Is treating Blood pressure alone enough to protect your

The challenge of protection in
hypertensive patients
Magdy Rashwan, MD
Professor of cardiology
University of Alexandria
Egypt

Is treating Blood pressure alone enough to protect your
hypertensive patient?
Does the elevation of blood pressure increase the atherogenecity
of cholesterol-rich lipoproteins ?
Want to go beyond blood pressure in patients with hypertension?
EBM.
Is it just an antihypertensive treatment + statin?
Who are those hypertensive patients at high CVD risk?
Conclusion.
Is treating Blood pressure alone enough to protect your
hypertensive patient?
Does the elevation of blood pressure increase the atherogenecity
of cholesterol-rich lipoproteins ?
Want to go beyond blood pressure in patients with hypertension?
EBM.
Is it just an antihypertensive treatment + statin?
Who are those hypertensive patients at high CVD risk?
Conclusion.

Treating a Single Risk Factor is Not Enough:
Event (%)
f Primary E
Risk of
100
90
80
70
60
50
40
30
20
10
0
Risk reduction (%) Events not avoided (%)
CV Risk 64
Remains Even After
75
72
86
Antihypertensive Therapy in
Placebo-Controlled 36
Studies
SHEP (chlorthalidone
+/- atenolol)
25
MRC-O (HCTZ +
atenolol)
14
Syst-Eur (nitrendipine,
enalapril, HCTZ)
28
PROGRESS
(perindopril +/-
diuretic)
SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264. MRC Working Party. BMJ. 1992;304:405-412.
Staessen JA et al, for the Syst-Eur Trial Investigators. Lancet. 1997;350
350:757-764. PROGRESS Collaborative Group.
Lancet. 2001;358:1033-1041.

Treating single risk factor is not enough
CV risk remains even after statin therapy
CV Risk Remains Even After
Antidyslipidemic Therapy in
Placebo-Controlled Studies
Adapted from reference 1
Landmark studies in patients with varying degrees of
CV risk show that statins reduce CV events by 9 -
1. Kastelein 37% JJP. 1 Eur Heart J 2005; 7:F27-F33.
Risk Factors Are Part of the Same
Atherosclerotic ti Disease Process
CV Risk
Atherosclerosis
Dyslipidaemia
Remodeling
Hypertension
Hypoxia/
Ischemia
Diabetes
Smoking
Obesity
Promotion
Inflammation
Vasoconstriction
Plaque
Rupture
CV Events
Stroke
MI
Heart Failure
Angina
Thrombosis
Adapted from Schiffrin EL et al. Am J Hypertens. 2002;15:115s-122s.

Current Guidelines Recognize the Relationship
Among Risk Factors
All patients should be classified
not only in relation to the grades
of hypertension but also in
terms of the total cardiovascular
risk resulting from the
coexistence of different risk
factors, organ damage and
disease.
Decisions on treatment
strategies (initiation of drug
treatment, BP threshold and
target t for treatment, t t use of
combination treatment, need of
a statin and other nonantihypertensive
drugs) all
importantly depend on the initial
level of risk.
ABCs of multiple risk factor management
A
treatment.
Blood
BC Cholesterol
D
Diabetes
is
E Eye
F
Feet
G
‘‘Guardian’’
Advice—Education, self
management, concordance with
t t t Special focus on smoking
cessation, diet, physical activity, and
weight reduction
Blood pressure targets — Blood
pressure , 130/80 mm Hg, which may
require combinations of a diuretic,
ACE inhibitor/ARB, and a CCB
and LDL cholesterol
targets
control —A normal HbA1c%
ideal but the practical target is
6.5%.
care
care
Hypertension
Dyslipidemia
Hyperglycemia/
Insulin resistance
Platelet activation
and aggregation
Adapted from JBS 2: Joint British Societies’ guidelines on prevention
drugs for cardiovascular
of cardiovascular disease in clinical practice Heart 2005;91;1-52
prevention—Aspirin75 mg daily

Is treating Blood pressure alone enough to protect your
hypertensive patient?
Does the elevation of blood pressure increase the atherogenecity
of cholesterol-rich lipoproteins ?
Want to go beyond blood pressure in patients with hypertension?
EBM.
Is it just an antihypertensive treatment + statin?
Who are those hypertensive patients at high CVD risk?
Conclusion.
Hypertension and Dyslipidemia
• Mechanism:
1. Increase Shear force on Endothelium.
2. Decreased NO Availability
3. Increased Oxidized LDL-Cholesterol

Circulating oxidized LDL and
Hypertension
80
70 Hypertensive
60
men had 62%
50
higher mean
40
Ox LDL levels
30
compared with
20 normotensive
controls
10
0
Normotensive
Subjects
Borderline Hypertensive
Subjects
Toikka JO. Hypertension 2000; 36: 929-33
Is treating Blood pressure alone enough to protect your
hypertensive patient?
Does the elevation of blood pressure increase the atherogenecity
of cholesterol-rich lipoproteins ?
Want to go beyond blood pressure in patients with hypertension?
EBM.
Is it just an antihypertensive treatment + statin?
Who are those hypertensive patients at high CVD risk?
Conclusion.

Treatment of Associated Risk Factors
• Statins: small doses of statins e.g. atorvastatin 10
mg are added to antihypertensive therapy in
patients with borderline elevation of LDL-C (> 130
mg/dl) and multiple RFs.
M h M Ib hi t l E ti G id li P ti f
Mohsen. M.Ibrahim et al. Egyptian Guidelines: Prevention of
Atherosclerotic CV Disease (Executive Summary):2006; 1-34

Treatment of Associated Risk Factors
Journal of Hypertension 2007, Vol 25 No 6

Cardiovascular risk factors for consideration of statin
therapy in non-dyslipidemic id i patients t with
hypertension*
• Male sex
• Smoking
• Left ventricular hypertrophy
• Total cholesterol to HDL ratio > 6
Risk Factors
• Age 55 years or older
• Family history of premature CVD
• Other ECG abnormalities
• Microalbuminuria or proteinuria
If hypertensive patients have 3 or more of these RFs,
statins should be considered.
In addition, patients should be treated according to
the most recent Canadian Lipid Recommendations
2008 Canadian Hypertension Education Program Recommendations
Heart 2005;91(Suppl V):v1–v52. doi: 10.1136/hrt.2005.079988

Want to go beyond blood pressure in
patients with hypertension?
•Add a Statin !
–Further reduction in CHD by >30%
–Further reduction in stroke by 25%
Irrespective of Baseline Cholesterol Values
Is treating Blood pressure alone enough to protect your
hypertensive patient?
Does the elevation of blood pressure increase the atherogenecity
of cholesterol-rich lipoproteins ?
Want to go beyond blood pressure in patients with hypertension?
EBM.
Is it just an antihypertensive treatment + statin?
Who are those hypertensive patients at high CVD risk?
Conclusion.

ASCOT: Integration of antihypertensive regimens with
statin ( CADUET)
Primary endpoint: Nonfatal MI and fatal CHD
P=0.001
Significant effects
evident within the
first 3 months of
treatment (p=0.02)
A previously
unseen 53%
reduction
in CV events in just
3.3 years
Courtesy of Appel G, 2006.
Adapted from Dahlöf B et al. www.ascotstudy.org.
The Collaborative Atorvastatin Diabetes
Study y( (CARDS) 1 :
Can atorvastatin protect patients at increased CV risk?
Cumulative hazard of primary endpoint 1
CARDS: Multicentre, randomised study in
Type II diabetes patients without
dyslipidaemia or documented history of
CVD, given atorvastatin 10mg/day
(n=1428) or placebo (n=1,410). Primary
endpoint was time to first occurrence of
acute CHD events, coronary
revascularisation or stroke. The trial was
stopped 2 years earlier than planned
because the pre-specified early stopping
rule for efficacy had been met. Median
duration of follow-up: 3.9 years.
84% of patients in both groups were hypertensive
1.Colhoun HM et al. on behalf of the CARDS investigators. Lancet
2004; 364: 685-696.

CADUET.. The Dual Efficacy in a Single Pill
Gemini data show that Caduet reduces components of CV risk across a
broad range of patients you see every day
n=1220
14 week
These results demonstrate that treatment with Caduet either alone, or in
addition to existing antihypertensive agents, is an effective and safe
treatment to reduce total CHD risk.
Physicians were able to titrate from 5 mg/10 mg to 10 mg/80 mg.
Erdine S, et al. Single-pill amlodipine / atorvastatin helps patients of diverse ethnicity attain recommended goals for blood pressure and lipids (the Gemini-AALA
,1-15.2008study). Journal of Human Hypertension.
CADUET.. The Dual Efficacy in a Single Pill
Caduet - significantly reduced blood pressure and LDL-C
JEWEL l Study - 1138 patients with hypertension and dyslipidaemia
16 week
Caduet effectively reduced systolic BP (SBP) and low-density lipoprotein cholesterol
(LDL-C) levels, and enabled more patients to achieve BP and LDL-C goals.
Physicians were able to titrate from 5 mg/10 mg to 10 mg/80 mg.
Curran MP. Amlodipine/Atorvastatin A Review of its Use in the Treatment of Hypertension and Dyslipidaemia and the Prevention of Cardiovascular Disease. Drugs
2010; 70 (2): 191-213

CADUET.. The Dual Efficacy in a Single Pill
AVALON trial, 847 patient with hypertension and dyslipidemia at the end of
week 8. mean dose was 7.6/ 28.4 mg
Mean LDL-C ** reduction
Mean reduction in SBP(mmHg)
Mean reduction in DBP(mmHg)
-12.5
-8.2
-37.2%
- Messerli FH, BaKris GL, et al. Efficacy and Safety of Coadministered Amlodipine and Atorvastatin in Patients With Hypertension and Dyslipidemia
Results of the AVALON Trial. Clin Hypertens. 2006;8:571–581
Is treating Blood pressure alone enough to protect your
hypertensive patient?
Does the elevation of blood pressure increase the atherogenecity
of cholesterol-rich lipoproteins ?
Want to go beyond blood pressure in patients with hypertension?
EBM.
Is it just an antihypertensive treatment + statin?
Who are those hypertensive patients at high CVD risk?
Conclusion.

Is it just an antihypertensive
t i
treatment + statin?
Or
Should we select molecules with
synergistic benefits?
Synergistic effect of CADUET on nitric oxide release
from human endothelial cells
Adapted from Mason RP. Cerebrovasc Dis. 2003;16(suppl 3):11-17.

Caduet … Early Improvements in Arterial Wall
Compliance
AVALON-AWC AWC * study strongly
suggests that a greater early
vascular benefit can be
obtained from simultaneous
treatment with amlodipine and
atorvastatin, vs. either agent
alone, in patients with
hypertension and
dyslipidemia.
11.70%
19.30%
1.30%
3.10%
Placebo Atorvastatin Amlodipine Caduet 5/10
Effect of treatment on small artery compliance (c2) At week 8,
1- Cohn JN. AVALON-AWC: Arterial Wall Compliance in the Atorvastatin and Amlodipine in Patients With Elevated Lipids and Hypertension Trial. Am J
Hypertens 2009; 22:137-44.
Caduet … Reversal of LDL-induced Endothelial Dysfunction
Endothelial dysfunction contributes to mechanisms of atherogenesis and its
clinical manifestations, including coronary artery disease. 1
Effect of Caduet ®1
100%
90%
80%
60%
40%
20%
0%
‐20%
‐40%
‐60%
% increase in NO ¤
% d ti i i ONOO º
‐50%
Caduet partially restored the NO level of LDL*-induced dysfunctional
endothelium. 1
Effect of Caduet may be enhanced by antioxidant properties related to their
intermolecular actions in the cell membrane and an increase in the
expression and coupling of endothelial nitric oxide synthase. 1
¤ NO: Nitric Oxide,
º ONOO-: Cytotoxic Peroxynitrite
*LDL: Low-density Lipoprotein
1- Mason RP. A rationale for combination therapy in risk factor management: a mechanistic perspective. The American Journal of
Medicine. 2005; 118(12A): 54S-61S.

ASCOT: Integration of antihypertensive regimens with
statin
Primary endpoint: Nonfatal MI and fatal CHD
Courtesy of Appel G, 2006.
Adapted from Dahlöf B et al. www.ascotstudy.org.
.Baghdasarian SB, Thompson PD, Shi H, et al. effect of amlodipine and enalapril on cardiovascular events in normotensive
coronary artery disease patients with concomitant statin use in the CAMELOT Trial(abstr) J AM Coll Cardiol 2006;47(Suppl 1):310A.

A single, once-daily tablet for improved
adherence and compliance
CARPE study: Caduet 2-Pill Combination
Therapies on Adherence 1
1. Nichol MB et al. J Clin Hypertens 8; 4: S6 Abstract P-526A.
Is treating Blood pressure alone enough to protect your
hypertensive patient?
Does the elevation of blood pressure increase the atherogenecity
of cholesterol-rich lipoproteins ?
Want to go beyond blood pressure in patients with hypertension?
EBM.
Is it just an antihypertensive treatment + statin?
Who are those hypertensive patients at high CVD risk?
Conclusion.

Case Study
– Female
– 45 years old
– Non smoker
– BP : 145/95 mm Hg
– FBS : 97 mg/dl (on treatment)
– TC : 195 mg/dL
– LDL : 118 mg/dL
– HDL : 35 mg/dL
– TG : 185 mg/dL
– Diabetic Neuropathy
Current Treatment:
– Diet and
exercise
– ACE
45 yr old Female
Non-smoker
Diabetes
No LVH
BP: 145/95
mm Hg
LDL cholesterol: (118mg/dL)
HDL cholesterol: (35mg/dL)
Diabetic
10 year CHD risk: 20%

ADA 2009 Guidelines
DIABETES CARE, VOLUME 32, SUPPLEMENT 1, JANUARY 2009
Framingham: 10-Year Risk of CHD
Age (years)
Points
30-3434 -9
35-3939 -4
40-44
44 0
45-4949 3
50-5454 6
55-5959 7
60-6464 8
65-6969 8
70-7474 8 Smoking
LDL-C
mg/dL Could You Be at Risk mmol/L for a Cardiovascular Points
Event?
A Scorecard for Men

3
0
5
2
4
0
14
Framingham: 10-Year Risk of CHD after adding
CCB ,Diuretic , or BB
Age (years)
Points
30-34
34 -9
35-3939 -4
40-4444 0
45-49
49 3
50-5454 6
55-5959 7
60-6464 8
65-6969 8
70-7474 8
LDL-C
mg/dL Could You Be at Risk mmol/L for a Cardiovascular Points
Event?
A Scorecard for Men

3
0
5
0
4
0
12
Framingham: 10-Year Risk of CHD after adding
Caduet 5/10
Age (years)
Points
30-34
34 -9
35-3939 -4
40-4444 0
45-49
49 3
50-5454 6
55-5959 7
60-6464 8
65-6969 8
70-7474 8
LDL-C
mg/dL Could You Be at Risk mmol/L for a Cardiovascular Points
Event?
A Scorecard for Men

3
-3
5
0
4
0
9
ASCOT: Integration of antihypertensive regimens with
statin ( CADUET)
Primary endpoint: Nonfatal MI and fatal CHD
P=0.001
Significant effects
evident within the
first 3 months of
treatment (p=0.02)
A previously
unseen 53%
reduction
in CV events in just
3.3 years
Courtesy of Appel G, 2006.
Adapted from Dahlöf B et al. www.ascotstudy.org.

Is treating Blood pressure alone enough to protect your
hypertensive patient?
Does the elevation of blood pressure increase the atherogenecity
of cholesterol-rich lipoproteins ?
Want to go beyond blood pressure in patients with hypertension?
Evidence Based Medicine.
Is it just an antihypertensive treatment + statin?
Who are those hypertensive patients at high CVD risk?
Conclusion.
Conclusion
AA Statin Should Be Given To All High Risk
Hypertensive Patients
Caduet (Amlodipine+Atorvastatin 10 mg) Reduced
Fatal CHD and Non Fatal MI By 53% Within the First 3
Months in Hypertensive Patient at High Risk
Caduet Improves Endothelial Function which will
help in Retarding the Atherosclerotic Process in
Hypertensive Patients at high Risk.