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The story of
man…..
The short version
God
populated the earth with broccoli,
cauliflower and spinach……
green & yellow vegetables
of all kinds,
“A HEALTHY DIET”
so man and woman
would live long, healthy
lives
Satan created
McDonalds and brought
forth the 99 cent double
cheeseburger, and the
value meal
Man said
“Super size that”
and gained
pounds
GOD
created healthful
yogurt
Satan
created
chocolate
God said
“try my crispy
fresh salad”
Satan said
“enjoy my Ben
and Jerry’s”
God said
“I have sent you heart healthy
vegetables and olive oil with
which to cook them”
Satan said
“order a pizza…
you won’t have to cook….
We deliver !”
Man gained pounds
and his cholesterol
went through the
roof
God brought forth
running shoes
Man repented, and
resolved to lose
all those extra
pounds
Satan brought forth
cable TV, with remote
control, so man would
not have to get up to
change channels .
Man’s waist continued
to expand until his
pant’s size far
exceeded his age
Satan
Began to sponsor
Monday Night
Football in order to
extend man’s weekend
celebration
God said
“You’re running
up the score,
Satan”
God brought forth
the potato,
a vegetable low in fat
and brimming with
nutrition
Satan
peeled off the skin,
sliced the starchy
center into chips and
deep fat fried them
MAN
clutched his remote control,
ate the potato chips and
was drowning in his
LDL
Satan said
“This endothelium is
inflamed….
Let’s hope it becomes
unstable!”
Man went into
cardiac arrest!!!
God sighed, and created
interventional cardiologists,
angioplasty, drug eluting stents
and finally
quadruple cardiac bypass
surgery!
Satan started
enrollment in
HMO’s
GOD
Finally growing weary of Satan
antics created:
REFERENCES
• WWW.HYPERTENSIONONLINE.ORG
• WWW.LIPIDSONLINE.ORG
CONTENTS
LOGIC
ASCOT
SOLACE
SELECT
SHIELD
LEAAD
ALERT
DIOVAN
RAAS
• Endocrine (Systemic) Phenomenon
Servomechanism to Maintain Blood
Pressure
• Autocrine/Paracrine (Tissue Level)
– Effects Target Organ Damage
• Irrespective of the Systemic Renin Profile
Complications of Hypertension:
Target-Organ Damage
Oxidative Stress: Endothelial
Dysfunction and CAD/Renal Risk
Factors
Hypertension
Diabetes
Smoking
LDL
Homocysteine
 O2
Endothelial Cells and
 H2O2 Vascular Smooth Muscle
Endothelial Dysfunction
Apoptosis
Leukocyte
adhesion
Lipid
deposition
Vasoconstriction
VSMC
growth
Thrombosis
www.hypertensiononline.org
Albuminuria
• Reflects
– Endothelial Dysfunction
– Glomerular Pressures
• “Nephrological Hgb A1c/ Ldl
Cholesterol”
Definitions of Microalbuminuria
and Macroalbuminuria
Parameter
Normal
Urine AER
< 20
(g/min)
Urine AER
< 30
(mg/24h)
Urine
albumin/
< 30
#
Cr ratio
(mg/gm)
AER=Albumin excretion rate
Microalbuminuria
Macroalbuminuria
20 - 200
>200
30 - 300
>300
30 - 300
>300
CR# =creatinine
www.hypertensiononline.org
TITRATION of ACEI/ARB
AGAINST PROTEINURIA
• It takes ~ 3 months to reduce proteinuria and ~ 6
months for the maximal impact
– Use the Uprotein/Ucreatinine ratio
• The creatinine negates any hydration/dehydration issues.
• You want at least a 50% reduction. Why 50%?
– There is ~ 30% variation in protein excretion,
independently of any intervention.
– Many of the studies re: benefit with AII intervention
was associated with ~ 50% reduction.
Additional Parameters for Titration
of the ACEI/ARB
• With CKD and HTN
– One may tolerate ~ 20-25% rise in serum
creatinine
• Equilibrates in ~ 3 months and creatinine may be
lower than pretreatment levels
• Metabolic Issues
– Revert to the previous dose if the potassium is
> 5.5 in the absence of a metabolic acidosis
(CO2 >18)
Rationale for Combination Therapy
Lotrel®
Rationale for ACE-I/CCB Combination
Lotrel: Gauging Improved Control (LOGIC)
LOGIC: Background (cont)
LOGIC: Group 1
LOGIC: Change in BP With Lotrel®
Group 1: Inadequate BP Control With Norvasc®
LOGIC: Group 2
LOGIC: Improvement in Edema at Week 4 With Lotrel®
Group 2: BP Control but Unacceptable Edema With Norvasc?
LOGIC: Conclusions
Effects of Combination Therapy on
Capillary Pressure and Edema
Glomerular Effects of CCBs and ACE
Inhibitors
Dilation of both afferent
and efferent arteriole
Dilation of afferent arteriole
only
Glomerulus
Bowman’s
capsule
Glomerulus
Bowman’s
capsule
Afferent
arteriole
Afferent
arteriole
Efferent arteriole
 Glomerular
pressure
 Albumin excretion
rate
DHPCCB
Valentino VA et al. Arch Intern Med. 1991;151:2367-2372.
Vivian EM et al. Ann Pharmacother. 2001;35:452-463.
Efferent arteriole
Glomerular
pressure
Albumin excretion
rate
ACE inhibitor
Incidence of Renal Events and Death: AASK
25
GFR event, ESRD, or death
20
ESRD or death
Amlodipine besylate
Ramipril
RR=
38%*
Cumulative 15
incidence
10
(%)
RR=
41%†
5
0
0 3
No. at risk
Amlodipine 216
432
Ramipril
12
24
Months
36
209
422
131
278
191
391
0 3
216
432
12
24
Months
36
210
428
139
290
193
405
GFR, glomerular filtration rate; ESRD, end-stage renal disease; RR, adjusted risk reduction.
*P=0.005 (95% CI, 13-56%); †P=0.007 (95% CI, 14-60%).
Agodoa LY et al. JAMA. 2001;285:2719-2728.
Change in Proteinuria From Baseline: AASK
Baseline UP:Cr 0.22
230
Baseline UP:Cr >0.22
125
Din
UP/Cr
(%)
50
0
-35
Amlodipine
Ramipril
-55
-70
0
6 12
24
Months
UP:Cr, urinary protein:creatinine ratio.
AASK Study Group. JAMA. 2001;285:2719-2728.
36
0
6
12
24
Months
36
• Remember that the glomerulus is a capillary, so
anything that makes your feet swell (dhpccb,
hydralazine, or minoxidil) can increase glomerular
pressures and beget proteinuria and a decline in
renal function. That is what happened in the
AASK trial. At the same mean BP, Norvasc had
more renal failure compared to ramipril.
• Those previous slides point out the issue of
capillary hypertension,which is the cause of the
edema.
• Lotrel does decrease proteinuria even in the face
of the DHPCCB so this combination still offers
benefit above both Lotensin or Norvasc alone.
Amlodipine/Fosinopril Combination Therapy in
DM-HTN Patients With Microalbuminuria
Effects on Blood Pressure
SBP
mmHg
DBP
mmHg
Amlodipine besylate (n=103)
Fosinopril (n=102)
Combination (n=104)
100
170
160
90
150
140
80
130
120
70
0
3
6 12 18 24 30 36 42 48
Months
DM-HTN, concomitant type 2 diabetes and hypertension.
Fogari R et al. AJH. 2002;15:1042-1049.
0
3
6 12 18 24 30 36 42 48
Months
Amlodipine/Fosinopril Combination Therapy in
DM-HTN Patients With Microalbuminuria
Effects on Microalbuminuria
Amlodipine besylate (n=103)
Fosinopril (n=102)
Combination (n=104)
100
90
80
Proteinuria
mg/24h
*
*
70
†
60
*
50
†
†
†
40
*
*
†
*
†
*
†
†
*
*
†
†
†
†
30
†
‡
†
20
0
3
6
12
*P<.05; †P<.01; ‡P<.001 vs. baseline.
DM-HTN, concomitant type 2 diabetes and hypertension.
Fogari R et al. AJH. 2002;15:1042-1049.
18 24
Months
30
36
42
48
ASCOT - BPLA
Background and Objective
•Rationale
– Insufficient outcome data on newer types of BP-lowering
agents, especially in specific combination treatment
regimens
– Less-than-expected CHD prevention using standard
therapy
Objective
– To compare the effect on non-fatal MI and fatal CHD of
the standard anti-HTN regimen (ß-blocker + diuretic) with
a more contemporary regimen (CCB + ACE inhibitor)
Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005.
ASCOT Entry Criteria
• No treated angina or prior MI
• Age: 40–79 yr
• Blood pressure
– Untreated: SBP 160 and/or DBP 100 mm Hg
– Treated: SBP 140 and/or DBP 90 mm Hg
• 3 CV risk factors:
– Smoking
 ECG abnormalities
– LVH
 NIDDM
– Family Hx
 PVD
– Age 55 yr
 Hx CVA
– Male sex
 TC/HDL-C 6
– Microalbuminuria/proteinuria
• TG 400 mg/dL
• TC 250 mg/dL (in lipid-lowering arm)
Sever PS et al. J Hypertens 2001;19:1139–1147. | Sever PS
et al. Lancet 2003;361:1149–1158.
ASCOT – BPLA - Preliminary results
Baseline Characteristics
Female
Amlo/ACEI
n = 9639
2258 (23.4%)
Atenolol/thiaz
n = 9618
2257 (23.5%)
White
9187 (95.3%)
9170 (95.3%)
Current smoker
3168 (32.9%)
3110 (32.3%)
63.0 (8.5)
63.0 (8.5)
164.1/94.8
163.9/94.5
28.7 (4.6)
28.7 (4.5)
3.7 (0.9)
3.7 (0.9)
Age (yrs)
BP
BMI
Risk factors
.
Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005.
ASCOT – BPLA
Methods
19,342 patients
aged 40–79
with
UNTREATED
SBP ≥160 mmHg
and/or
DBP ≥100 mmHg
OR
TREATED
SBP ≥140 mmHg
and/or
DBP ≥90 mmHg
RANDOMIZATION
Blood pressure medication titrated to next step
to achieve target blood pressures:
No diabetes: <140/90 mmHg
Patients with diabetes: <130/80 mmHg
In each arm,
patients
with total
chol of ≤ 6.5
mmol/L
randomized
to
atorvastatin
(10 mg) or
placebo
daily
(n=10,297)
amlo
5 mg
atenolol
50 mg
amlo
10 mg
atenolol
100 mg
amlo10 mg
+
perindopril
4 mg
atenolol
100 mg +
BFZ 1.25
mg + K+
amlo 10
mg +
peri 8 mg
amlo10 mg (2 x4 mg)
+
+
doxa
4 mg
peri 8 mg
(2 x 4 mg)
atenolol
100 mg +
BFZ 2.5
mg + K+
atenolol
100 mg +
BFZ 2.5
mg + K+ +
doxazosin
GITS 4 mg
amlo 10
mg +
peri 8 mg
(2 x 4 mg)
+
doxa 8 mg
atenolol
100 mg +
BFZ 2.5 mg
+ K+ +
doxazosin
GITS 8 mg
5 Years or 1,150 Primary Events
amlo = amlodipine; peri= perindopril
doxa = doxazosin GITS (gastrointestinal
Sever PS, for the ASCOT Investigators. J Hypertens. 2001;19:1139–1147. Transport system); BFZ = bendroflumethiazide
ASCOT – BPLA
Preliminary Results
– Similar BP lowering good in traditional arm (to
136/78 mm Hg) and in newer therapy arm (to 136/77
mm Hg) by end of study
– Medication use in “traditional” arm (atenolol 73%,
thiazide 67%) and in “newer” therapy arm
(amlodipine 78%, perindopril 63%) were comparable
– Average BP 2.9/1.8 mm Hg higher with ßblocker/diuretic early in trial, prior to addition of
other drugs
Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005.
ASCOT-BPLA Secondary
Endpoints
Unadjusted Hazard Ratio
(95% CI)
Endpoint
P Value
Non-fatal MI* +fatal CHD
P = 0.0003
Total coronary endpoint
P = 0.0070
Total CV event and procedures
P < 0.0001
All-cause mortality
P = 0.0247
Cardiovascular mortality
P = 0.0010
Fatal and non-fatal stroke
P = 0.0003
Fatal and non-fatal heart failure
P = 0.1257
0.50
0.70
1.00
Favors
amlodipine  perindopril
1.45
2.00
Favors
atenolol  thiazide
The area of each square is proportional to the amount of statistical information.
*Excludes silent non-fatal MI.
Adapted from Dahlöf B et al. Lancet. 2005;366:895–906.
ASCOT-BPLA Tertiary Endpoints
Unadjusted Hazard Ratio
(95% CI)
Endpoint
P Value
Silent MI
P = 0.3089
Unstable angina
P = 0.0115
Chronic stable angina
P = 0.8323
Peripheral arterial disease
P = 0.0001
Life-threatening arrhythmias
P = 0.8009
New-onset diabetes mellitus
P < 0.0001
New-onset renal impairment
P = 0.0187
0.50
0.70
1.00
Favors
amlodipine  perindopril
1.45
Favors
atenolol  thiazide
The area of each square is proportional to the amount of statistical
information.
Adapted from Dahlöf B et al. Lancet. 2005;366:895–906.
2.00
ASCOT-BPLA: Summary
In ASCOT-BPLA, a CCB/ACEi regimen (amlodipine ±
perindopril) vs. a β-blocker/thiazide regimen (atenolol ±
BFZ) resulted in:
 Earlier and better blood pressure control
 Greater reduction in morbidity and mortality
 Fewer adverse effects:
 reduction of new-onset diabetes,
 reduction of peripheral arterial disease
 reduction of new-onset renal impairment
BFZ=bendroflumethiazide.
Dahlöf B et al. Lancet. 2005;366:895–906.
ASCOT-BPLA Conclusions
• The effective blood-pressure lowering
achieved by the amlodipine/ACEi regimen
—particularly in the first year — may
account for the differential cardiovascular
benefits
• Reaffirm that most hypertensive patients
require at least two agents to reach blood
pressure targets
Dahlöf B et al. Lancet. 2005;366:895–906.
SOLACE: Safety of Lotrel® vs.
Amlodipine in a Comparative Efficacy Trial
SOLACE: Study Design
SOLACE: Change from Baseline in SBP
SOLACE: Change in SBP
Baseline SBP =180 mm Hg
SELECT: Primary Study Objective
SELECT: Study Design
ITT Population
SELECT: Change From Baseline in Mean
24-Hour ABPM SBP
SELECT: Change from Baseline in
Mean 4-hour ABPM DBP
SHIELD: Study Design
SHIELD: Time to Target BP (<130/85 mm Hg)
SHIELD: Conclusions
Fixed-dose amlodipine besylate/benazepril HCl therapy
– reduced BP to goal (<130/85 mm Hg) faster and to a
greater extent than enalapril monotherapy
– achieved lower BP than ACE inhibitor alone
– resulted in a significantly greater percentage of
patients who achieved and maintained BP goal than
enalapril monotherapy, even after the addition of
HCTZ to enalapril
– was well tolerated
– had no adverse effects on glycemic control or lipid
levels
ACE, angiotensin-converting enzyme; HCTZ, hydrochlorothiazide.
Bakris GL, Weir MR. J Clin Hypertens. 2003 [in press].
LEAAD
Conclusions
– In African American patients with high BP and type 2
diabetes, combination therapy with the amlodipine
besylate/benazepril HCl regimen achieved
significantly faster control of BP, compared with the
enalapril monotherapy regimen
– The results of LEAAD support a strategy of initiating
fixed-dose combination therapy in high-risk patients
in whom lower BP goals are indicated
Flack JM et al. Am J Hypertens 2004;17(5) part 2:180A.
ALERT: Conclusions
• Low-dose amlodipine besylate/benazepril HCl
demonstrated BP reduction comparable to high-dose
amlodipine besylate (10 mg)
• Compared with high-dose amlodipine besylate (10 mg)
and benazepril HCl (40 mg) monotherapies, low-dose
amlodipine besylate/benazepril HCl combination
therapy
showed significantly greater improvement in arterial
stiffness and significantly greater regression of LVH
• These results demonstrate the importance of BP
reduction and drug selection for target-organ protection
LVH, left ventricular hypertrophy.
Neutel JM et al. Am J Hypertens. 2002;15:166A.
Relative Potency of ACE Inhibitors in Tissue
ACE inhibitor
Relative tissue
potency
Quinaprilat
22.3
Benazeprilat
21.6
Perindoprilat
13.3
Ramiprilat
10.0
Lisinopril
3.4
Fosinoprilat
0.6
Fabris B et al. Br J Pharmacol. 1990;100:651-655.
High tissue
affinity
Low tissue
affinity
DIOVAN
Plasma ACE,
nmol/mL/min
Angiotensin II Escape With Longterm ACEI Therapy
100
80
60
40
20
0
Plasma A II levels increase with time,
although plasma angiotensin-converting
enzyme activity remained suppressed
*
*
*
*
*
*
*
*
1
2
3
4
Months
5
6
Plasma A II,
pg/mL
30
20
10
*
0
Placebo 4h
24h
Hospital
*P < 0.001 vs placebo.
Adapted with permission from Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4:966–972.
Clinical Significance of AT1 Receptor
Blockade
ARB
AT1 receptor
blockade
A II binding at the AT2
receptor
BP
Atherosclerosis
Endothelial Neuroendocrine
LVH
Function
Activation
Benefits Cardiac,
Vascular, and
Renal Function
LVH = left ventricular
hypertrophy.
The Effect of ARBs on Diabetic Nephropathy
IDNT
IRMA 2
Endpoints Primary
Time to onset of
composite:
nephropathy with
doubling of serum UAER > 200 g/
creatinine/ESRD/ min. 30% greater
death
than baseline
Results
Risk of primary
endpoint 20% lower
with IRB vs. PLA;
(P = 0.02); 23% lower
vs. AML (P = 0.006)
– lower doubling of
serum creatine,
ESRD with IRB
– no difference in
deaths
IRB was
renoprotective; 5.2%
reached endpoint in
300 mg group; 9.7%
reached endpoint in
150 mg group vs.
14.9% in PLA
(P =.08)
RENAAL
MARVAL
Primary
composite:
doubling of
serum
creatinine/ESRD/
death
D UAER
Risk of primary
endpoint lower by
16% (P = .02) with
LOS
VAL
significantly
lowered UAER
(44%) vs. AML
(17%) (P<.001)
– lower doubling of
serum creatine,
ESRD with LOS;
no difference in
deaths
Lewis E, et al. N Engl J Med. 2001. Parving H-H, et al. N Engl J Med. 2001.
Brenner BM, et al. N Engl J Med. 2001.
Wheeldon NM, Viberti GC, for the MARVAL Trial. Am J Hypertens. 2001.
Cardiovascular
Benefits of ARBs
Aims
VALIANT was designed as a mortality trial in high-risk MI
patients (SAVE, AIRE, TRACE) who derived particular benefits
from an ACE inhibitor.
To determine whether:
• the ARB valsartan was superior to captopril in improving
survival
and with equal statistical power
• the addition of the ARB valsartan to captopril was superior to the
proven dose of captopril in improving survival
• If valsartan was not superior to captopril, a non-inferiority analysis
was prespecified to determine whether valsartan could be
considered “as effective as” captopril
Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible
(either clinical/radiologic signs of HF or LV systolic dysfunction)
Major Exclusion Criteria:
— Serum creatinine > 2.5 mg/dL
— BP < 100 mm Hg
— Prior intolerance of an ARB or
ACE-I
— Nonconsent
double-blind active-controlled
Captopril 50 mg tid
(n = 4909)
Valsartan 160 mg bid
(n = 4909)
Captopril 50 mg tid +
Valsartan 80 mg bid
(n = 4885)
median duration: 24.7 months
event-driven
Primary Endpoint:
All-Cause Mortality
Secondary Endpoints: CV Death, MI, or HF
Other Endpoints:
Safety and Tolerability
Study Drug
Dose Titration
Step I
Step II
Step III
Step IV
Cap 50 mg (tid)
Cap 25 mg
CAPTOPRIL (tid) Cap 6.25 mg
Cap 12.5 mg
Val 160 mg (bid)
Val 80 mg
Val 40 mg
VALSARTAN (bid) Val 20 mg
COMBINATION
Cap 12.5 mg
Cap 6.25 mg Val 20 mg
Val 20 mg
Cap 25 mg
Val 40 mg
Cap 50 mg (tid)
Val 80 mg (bid)
GOAL by 3 months
Am Heart J. 2000;140:727–734.
0.3
Mortality by Treatment
Captopril
Valsartan
Probability of Event
0.25
Valsartan + Captopril
0.2
0.15
0.1
0.05
Valsartan vs. Captopril: HR = 1.00; P = 0.982
Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726
0
Months
0
Captopril 4909
Valsartan 4909
Valsartan + Cap 4885
6
12
18
24
30
36
4428
4464
4414
4241
4272
4265
4018
4007
3994
2635
2648
2648
1432
1437
1435
364
357
382
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
All-Cause Mortality:
Non-Inferiority Analyses
Hazard Ratio
(97.5% CI)
P-value
noninferiority
margin
(noninferiority)
Intention-to-Treat
Patient Population
(n = 14,703)
0.004
Per Protocol
Patient Population
(n = 14,285)
0.002
Noninferiority not
Demonstrated
Noninferiority
Val Superior to Cap
0.8
Cap Superior to Val
1
Favors Valsartan
1.13
Favors Captopril
1.2
Mortality in SAVE,
TRACE, AIRE, and VALIANT
Hazard Ratio for Mortality
SAVE
Valsartan
preserves
99.6% of
mortality
benefit of
captopril.
TRACE
AIRE
Combined
VALIANT
(imputed placebo)
0.5
Favors
Active Drug
1
Favors
Placebo
2
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Conclusion
In patients with MI complicated by heart failure, left
ventricular dysfunction or both:
• Valsartan is as effective as a proven dose of captopril in
reducing the risk of:
– Death
– CV death or nonfatal MI or heart failure admission
• Combining valsartan with a proven dose of captopril
produced no further reduction in mortality—and more
adverse drug events.
Implications:
In these patients, valsartan is a clinically effective
alternative to an ACE inhibitor.
Rationale for Diuretic/ARB Combination
SUMMARY
• Blood Pressure Control is Paramount
• Target Organ Damage ~ AII Expression
at the Tissue Level
– AII intervention is the “pharmacological
balm”
• Doses of ARB or ACEI needed for TOD
impact may exceed dose needed for BP
control
– Follow a TOD parameter rather than BP
alone
THE END
Additional Trandolapril Studies
Effects on Proteinuria
Verapamil
n=11
Trandolapril +
Verapamil
n=14
Trandolapril
n=12
Proteinuria
Mean arterial pressure
Changes from Baseline (%)
-10
•
•
•
•
-27%
-33%
-30
-50
-70
Baseline = 604
Endpoint = 421
Baseline = 616
Endpoint = 399
-62%
Baseline = 672
Endpoint = 234
Proteinuria baseline and endpoint expressed in mg/d.
Bakris et al. Kidney Int. 1998;54:1283-1289.
N=37
2-week placebo run-in
52 weeks’ active treatment
Mean daily doses:
T alone
5.5 mg
T in combination 2.9 mg
V alone
314.8 mg
V in combination 219.0 mg