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”A HEALTHY DIET”

so man and woman

would live long, healthy

lives

Satan createdMcDonalds and brought

forth the 99 cent double cheeseburger, and the value meal

Man said

“Super size that” and gained pounds

GOD created healthful

yyooggurturt

Satan created

chocolatechocolate

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

SatanBegan 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

LDLLDL

Satan said“This endothelium is

inflamed….inflamed….Let’s hope it becomes

unstable!”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’sHMO’s

GOD Finally growing weary of Satan

antics created:

REFERENCES

• WWW.HYPERTENSIONONLINE.ORG

• WWW.LIPIDSONLINE.ORG

CONTENTS

LOGICASCOT

SOLACESELECT SHIELDLEAADALERT

DIOVAN

RAAS

• Endocrine (Systemic) PhenomenonServomechanism to Maintain Blood Pressure

• Autocrine/Paracrine (Tissue Level)– Effects Target Organ Damage

• Irrespective of the Systemic Renin Profile

Complications of Hypertension:Target-Organ Damage

O2 Endothelial Cells and

H2O2 Vascular Smooth Muscle

Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk

Factors

Endothelial Dysfunction

Apoptosis

VasoconstrictionLeukocyteadhesion

Lipiddeposition

ThrombosisVSMCgrowth

HypertensionSmokingDiabetes LDL Homocystein

e

www.hypertensiononline.org

Albuminuria

• Reflects

– Endothelial Dysfunction

– Glomerular Pressures

• “Nephrological Hgb A1c/ Ldl Cholesterol”

Definitions of Microalbuminuria and Macroalbuminuria

Parameter NormalMicro-

albuminuriaMacro-

albuminuria

Urine AER

(g/min)< 20 20 - 200 >200

Urine AER

(mg/24h)< 30 30 - 300 >300

Urine albumin/

Cr# ratio (mg/gm)

< 30 30 - 300 >300

AER=Albumin excretion rate 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 Glomerular Effects of CCBs and ACE InhibitorsInhibitors

Valentino VA et al. Arch Intern Med. 1991;151:2367-2372.Vivian EM et al. Ann Pharmacother. 2001;35:452-463.

Dilation of afferent arteriole only

Dilation of both afferent and efferent arteriole

Glomerular pressureAlbumin excretion rate

Glomerular pressureAlbumin excretion rate

Efferent arteriole

Glomerulus

DHPCCBACE inhibitor

Bowman’s capsule

Afferentarteriole

Efferent arteriole

Afferentarteriole

Glomerulus Bowman’s capsule

216432

209422

191391

131278

216432

210428

193405

139290

Incidence of Renal Events and Death: AASK

Cumulativeincidence

(%)

No. at risk Amlodipine Ramipril

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.

3 12 24 36 3 12 24 360

Months

10

20

25

5

0

15

GFR event, ESRD, or death

0

Months

ESRD or death

Amlodipine besylateRamipril

RR=41%†

RR=38%*

Change in Proteinuria From Baseline: AASKChange in Proteinuria From Baseline: AASK

Months

inUP/Cr

(%)-35

0

50

125

230

0 6 24 36

-55

-700 6 24 36

UP:Cr, urinary protein:creatinine ratio. AASK Study Group. JAMA. 2001;285:2719-2728.

Baseline UP:Cr 0.22 Baseline UP:Cr >0.22

AmlodipineRamipril

12 12

Months

• 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 inDM-HTN Patients With Microalbuminuria

Effects on Blood Pressure

DM-HTN, concomitant type 2 diabetes and hypertension.Fogari R et al. AJH. 2002;15:1042-1049.

170

160

150

140

130

1200 3 6 12 18 24 30 36 42 48

Months

SBPmmHg

0 3 6 12 18 24 30 36 42 48

100

90

80

70

Months

DBPmmHg

Amlodipine besylate (n=103)Fosinopril (n=102)Combination (n=104)

30

Amlodipine/Fosinopril Combination Therapy inDM-HTN Patients With Microalbuminuria

Effects on Microalbuminuria

*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.

100

90

80

70

60

50

40

200 3 6 12 18 24 30 36 42 48

*†

†† †

†

† ‡ †

†††

††*†

†

** *

** * *

Months

Proteinuriamg/24h

Amlodipine besylate (n=103)Fosinopril (n=102)Combination (n=104)

Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005.Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005.

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)

ASCOT Entry Criteria

Sever PS et al. J Hypertens 2001;19:1139–1147. | Sever PS et al. Lancet 2003;361:1149–1158.

• 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)

..

Amlo/ACEIn = 9639

Atenolol/thiazn = 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)

ASCOT – BPLA - Preliminary results

Baseline Characteristics

Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005.Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005.

19,342 patientsaged 40–79

withU N T R E A T E DSBP ≥160 mmHg

and/orDBP ≥100 mmHg

ORT R E A T E D

SBP ≥140 mmHg and/or

DBP ≥90 mmHg

In each arm, patients

with total chol of ≤ 6.5

mmol/L randomized

to atorvastatin (10 mg) or placebo

daily(n=10,297)

RA

ND

OM

IZA

TIO

RA

ND

OM

IZA

TIO

NN

atenolol50 mg

amlo5 mg

amlo 10 mg

atenolol100 mg

amlo10 mg +

perindopril4 mg

amlo10 mg +

peri 8 mg(2 x 4 mg)

amlo 10 mg +

peri 8 mg(2 x4 mg)

+doxa 4 mg

amlo 10 mg +

peri 8 mg(2 x 4 mg)

+doxa 8 mg

atenolol100 mg +BFZ 2.5 mg + K+

atenolol100 mg +BFZ 2.5

mg + K+ + doxazosin GITS 4 mg

atenolol100 mg +BFZ 1.25 mg + K+

atenolol100 mg +

BFZ 2.5 mg + K+ +

doxazosin GITS 8 mg

5 Years or 1,150 Primary Events

Blood pressure medication titrated to next step to achieve target blood pressures:No diabetes: <140/90 mmHgPatients with diabetes: <130/80 mmHg

Sever PS, for the ASCOT Investigators. J Hypertens. 2001;19:1139–1147.

amlo = amlodipine; peri= perindoprildoxa = doxazosin GITS (gastrointestinalTransport system); BFZ = bendroflumethiazide

ASCOT – BPLAASCOT – BPLA

MethodsMethods

– 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

ASCOT – BPLA Preliminary Results

Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005.Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005.

ASCOT-BPLA Secondary Endpoints

The area of each square is proportional to the amount of statistical information.*Excludes silent non-fatal MI.

FavorsFavorsamlodipine amlodipine perindopril perindopril

FavorsFavorsatenolol atenolol thiazide thiazide

0.50 0.70 1.00 1.45

EndpointEndpoint

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

2.00

PP Value Value

P = 0.0003

P = 0.0070

P < 0.0001

P = 0.0247

P = 0.0010

P = 0.0003

P = 0.1257

Adapted from Dahlöf B et al. Lancet. 2005;366:895–906.

Unadjusted Hazard Ratio Unadjusted Hazard Ratio (95% CI)(95% CI)

0.50 0.70 1.00 1.45

EndpointEndpoint

Silent MI

Unstable angina

Chronic stable angina

Peripheral arterial disease

Life-threatening arrhythmias

New-onset diabetes mellitus

New-onset renal impairment

2.00

FavorsFavorsamlodipine amlodipine perindopril perindopril

FavorsFavorsatenolol atenolol thiazide 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.

ASCOT-BPLA Tertiary Endpoints

PP Value Value

P = 0.3089

P = 0.0115

P = 0.8323

P = 0.0001

P = 0.8009

P < 0.0001

P = 0.0187

Unadjusted Hazard Ratio Unadjusted Hazard Ratio (95% CI)(95% CI)

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 DesignITT Population

SELECT: Change From Baseline in Mean24-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: ConclusionsFixed-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

levelsACE, angiotensin-converting enzyme; HCTZ, hydrochlorothiazide.Bakris GL, Weir MR. J Clin Hypertens. 2003 [in press].

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 2004;17(5) part 2:180A.

ALERT: Conclusions

LVH, left ventricular hypertrophy.Neutel JM et al. Am J Hypertens. 2002;15:166A.

• 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

Quinaprilat

22.3

Benazeprilat

21.6

Perindoprilat

13.3

Ramiprilat

10.0

Lisinopril

3.4

Fosinoprilat

0.6

Relative Potency of ACE Inhibitors in Tissue

Relative tissue potencyACE inhibitor

Fabris B et al. Br J Pharmacol. 1990;100:651-655.

High tissue affinity

Low tissue affinity

DIOVAN

*P < 0.001 vs placebo. Adapted with permission from Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4:966–972.

Plasma A II levels increase with time, although plasma angiotensin-converting enzyme activity remained suppressed

Angiotensin II Escape With Long-term ACEI Therapy

Pla

sma

AC

E,

nm

ol/

mL

/min

100806040

200

* * * * * * * *

30

20

10

0

Pla

sma

A I

I,

pg

/mL

*

Placebo 4h 24h 1 2 3 4 5 6

Hospital Months

Clinical Significance of AT1 Receptor Blockade

A II

AT2

BPBP AtherosclerosisAtherosclerosis EndothelialFunction

EndothelialFunction

NeuroendocrineActivation

NeuroendocrineActivation LVHLVH

Benefits Cardiac, Vascular, and

Renal Function

Benefits Cardiac, Vascular, and

Renal Function

AT1 receptor

blockadeA II binding at the AT2

receptor

ARB

LVH = left ventricular hypertrophy.

AT1

IDNT IRMA 2 RENAAL MARVAL

Primary composite: doubling of serum creatinine/ESRD/ death

Time to onset of nephropathy with UAER > 200 g/ min. 30% greater than baseline

Primary composite: doubling of serum creatinine/ESRD/ death

UAEREndpoints

Results VAL significantly lowered UAER (44%) vs. AML (17%) (P<.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)

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.

– lower doubling of serum creatine, ESRD with IRB

– no difference in deaths

– lower doubling of serum creatine, ESRD with LOS; no difference in deaths

The Effect of ARBs on Diabetic Nephropathy

Cardiovascular Benefits of ARBs

AimsVALIANT was designed as a mortality trial in high-risk MIpatients (SAVE, AIRE, TRACE) who derived particular benefitsfrom 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

Primary Endpoint: All-Cause MortalitySecondary Endpoints: CV Death, MI, or HFOther Endpoints: Safety and Tolerability

Captopril 50 mg tid(n = 4909)

Valsartan 160 mg bid

(n = 4909)

Captopril 50 mg tid + Valsartan 80 mg

bid(n = 4885)

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

median duration: 24.7 monthsevent-driven

Cap 6.25 mgVal 20 mg

Cap 12.5 mgVal 20 mg

Cap 25 mgVal 40 mg

Cap 50 mg (tid)Val 80 mg (bid)

COMBINATION

Cap 6.25 mgCap 12.5 mg

Cap 25 mgCap 50 mg (tid)

CAPTOPRIL (tid)

Val 20 mgVal 40 mg

Val 80 mgVal 160 mg (bid)

VALSARTAN (bid)

Step I

GOAL by 3 months

Step IVStep IIIStep II

Study DrugDose Titration

Am Heart J. 2000;140:727–734.

Captopril

0

0.05

0.1

0.15

0.2

0.25

0.3

0 6 12 18 24 30 36

Pro

bab

ilit

y o

f Even

tMortality by Treatment

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

Valsartan 4909 4464 4272 4007 2648 1437 357

Months

Valsartan vs. Captopril: HR = 1.00; P = 0.982

Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726

Captopril 4909 4428 4241 4018 2635 1432 364

Valsartan + Cap 4885 4414 4265 3994 2648 1435 382

Valsartan

Valsartan + Captopril

All-Cause Mortality:Non-Inferiority Analyses

0.8 1 1.2

Hazard Ratio(97.5% CI)

1.13

P-value(noninferiority)

0.002Per Protocol

Patient Population

(n = 14,285)

0.004Intention-to-

TreatPatient

Population(n = 14,703)

Noninferiority

Val Superior to Cap

Cap Superior to Val

Noninferiority not Demonstrated

noninferiority margin

Favors Valsartan Favors Captopril

Mortality in SAVE,TRACE, AIRE, and VALIANT

Hazard Ratio for Mortality

FavorsActive Drug

FavorsPlacebo

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

0.5 1 2

Combined

TRACE

SAVE

AIRE

VALIANT(imputed placebo)

Valsartan preserves 99.6% of mortality benefit of captopril.

ConclusionIn patients with MI complicated by heart failure, leftventricular 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 effectivealternative 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 StudiesEffects on Proteinuria

Proteinuria baseline and endpoint expressed in mg/d.

-27%

-33%

-62%

-70

-50

-30

-10

Verapamiln=11

Trandolapriln=12

Trandolapril +Verapamil

n=14

Ch

ang

es

fro

m B

ase

lin

e (%

)

Proteinuria

Mean arterial pressure

Baseline = 604Endpoint = 421 Baseline = 616

Endpoint = 399

Baseline = 672Endpoint = 234

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