The story of man

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The story of man..

• The short version

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God

• populated the earth with broccoli, cauliflower
  and spinach
• green yellow vegetables
• of all kinds,
• A HEALTHY DIET

3

• so man and woman
• would live long, healthy
• lives

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Satan created

• McDonalds and brought forth the 99 cent double
  cheeseburger, and the value meal

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Man said

• Super size that and gained pounds

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GOD

• created healthful
• yogurt

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Satan

• created
• chocolate

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God said

• try my crispy fresh salad

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Satan said

• enjoy my Ben
• and Jerrys

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God said

• I have sent you heart healthy vegetables and
  olive oil with which to cook them

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Satan said

• order a pizza
• you wont have to cook.
• We deliver !

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Man gained pounds and his cholesterol went
through the roof
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God brought forth running shoes
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Man repented, and resolved to lose all those
extra pounds
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Satan brought forth cable TV, with remote
control, so man would not have to get up to
change channels .
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Mans waist continued to expand until his pants
size far exceeded his age
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Satan

• Began to sponsor Monday Night Football in order
  to extend mans weekend celebration

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God said

• Youre running up the score, Satan

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God brought forth

• the potato,
• a vegetable low in fat and brimming with
  nutrition

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Satan

• peeled off the skin, sliced the starchy center
  into chips and deep fat fried them

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MAN

• clutched his remote control, ate the potato
  chips and
• was drowning in his
• LDL

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Satan said

• This endothelium is inflamed.
• Lets hope it becomes unstable!

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• Man went into cardiac arrest!!!

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God sighed, and created

• interventional cardiologists, angioplasty, drug
  eluting stents and finally
• quadruple cardiac bypass
• surgery!

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Satan started enrollment in

• HMOs

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GOD

• Finally growing weary of Satan antics
  created

Texas
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REFERENCES

• WWW.HYPERTENSIONONLINE.ORG
• WWW.LIPIDSONLINE.ORG

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CONTENTS

• LOGIC
• ASCOT
• SOLACE
• SELECT
• SHIELD
• LEAAD
• ALERT
• DIOVAN

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RAAS

• Endocrine (Systemic) Phenomenon
• Servomechanism to Maintain Blood Pressure
• Autocrine/Paracrine (Tissue Level)
• Effects Target Organ Damage
• Irrespective of the Systemic Renin Profile

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Complications of HypertensionTarget-Organ Damage
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Oxidative Stress Endothelial Dysfunction and
CAD/Renal Risk Factors
Smoking
LDL
Homocysteine
Diabetes
Hypertension
? O2 Endothelial Cells and ? H2O2
Vascular Smooth Muscle
Endothelial Dysfunction
Lipid deposition
Thrombosis
Apoptosis
VSMC growth
Leukocyte adhesion
Vasoconstriction
www.hypertensiononline.org
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Albuminuria

• Reflects
• Endothelial Dysfunction
• Glomerular Pressures
• Nephrological Hgb A1c/ Ldl Cholesterol

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Definitions of Microalbuminuria and
Macroalbuminuria
Parameter Normal Normal Micro-albuminuria Macro-albuminuria
Urine AER (?g/min) lt 20 20 - 200 20 - 200 gt200
Urine AER (mg/24h) lt 30 30 - 300 30 - 300 gt300
Urine albumin/ Cr ratio (mg/gm) lt 30 30 - 300 30 - 300 gt300
www.hypertensiononline.org
AERAlbumin excretion rate CR creatinine
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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.

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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 gt
  5.5 in the absence of a metabolic acidosis (CO2
  gt18)

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Rationale for Combination Therapy
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Lotrel
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Rationale for ACE-I/CCB Combination
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Lotrel Gauging Improved Control (LOGIC)
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LOGIC Background (cont)
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LOGIC Group 1
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LOGIC Change in BP With Lotrel Group 1
Inadequate BP Control With Norvasc
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LOGIC Group 2
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LOGIC Improvement in Edema at Week 4 With
LotrelGroup 2 BP Control but Unacceptable
Edema With Norvasc?
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LOGIC Conclusions
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Effects of Combination Therapy on Capillary
Pressure and Edema
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Glomerular Effects of CCBs and ACE Inhibitors
Dilation of both afferent and efferent arteriole
Dilation of afferent arteriole only
Bowmans capsule
Bowmans capsule
Glomerulus
Glomerulus
Afferentarteriole
Afferentarteriole
Efferent arteriole
Efferent arteriole
Glomerular pressure Albumin excretion rate
? Glomerular pressure ? Albumin excretion rate
DHPCCB
ACE inhibitor
Valentino VA et al. Arch Intern Med.
19911512367-2372. Vivian EM et al. Ann
Pharmacother. 200135452-463.
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Incidence of Renal Events and Death AASK
GFR event, ESRD, or death
ESRD or death
Amlodipine besylate
Ramipril
RR38
Cumulativeincidence()
RR41
3
12
24
36
3
12
24
36
0
0
Months
Months
No. at risk Amlodipine Ramipril
216432
209422
191391
131278
216432
210428
193405
139290
GFR, glomerular filtration rate ESRD, end-stage
renal disease RR, adjusted risk
reduction. P0.005 (95 CI, 13-56) P0.007
(95 CI, 14-60). Agodoa LY et al. JAMA.
20012852719-2728.
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Change in Proteinuria From Baseline AASK
Baseline UPCr ?0.22
Baseline UPCr gt0.22
230
125
50
D inUP/Cr ()
0
-35
Amlodipine Ramipril
-55
-70
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0
6
24
0
6
24
36
12
12
Months
Months
UPCr, urinary proteincreatinine ratio. AASK
Study Group. JAMA. 20012852719-2728.
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• 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.

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Amlodipine/Fosinopril Combination Therapy
inDM-HTN Patients With MicroalbuminuriaEffects
on Blood Pressure
SBP mmHg
DBP mmHg
Amlodipine besylate (n103)
100
170
Fosinopril (n102)
160
Combination (n104)
90
150
140
80
130
120
70
Months
Months
DM-HTN, concomitant type 2 diabetes and
hypertension.Fogari R et al. AJH.
2002151042-1049.
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Amlodipine/Fosinopril Combination Therapy
inDM-HTN Patients With MicroalbuminuriaEffects
on Microalbuminuria
100
90
80



70

Proteinuriamg/24h





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50





40



30



20
0
3
6
12
18
24
30
36
42
48
Months
Plt.05 Plt.01 Plt.001 vs. baseline. DM-HTN,
concomitant type 2 diabetes and
hypertension.Fogari R et al. AJH.
2002151042-1049.
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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.
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ASCOT Entry Criteria

• No treated angina or prior MI
• Age 4079 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 20011911391147.
Sever PS et al. Lancet 200336111491158.
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ASCOT BPLA - Preliminary resultsBaseline
Characteristics
Amlo/ACEI n 9639 Atenolol/thiaz n 9618
Female 2258 (23.4) 2257 (23.5)
White 9187 (95.3) 9170 (95.3)
Current smoker 3168 (32.9) 3110 (32.3)
Age (yrs) 63.0 (8.5) 63.0 (8.5)
BP 164.1/94.8 163.9/94.5
BMI 28.7 (4.6) 28.7 (4.5)
Risk factors 3.7 (0.9) 3.7 (0.9)
.
Dalhof, B. Late Breaking Clinical Trials II. ACC
Scientific Session 2005.
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ASCOT BPLAMethods
amlo 10 mg peri 8 mg(2 x 4 mg) doxa 8 mg
Blood pressure medication titrated to next step
to achieve target blood pressures No diabetes
lt140/90 mmHg Patients with diabetes lt130/80 mmHg
amlo 10 mg peri 8 mg(2 x4 mg) doxa 4 mg
amlo10 mg peri 8 mg(2 x 4 mg)
amlo10 mg perindopril4 mg
amlo 10 mg
amlo 5 mg
In each arm, patients with total chol of 6.5
mmol/L randomized to atorvastatin (10 mg) or
placebo daily(n10,297)
19,342 patients aged 4079withU N T R E A T E
D SBP 160 mmHg and/orDBP 100 mmHg ORT R E A T
E D SBP 140 mmHg and/or DBP 90 mmHg
atenolol100 mg BFZ 2.5 mg K doxazosin
GITS 8 mg
atenolol100 mg BFZ 2.5 mg K doxazosin
GITS 4 mg
atenolol100 mg BFZ 2.5 mg K
atenolol100 mg BFZ 1.25 mg K
RANDOMIZATION
atenolol100 mg
atenolol50 mg
5 Years or 1,150 Primary Events
amlo amlodipine peri perindopril doxa
doxazosin GITS (gastrointestinal Transport
system) BFZ bendroflumethiazide
Sever PS, for the ASCOT Investigators. J
Hypertens. 20011911391147.
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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
  ß-blocker/diuretic early in trial, prior to
  addition of other drugs

Dalhof, B. Late Breaking Clinical Trials II. ACC
Scientific Session 2005.
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ASCOT-BPLA Secondary Endpoints
Unadjusted Hazard Ratio (95 CI)
Endpoint Non-fatal MI fatal CHD Total coronary
endpoint Total CV event and procedures All-cause
mortality Cardiovascular mortality Fatal and
non-fatal stroke Fatal and non-fatal heart
failure
P Value P 0.0003 P 0.0070 P lt 0.0001 P
0.0247 P 0.0010 P 0.0003 P 0.1257
1.00
1.45
2.00
0.50
0.70
Favorsatenolol ? thiazide
Favorsamlodipine ? perindopril
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.
2005366895906.
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ASCOT-BPLA Tertiary Endpoints
Unadjusted Hazard Ratio (95 CI)
Endpoint Silent MI Unstable angina Chronic stable
angina Peripheral arterial disease Life-threatenin
g arrhythmias New-onset diabetes
mellitus New-onset renal impairment
P Value P 0.3089 P 0.0115 P 0.8323 P
0.0001 P 0.8009 P lt 0.0001 P 0.0187
1.00
1.45
0.50
0.70
2.00
Favorsatenolol ? thiazide
Favorsamlodipine ? perindopril
The area of each square is proportional to the
amount of statistical information.
Adapted from Dahlöf B et al. Lancet.
2005366895906.
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ASCOT-BPLA Summary

• In ASCOT-BPLA, a CCB/ACEi regimen (amlodipine
  perindopril) vs. a ß-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

BFZbendroflumethiazide.
Dahlöf B et al. Lancet. 2005366895906.
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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. 2005366895906.
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Are Beta Blockers Cardioprotective in HTN ?

• No significant overall cardioprotective effect of
  beta blokers compared to other drugs
• Medical Research Council (MRC)
• propranolol
• International Prospective Primary Prevention in
  HTN Trial (IPPPSH)
• oxprenolol
• Heart Attack Primary Prevention in HTN Trial
  (HAPPHY)
• Atenolol, propranolol, metoprolol
• CAPPP TRIAL (captopril)

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Drug Trials (BB)

• Medical Research Council (MRC)
• propranolol
• International Prospective Primary Prevention in
  HTN Trial (IPPPSH)
• oxprenolol
• Heart Attack Primary Prevention in HTN Trial
  (HAPPHY)
• Atenolol, propranolol, metoprolol
• CAPPP TRIAL (captopril)

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Meta-Analysis of 5 antihypertensive therapies
(2004)

• Atenolol was associated with higher mortality
  (1.13.1.02-1.25)
• CV mortality (1.16,1.00-1.34)
• Rate of stroke (1.3, 1.12-1.50)
• HAPPHY
• MRC
• UKPDS
• LIFE
• ELSA (European Lacipidine Study on
  Atherosclerosis)

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SOLACE Safety of Lotrel vs.Amlodipine in a
Comparative Efficacy Trial
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SOLACE Study Design
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SOLACE Change from Baseline in SBP
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SOLACE Change in SBP Baseline SBP 180 mm Hg
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SELECT Primary Study Objective
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SELECT Study DesignITT Population
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SELECT Change From Baseline in Mean24-Hour ABPM
SBP
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SELECT Change from Baseline in Mean 4-hour ABPM
DBP
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SHIELD Study Design
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SHIELD Time to Target BP (lt130/85 mm Hg)
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SHIELD Conclusions

• Fixed-dose amlodipine besylate/benazepril HCl
  therapy
• reduced BP to goal (lt130/85 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.
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LEAADConclusions

• 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 200417(5) part
2180A.
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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-doseamlodipine besylate/benazepril HCl
  combination therapyshowed 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. 200215166A.
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Relative Potency of ACE Inhibitors in Tissue
Relative tissue potency
ACE inhibitor
High tissue affinity

• Quinaprilat 22.3
• Benazeprilat 21.6
• Perindoprilat 13.3
• Ramiprilat 10.0
• Lisinopril 3.4
• Fosinoprilat 0.6

Low tissue affinity
Fabris B et al. Br J Pharmacol. 1990100651-655.
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DIOVAN
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Angiotensin II Escape With Long-term ACEI Therapy
Plasma A II levels increase with time, although
plasma angiotensin-converting enzyme activity
remained suppressed
100
80
60
Plasma ACE, nmol/mL/min
40
20
0
30
20
Plasma A II, pg/mL

10
0
Placebo
4h
24h
1
2
3
4
5
6
Hospital
Months
P lt 0.001 vs placebo. Adapted with permission
from Biollaz J, et al. J Cardiovasc Pharmacol.
19824966972.
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Multiple Pathways of Angiotensin II Production
Angiotensinogen

• t-PA
• Cathepsin G
• Tonin

Renin
Kinins
Ang I
CAGE Cathepsin G Chymase
ACE
Ang II
Degradation products
ACE inhibitor site of action
AT1 receptor
AT2 receptor
ARB site of action

• Antiproliferation
• Apoptosis
• Differentiation
• Vasodilation

• Hypertrophy/proliferation
• Vasoconstriction
• Aldosterone release
• Antidiuretic hormone release

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Clinical Significance of AT1 Receptor Blockade
ARB
A II
AT1
AT1 receptor blockade
AT2
A II binding at the AT2 receptor
?BP
?Atherosclerosis
?EndothelialFunction
?NeuroendocrineActivation
?LVH
Benefits Cardiac, Vascular, and Renal Function
LVH left ventricular hypertrophy.
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The Effect of ARBs on Diabetic Nephropathy
IDNT
IRMA 2
RENAAL
MARVAL
Endpoints
Primary composite doubling of serum
creatinine/ESRD/ death
Time to onset of nephropathy with UAER gt 200 ?g/
min. 30 greater than baseline
Primary composite doubling of serum
creatinine/ESRD/ death
? UAER
Results
VAL significantly lowered UAER (44) vs. AML
(17) (Plt.001)
Risk of primary endpoint lower by 16 (P .02)
with LOS
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)
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 LOS
  no difference in deaths

• lower doubling of serum creatine, ESRD with IRB
• 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.
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Cardiovascular Benefits of ARBs
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Val-HeFT Study Design and Inclusion Criteria
5,010 patients ? 18 years EF lt 40 NYHA II
IV LVIDD gt 2.9 cm/m2
Receiving background therapy
ACEIs (93), diuretics (86),digoxin (67), beta
blockers (36)
Randomized to
Valsartan 40 mg BID titrated to 160 mg
BID
Placebo
Cohn JN, et al. N Engl J Med. 200134516671675.
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Val-HeFT Effect of Valsartan on Primary
Endpoints

• Valsartan reduced overall HF morbidity by 13 (P
  0.009)
• patients were also receiving other prescribed HF
  therapies 93 on ACEIs, 36 on BBs, 86 on
  diuretics, 67 on digoxin
• Overall mortality was similar in the 2 groups
• targeted maintenance dose valsartan 160 mg BID
  (starting dose 40 mg BID) 84 of patients
  achieved target dose
• no evidence of further clinical benefit when
  valsartan added to adequate dose of ACEI.
  Overall results largely driven by the 7 of
  patients not on ACEI

Morbidity defined as all-cause mortality, sudden
death with resuscitation, hospitalization for
worsening heart failure, or therapy with IV
inotropes or vasodilators.
Cohn JN, et al. N Engl J Med. 200134516671675.
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ACE-I Comparator MI Trial

• MI Trials with Mortality Benefit
• Early Use Long-Term
• GISSI 3 lisinopril SAVE captopril
• ISIS 4 captopril AIRE ramipril
• Chinese-Cap captopril TRACE trandolapril
• Captoprilmost extensively studied with survival
  benefits in both early initiation and long-term
  trials

Two prior direct ARB-ACE-I comparisons to
captopril (50 mg tid) showed a trend for fewer
deaths and major CV events with captopril therapy.
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CHARM Trial Program
CHF NYHA class II IV
Total N 7,500 Duration 42 mo.
EF gt 40 not on an ACEI (n 3,022)
EF ? 40
ACEI intolerant (n 2,000)
ACEI treated (n 2,548)
Randomization
Randomization
Randomization
Candesartan 4/8 32 mg
Placebo
Primary endpoint CV death and CHF
hospitalizationOverall endpoint all-cause
mortality
(McMurray J, et al. Presented at ESC 2000.
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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

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Acute MI (0.510 days)SAVE, AIRE or TRACE
eligible(either clinical/radiologic signs of HF
or LV systolic dysfunction)
Major Exclusion Criteria Serum creatinine gt
2.5 mg/dL BP lt 100 mm Hg Prior intolerance of
an ARB or ACE-I Nonconsent
double-blind active-controlled
Valsartan 160 mg bid (n 4909)
Captopril 50 mg tid Valsartan 80 mg bid (n
4885)
Captopril 50 mg tid (n 4909)
median duration 24.7 monthsevent-driven
Primary Endpoint All-Cause Mortality Secondary
Endpoints CV Death, MI, or HF Other
Endpoints Safety and Tolerability
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Study DrugDose Titration
Am Heart J. 2000140727734.
102
Mortality by Treatment
0.3
0.25
0.2
0.15
Probability of Event
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
6
12
18
24
30
36
Captopril 4909 4428 4241 4018 2635 1432 364

Valsartan 4909 4464 4272 4007 2648 1437 357
Valsartan Cap 4885 4414 4265 3994 2648 1435 382
Pfeffer, McMurray, Velazquez, et al. N Engl J Med
2003349
103
All-Cause MortalityNon-Inferiority Analyses
Hazard Ratio(97.5 CI)
P-value(noninferiority)
noninferiority margin
0.8
1
1.2
1.13
Favors Valsartan
Favors Captopril
104
Mortality in SAVE,TRACE, AIRE, and VALIANT
Hazard Ratio for Mortality
Valsartan preserves 99.6 of mortality benefit of
captopril.
FavorsActive Drug
FavorsPlacebo
105
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
  mortalityand more adverse drug events.
• Implications
• In these patients, valsartan is a clinically
  effective
• alternative to an ACE inhibitor.

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107
Patients With CRD and HTN Have Minimal Changes
in Serum Creatinine With ACEI or ARB Therapy
2.9 2.7 2.5 2.3 2.1 1.9 1.7 1.5 1.3 1.1 0.9 0.7
A
ACEI or ARBStarted
B
Serum Creatinine (mg/dL)
C
Baseline
1
2
3
4
Weeks
Bakris GL, Weir M. Arch Intern Med.
2000160(5)685-693. Reprinted by permission,
American Medical Association.
www.hypertensiononline.org
108
Rationale for Diuretic/ARB Combination
109
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

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111
THE END
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Additional Trandolapril StudiesEffects on
Proteinuria
Trandolapril Verapamil n14
Proteinuria
Verapamil
Trandolapril
n11
n12
Mean arterial pressure
-10

• N37
• 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

-27
-33
-30
Baseline 604 Endpoint 421
Baseline 616 Endpoint 399
Changes from Baseline ()
-50
-62
Baseline 672 Endpoint 234
-70
Proteinuria baseline and endpoint expressed in
mg/d.
Bakris et al. Kidney Int. 1998541283-1289.