development of atherosclerosis by causing
  endothelial dysfunction2-4
• Hyperlipidaemia causes endothelial dysfunction5
• Hypertension may affect vessel wall lipid uptake
  and metabolism, potentially contributing to
  atherosclerosis5-8

1. Libby. In Braunwald, Zipes, Libby, eds. Heart
Disease. 2001995-1006 2. Ross. N Engl J Med.
1999340115-126 3. Adapted from Mason.
Cerebrovasc Dis. 200316(suppl 3)11-17 4. Liao.
Clin Chem. 1998441799-1808 5. Sposito et al.
Eur Heart J Suppl. 20046(suppl G)G8-G12 6.
Taylor. Curr Hypertens Rep. 1999196-101 7.
Gimbrone Jr et al. Ann NY Acad Sci.
2000902230-240 8. Lee et al. J Biol Chem.
200127613847-13851.
32
??d?????a?? d?s?e?t?????a ?a??µet??
?a?d?a??e?a??? ???d?????
??as???? ?a?????te? ???d??????aß?t?? ??p??
????s?e?t?????a ??d?????????p??sµa?p??tas?????
?a ?pe???p?da?µ?a
Novel/Emerging Risk Factors Infection/Inflammation
Physical inactivityPostprandial
stateHomocysteineObesity
Intrinsic susceptibilityGenetic and
environmental factors
??d?????a?? ??s?e?t?????a
Impaired vasomotion/tone
Prothromboticstate
Proinflammatorystate
Proliferation inarterial wall
??µ??????a e?????? a????µat????
ß??ß????e???p???s? p???a? / ?????e??s? ????
a?µat?? ???? ???µß?s?? a??e??spasµ??
Widlansky ME et al. J Am Coll Cardiol.
2003421149-1160.
33
Progression of Atherosclerosis
Foam Cell
ScavengerReceptor
CellApoptosis
Monocytes
LDL
Macrophage
Vascular Endothelium
Cell Adhesion Molecule
Smooth MuscleProliferation
Smooth MuscleMitogens
IL-1
Oxidized LDL
Internal Elastic Lamina
MCP-1
Smooth Muscle Migration
Libby P. In Braunwald, Zipes, Libby, eds. Heart
Disease. 2001995-1006.
34
Integrated Perspective on CV Risk Factors and
Vascular Disease
Oxidative Stress Inflammation
Endothelial Dysfunction
Courtesy of Preston Mason, PhD, and Robert Jacob,
PhD. Modified from Ross. N Engl J Med.
1999340115-126.
35
Integrated Cellular Mechanisms of Cardiovascular
Disease
It has been hypothesized that, at the cellular
level, risk factors lead to the development of
vascular disease through the common pathway of
endothelial dysfunction1,2
1. Liao. Clin Chem. 1998441799-1808 2. Adapted
from Mason. Cerebrovasc Dis. 200316(suppl
3)11-17.
36
Mechanism by Which Hypercholesterolaemia
Interacts With and Disrupts NO Availability in
the Endothelium
LDL
Oxidized LDL
O2
?NO
O2
Inactivation
1
NADPHoxidase
L-citrulline
eNOS

2
L-arginine
Reduced eNOS transcription Reduced mRNA stability
? Production
3
? ADMA
Endothelial cell
Sposito et al. Eur Heart J Suppl. 20046(suppl
G)G8-G12.
37
In Patients With Hypertension, LDL-C Deposition
Is Greatest in Areas of Disturbed Blood Flow

• It has been hypothesized that hypertension causes
  disturbed flow, altering shear stress and
  biomechanical strain in the arterial wall1,2
• These altered biomechanical forces may lead to
  LDL-C accumulation in the arterial wall and
  promote LDL-C oxidation3

Disturbed flow andaltered shear stress
1. Taylor. Curr Hypertens Rep. 1999196-101 2.
Gimbrone Jr et al. Ann NY Acad Sci.
2000902230-240 3. Lee et al. J Biol Chem.
200127613847-13851.
38
Hypothesized Effects of Hypertension on
Hypercholesterolaemia
? AtherogenicVLDL, VLDL-RIDL, LDL
? BP
Pressure-drivenconvection
Intima-media
LP penetration LP retention
- Enhanced
- Pressure-induced distension
Media
- Stretching
Hypertension can (a) increase the pressure-driven
convection of atherogenic lipoproteins into the
intima-media and (b) induce a pressure-related
distension of the artery wall, facilitating the
penetration and potential retention of
atherogenic lipoproteins. Sposito et al. Eur
Heart J Suppl. 20046(suppl G)G8-G12.
39
???????? p?a?t???? ??a t?? a?t?µet?p?s? t??
?a?d/??? ???d????

• ?s?e?e?? µe p???ap???? pa?????te? ???d???? p??
  p??pe? ?a pa?????? a??et? ??p?a ????? ?aµ???
  p??a??t?ta pa?aµ???? ?a? s?µµ??f?s?? st?
  ?e?ape?a1
• ?e?????ta? t?? a???µ? t?? ?ap??? a??????µe t??
  s?µµ??f?s?1,2

1. Chapman et al. AHA Scientific Sessions 2003
2. Dezii. Manag Care. 20009(suppl)S2-S6.
40
Adherence in Patients Taking Both
Antihypertensive and Lipid-Lowering Therapy
Nonadherent
Adherent LL/nonad AH
Adherent AH/nonad LL
Adherent AH and LL
100
90
80
70
60
Patients ()
50
40
30
20
10
0
3
6
9
12
15
18
21
24
27
30
33
36
Months Since Index Date
AHantihypertensive LLlipid lowering. Index
date defined as date concomitant therapy (ie,
second drug) was initiated.Chapman et al. AHA
Scientific Sessions 2003.
41
Nonadherence and Patient Outcomes

• Studies have demonstrated that prolonged
  treatment with statins significantly reduces CV
  morbidity and mortality1-9
• Nonadherence to lipid-lowering therapy is linked
  to elevated cardiac morbidity and mortality8,9

1. Lipid Study Group. N Engl J Med.
19983391349-1357 2. Sacks et al. N Engl J Med.
1996 3351001-1009 3. Lancet.
19943441383-1389 4. Shepherd et al. N Engl J
Med. 1995333 1301-1307 5. Downs et al. JAMA.
19982791615-1622 6. Heart Protection Study
Collaborative Group. Lancet. 20023607-22 7.
West of Scotland Coronary Prevention Study Group.
Eur Heart J. 1997181718-1724 8. Heeschen et
al. Circulation. 20021051446-1452 9. Wei et
al. Heart. 200288229-233.
42
Pill Burden Predicts Nonadherence in Patients
Taking Both Antihypertensive and Lipid-Lowering
Therapy
????µ?? fa?µ????
0
1
2
3-5
6
0.5
1.0
1.5
2.0
2.5
Adjusted Odds Ratio for Adherence
Chapman et al. AHA Scientific Sessions. 2003.
Abstract.
43
?p??p????ta? t? s??µa ße?t?????µe t? s?µµ??f?s?
100
90
1-pill combination therapy
2-pill therapy
80
Patients Adherent ()
70
20
60
50
0
1
2
3
4
5
6
7
8
9
10
11
12
Months Since Initiation of Therapy
Retrospective, database-based study of members of
a national commercial pharmacy benefit manager
(N3942). Dezii. Manag Care. 20009(suppl)S2-S6.
44
?a?t?????? ?e????µa 2 fa?µ???? ße?t???e? t?
s?µµ??f?s?
OR for Adherence
1-30 days
31-60 days
61-90 days
Time Between Start of Antihypertensive and
Lipid-Lowering Therapies
Retrospective cohort study in a large
managed-care population (N8406). Relative odds
of being adherent with both antihypertensive and
lipid-lowering therapy at any point in
time. Chapman et al. Poster presented at AHA
Scientific Sessions 2003.
45
Common Aspects of Successful Interventions

• More instruction for patients
• Written, verbal, programmed learning
• Improve the convenience of care
• Dose frequency, cost, work-site education
• Involve patients in their care
• Self-monitoring, tailoring doses
• Reminders
• Refills (phone, mail), doses (pill dispensers)
• Reinforcement or rewards
• Reduced visit frequency, payment for BP
  monitoring device

Haynes et al. Lancet. 1996348383-386.
46
F???t µe ??????p?
47
Polypill a strategy to reduce CVD by more than
80
???sp??e?a ?a????sµ?? t?? s??d?asµ?? fa?µ???? ?a?
ß?taµ????, ?a??? ?a? t?? d?se??, ??a ???s? se ??a
d?s??? ?µe??s??? ??a ep?te??? µe????? µe??s??
CVD, µe e????ste? pa?e????e?e?

• ??t???a?? p?es?
• LDL-C
• ?µ???ste???
• ??µ?peta??a?? ?e?t?????a

Wald et al BMJ Iune 2003
48
??????p? ?e??s? ???d???? ?s?a?µ????
?a?d??p??e?a? ?a? ??? se 2 ?????a se ?????a 55-64
risk reduction (CI) risk reduction (CI)
Risk Factor Agent ?RF IHD event STROKE
LDL-C Statin ?70mg/dl 61(51-71) 17(9-25)
BP 3 drugs ½ dose 11mmHg 46(39-53) 63(55-70)
Homocysteine Folic acid (0.8mg) ? 3µmol/l 16 (11-20) 24(15-33)
Platelet Function Aspirin (75mg) 32(23-40) 16(7-25)
Combined effect ALL 88(84-91) 80(71-87)
?a?e????e?e? 8-15 (??a?1-2, Ta?at?f??a
s?µß??ta1/10000)
Wald et al BMJ Iune 2003
49
?sp????? ?aµ???? ??s? 15 ?e??te?
50
?? 1/3 t?? at?µ?? ?a ????? ?µes? ?fe???,
?e?d????ta? ?at? µ?s? ??? 11-12 ?????a ???? ?????
?a?d?a?? epe?s?d?a ? ??? (20 ?????a ??a ?????a
55-64)
Wald et al BMJ Iune 2003
51
A Poly-Portfolio for Prevention A Strategy to
reduce subsequent events by up to 97 over 5 years

• Low to standard doses of antihypertensive therapy
• High-dose statin
• Aspirin
• Omega-3 Fish oil
• Cardiac Rehabilitation
• Diet

Robinson J et al Am J Cardiol 200595373-378
52
Polymealmore natural, safer, probably tastier
strategy to reduce CVD by more than 75
S?stat??? ????d???? CVD () ß?ß?????af?a
??as? (150ml/day) 32 (23-41) Di Castelnuovo
???? (114grX4/week) 14 (8-19) Whelton
?. S?????ta (100gr) 21 (14-27) Taubert
F???ta-?a?a???? (400gr) 21 (14-27) John
S???d? (2.7gr) 25 (21-27) Ackerman
?µ??da?a (68gr) 12.5 (10.5-13.5) Jenkins, Sabate
S??d?asµ?? 76 (63-84)
Franco O.et al BMJ Dec 2004
53
Section 4 Lipid-Lowering Trials

• Recent lipid trials have shown that statin
  treatment in addition to antihypertensive therapy
  led to further benefits in hypertensive patients
  with other risk factors1,2
• In the ASCOT-LLA study, 10 mg of atorvastatin
  given to controlled hypertensives who were
  slightly or nondyslipidaemic, led to significant
  reductions in CHD early in the study, and to
  early termination of the trial1
• In the CARDS study in patients with diabetes,
  many also having hypertension, 10 mg atorvastatin
  produced significant reductions in the primary
  end point that occurred early, and led to early
  termination of the trial3

1. Sever et al, for the ASCOT Investigators.
Lancet. 20033611149-1158 2. ALLHAT Officers
and Coordinators. JAMA. 20022882998-3007 3.
Colhoun et al. Lancet. 2004364685-696.
54
ASCOT Study Design
Moderate-Risk Hypertensive Patients

Randomised N19,342
Amlodipine ? Perindopril ? Doxazosin GITs
Atenolol ? Bendroflumethiazide ? Doxazosin GITs
Eligible for Lipid Lowering
Not Eligible for Lipid Lowering
n5168 Atorvastatin 10 mg
n5137 Placebo
1. Study design adapted from Sever et al, for the
ASCOT Investigators. J Hypertens.
2001191139-1147 2. Data from Sever et al.
Lancet. 20033611149-1158
55
ASCOT-LLA Patient Population Risk Factor Profile
All patients in ASCOT-LLA had hypertension plus
?3 risk factors for CHD
Hypertension
Age ?55 years
Male
Microalbuminuria/proteinuria
Smoker
Family history of early coronary disease
Plasma TCHDL-C ?200 mg/dL
Type 2 diabetes
Certain ECG abnormalities
LVH
Previous cerebrovascular events
Peripheral vascular disease
Patients With Risk Factor ()
Adapted from Sever et al, for the ASCOT
Investigators. J Hypertens. 2001191139-1147.
56
ASCOT-LLA Blood Pressure Changes
SBP (mm Hg)
Baseline 164/95 mm Hg Treated 138/80 mm Hg
DBP (mm Hg)
Years
Sever et al, for the ASCOT Investigators. Lancet.
20033611149-1158.
57
ASCOT-LLA Reductions in Total and LDL
Cholesterol
1.3 mmol/L
1.0 mmol/L
Total Cholesterol (mmol/L)
1.2 mmol/L
1.0 mmol/L
LDL Cholesterol (mmol/L)
Years
Sever et al, for the ASCOT Investigators. Lancet.
20033611149-1158.
58
ASCOT-LLA Primary End Point of Nonfatal MI and
Fatal CHD
Atorvastatin (10 mg) Placebo
4
Final LDL-C ? -29
Trial was stopped early because of 36
reductionin events
3
Cumulative Incidence ()
2
HR 0.64 (0.50-0.83)
1
P.0005
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Sever et al, for the ASCOT Investigators. Lancet.
20033611149-1158.
59
ASCOT-LLA Secondary End Point of Fatal and
Nonfatal Stroke
Atorvastatin (10 mg) Placebo
3
27 Reduction
2
Cumulative Incidence ()
1
HR 0.73 (0.56-0.96)
P.0236
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Sever et al, for the ASCOT Investigators. Lancet.
20033611149-1158.
60
Multiple risk intervention with a single pill
combination (amlodipine/atorvastatin) helps
patients to attain recommended target levels for
blood pressure and lipids (The JEWEL Programme)
JEWEL I UK and Canada JEWEL II 11 European
countries 2245 patients achieved both
country-specific BP and LDL-C goals JEWEL I
(62.9) JEWEL II (50.6) Conclusion
Single-pill (amlodipine/atorvastatin) therapy is
an effective and well-tolerated treatment, which
helps physicians treat their patients to achieve
both BP and LDL-C targets recommended by their
local guidelines. Amlodipine/atorvastatin
single-pill therapy should therefore improve
management of total CV risk in patients requiring
BP-and lipid-lowering therapy.


FDR Hobbs, G Gensini,
GBJ Mancini, AJ Manolis, o? behalf of the JEWEL
Study Group
61
VALUE ????? ?e???? S?µe?? ?a? d?af???? st? S??
se d??f??e? ???????? pe???d???
????? ?????? S?????
S??
D
???e?
mmHg
S??????? st? µe??t?
2.2
03
3.8
36
2.3
612
2.0
1224
1.8
2436
1.6
3648
1.4
????? µe??t??
1.7
1.0
2.0
0.5
4.0
Favours amlodipine
Favours valsartan
Julius S et al. Lancet. June 2004363.
62
Se as?e?e?? ?????? ???d???? e??a??? ?a? ???????
a?t?µet?p?s? t?? ?pe?tas??
63
Common Aspects of Successful Interventions

• More instruction for patients
• Written, verbal, programmed learning
• Improve the convenience of care
• Dose frequency, cost, work-site education
• Involve patients in their care
• Self-monitoring, tailoring doses
• Reminders
• Refills (phone, mail), doses (pill dispensers)
• Reinforcement or rewards
• Reduced visit frequency, payment for BP
  monitoring device

Haynes et al. Lancet. 1996348383-386.
64
Conclusions

• There is a worldwide epidemic of CVD related to
  the high and growing prevalence of hypertension,
  dyslipidaemia, and other CV risk factors in
  developed and developing regions1
• Prompt, aggressive BP reduction improves CV
  outcomes in hypertensive patients2,3
• Lipid lowering leads to additional improvements
  in CV outcomes in treated hypertensive
  patients4,5
• Antihypertensive agents have reduced CV end
  points in large outcome trials2,6,7
• Statins have reduced CV end points in large
  clinical trials4,8-10
• Patients treated for multiple conditions can be
  helped to improve their medication adherence by
  using combination medications that reduce the
  pill burden11,12

1. World Health Organization. The World Health
Report 2003 Shaping the Future. 2003 2. Julius
et al. Lancet. 20043632022-2031 3. Williams. J
Am Coll Cardiol. 200545 813-827 4. Sever et
al, for the ASCOT Investigators. Lancet.
20033611149-1158 5. ALLHAT Officers and
Coordinators. JAMA. 20022882998-3007 6. ALLHAT
Collaborative Research Group. JAMA.
20022882981-2997 7. Nissen et al, for the
CAMELOT investigators. JAMA. 20042922217-2226
8. Colhoun et al. Lancet. 2004364685-696 9.
Cannon et al. N Engl J Med. 20043501495-1504
10. LaRosa et al. N Engl J Med. 2005352 11.
Chapman et al. AHA Scientific Sessions. 2003.
Poster 12. Dezii. Manag Care. 20009(suppl)S2-S6
.