Optimal Therapeutic Decisionsin HTN

and Combined Diseases

Timothy A. Denton, M.D., F.A.C.C.High Desert Heart Institute

Victorville, CA

Barney Gumble

• 57 year old male• Central obesity• LDL-C 190 mg/dl• TG’s 280 mg/dl• HDL 30 mg/dl• BP 158/96

Review Articles

Franco V, et al. Hypertensive Therapy: Part ICircluation 2004;109:2953-2958

Franco V, et al. Hypertensive Therapy: Part IICirculation 2004;109:3081-3088

Epidemiology of HTNDiagnosis % Population

PrimaryRenal Parenchymal RenovascularEndocrine Primary aldo Cushing’s Pheo Oral contraceptiveMisc

92-94

2-31-2

0.3<0.1<0.12-40.2

Harrison’s Principles of Internal Medicine, 12th Edition

Physiology of HTN

Primary Hypertension• ? Central / peripheral adrenergic• ? renal• ? hormonal• ? vascular

Classification of BP for Adults

BP Classification SBP mm Hg or DBP mm Hg

Normal <120 or <80

Prehypertension 120–139 or 80–89

Stage 1 Hypertension 140–159 or 90–99

Stage 2 Hypertension ≥160 or ≥100

SBP=systolic BP; DBP=diastolic BP.*JNC 7 Report. JAMA 2003;289:2560-2572.

EyesspasmAV nickingexudatesedema

HTN End-organ Damage

NeckbruitsJVD

HeartS4S3MurmurCADMI

AbdBruitsARF/CRFProteinuria

Extpulsesedema

Lungsrales

BrainCVA

Prevalence of Hyperglycemia in US

2.8

7.1 8.0

14.0 14.1

5.1

0.62.5

4.66.2 5.7

2.7

0

5

10

15

20

25

30

35

40

45

50

20-39 40-49 50-59 60-74 >75 ALL

Age

Per

cent DM

UnDx DM

DM = 10.2 million, UnDx DM = 5.4 million

Diabetes Care 1998;21:518

Hypertension is Prevalent Among Diabetic Adults

Geiss LS et al. Am J Prev Med. 2002;22:42-8.

NHANES III = Third US National Health and Nutrition Examination Survey (1988–1994).

29%

71%

Diabetes + HTN*

Diabetes alone

* Hypertension defined according to JNC-6: BP 130/85 mm Hg

Kannel WB. Am J Hypertens. 2000;13:3S-10S.

No additional CV risk factors

Framingham Offspring Study Men aged 18–74

1 additional CV risk factor

81%

19%

Most Hypertensive Patients Have Complex Hypertension

7

Adipocyte Secretion

Kahn JCI 2000;106:473 (modified)

Insulinsensitizer

Leptin Effects

Kahn JCI 2000;106:473 (modified)

HTN - DM Interaction

• Obesity increases blood pressure• 50% of HTN pts are insulin resistant• Hi insulin levels raise BP• FFA’s inhibit vasodilatation• Poor vasodilation = no glucose to muscles

HOPE - ACE decreases insulin resistance• Hi insulin increases Na and H20 renal

tubular cells

Ginsberg, JCI 2000;106:453

100+90-99

80-8975-79

70-74<70 <120

120-139

140-159

160+

SBP is a Stronger Predictor of CHD Mortality than DBP

Adapted from Neaton and Wentworth.

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

CHD Death Rate/10,000 Person-Years

MRFIT10

Complex Hypertension Increases Mortality Risk

Kannel WB. Am J Hypertens. 2000;13:3S-10S.

10-Y

ear

Pro

bab

ilit

y o

f E

ven

t (%

)

SBP 150-160 + + + + + +Cholesterol 240-262 - + + + + +HDL-C 33-35 - - + + + +Diabetes - - - + + +Cigarettes - - - - + +ECG-LVH - - - - - +

46

1014

21

40

0

6

12

18

24

30

36

42

11

CVD Death Rates - MRFIT

30

60

90

125

611

25

44

0

1020

3040

50

6070

80

90100

110120

130

0 1 2 3

Number of Risk Factors

Dea

th R

ate

/ 10,

000

pers

on-y

rs

DM

No DM

Stamler, Diabetes Care 1993

Outcome Effects of DM and HTN - UKPDS

Adler BMJ 2000;321:412

Barney Gumble

• 57 year old male• Central obesity• LDL-C 190 mg/dl• TG’s 280 mg/dl• HDL 30 mg/dl• BP 158/96

CHF

What is diastolic dysfunction?

CHF

Dilated Normal Hypertrophic

What are the effects ofLDL, DM and HTN?

• Endothelial dysfunction• Endothelial damage• Low HDL• High LDL• Lipid deposition• Protein glycosylation• Plaque instability• Acute coronary events• Death

Lowering of SBP by 20 mm Hg Reduces Cardiovascular Risk by Half

*Data from a meta-analysis of 1 million adults in 61 prospective studies who had no prior vascular disease.Lewington S et al. Lancet. 2002;360:1903-1913.

% m

o rt a

l ity

r ed u

c ti o

n f o

r ea

c h

2 0 m

m H

g d r

o p in

SB

P

-70

-60

-50

-40

-30

-20

-10

0

Stroke IHD Other vascular causes

N=958,074

40-4950-5960-6970-7980-89

Years o

f age

17

Goals of Medical Therapy

• Lower blood pressure• Prolong survival• Improve QOL• Decrease complications

Therapy of HTN

• DietDASH diet (~11 mmHg)Low Na (~4.7 mmHg)

• Exercise (~9 mmHg)• Modify ETOH intake (~3 mmHg)• Weight loss (~5 mmHg / 10 lbs)• Drugs

Effect of Weight Change on DM Onset

BMI @18 -5 to-10kg

-5 to +5 kg

+5 to+7 kg

+7 to+11kg

+11 to+20 kg

+20 kg

<22 1.0 1.0 2.1 2.5 7.9 30.422-24.9 1.4 2.9 4.8 9.0 15.7 48.825-28.9 2.4 9.7 15.4 16.0 43.1 64.4>29 27.8 33.3 32.6 49.4 54.4 76.1

Relative Risk for DM Development

Colditz et al, AIM 1995;122:481

Angiotensinogen

Angiotensin I

Angiotensin II

ReninInhibitor

ACEInhibitor

AT1 receptorInhibitor

Renin

ACE

Endothelin-1

Vasopressin

Vaso-constriction

Vaso-dilatation

Adapted, Bonn, D. Lancet 1998;352:378

non-ACEalternativepathways(chymase,

cathepsin G,chymostatin

ATII generation)

Bradykinin

Inactiveproducts

ACE

? angioedema

cough

increase nitric oxide,prostacyclin

(improved endothelial function ?anti-atherosclerotic?)

hypotension

HOPE Trial

HeartOutcomesPrevention

Evaluation Study

NEJM 2000;342:145-153

Results

Systolic BP (placebo/ramipril)

139 137 138 139139 133 135 136

0

20

40

60

80

100

120

140

160

180

200

Baseline 1 month 2 years end

Visit

mm

Hg

HOPE Trial, NEJM 2000;342:145-153

Results

Diastolic BP (placebo/ramipril)

79 78 78 7779 76 76 76

0

20

40

60

80

100

120

140

160

180

200

Baseline 1 month 2 years end

Visit

mm

Hg

HOPE Trial, NEJM 2000;342:145-153

Results

HOPE Trial, NEJM 2000;342:145-153

Results

HOPE Trial, NEJM 2000;342:145-153

Outcome Ramipril(n=4,645)

Placebo(n=4,652)

P Value

MI, CVA or Death CV Death MI CVA

651 (14%)282 (6.1%)459 (9.9%)156 (3.4%)

826 (17.8%)377 (8.1%)570 (12.3%)226 (4.9%)

<0.001<0.001<0.001<0.001

Non-CV Death 200 (4.3%) 192 (4.1%) 0.74All Cause Death 482 (10.4%) 569 (12.2%) 0.005

Results

HOPE Trial, NEJM 2000;342:145-153

Outcome Ramipril(n=4,645)

Placebo(n=4,652)

P Value

Secondary Outcomes Revascularization Hosp for Unstable Angina DM complications Hosp for CHF

742 (16.0%)554 (11.9%)299 (6.4%)141 (3.0%)

852 (18.3%)565 (12.1%)354 (7.6%)160 (3.4%)

<0.0020.680.030.25

Other Outcomes CHF Arrest Worsening Angina New DM Unstable Angina w ECG

417 (9.0%)37 (0.8%)

1107 (23.8%)102 (3.6%)175 (3.8%)

535 (11.5%)59 (1.3%)

1220 (26.2%)155 (5.4%)180 (3.9%)

<0.0010.02

0.004<0.001

0.76

Results

HOPE Trial, NEJM 2000;342:145-153

Summary• Ramipril decreased

CV mortalityMI and CVAall-cause mortalityRevascularization ratesDM complicationsCHFWorsening anginaNew onset DM

• Effects were see in all groups except those without

cardiovascular disease

HOPE Trial, NEJM 2000;342:145-153

Implications

• We have a new standard of care

• All patients with vascular disease should beconsidered for ACE inhibition (e.g., ramipril)

atenolol ± HCTZ or 17% vs verapamil SR ± HCTZ ortrandolapril trandolapril

INVEST

Antihypertensive Treatments and Incidence of New Onset Diabetes

% Higher Incidence in Patients Using Diuretics, β-blockers

Study

chlorthalidone 18% vs amlodipine

43% vs lisinoprilALLHAT

atenolol 33% vs losartan LIFE

diuretics, β-blockers 13% vs captoprilCAPPP

co-amilozide ± β-blocker 30% vs nifedipine GITSINSIGHT

placebo ± SOC 16% vs candesartan ± SOCCHARM

placebo ± SOC 50% vs ramipril ± SOCHOPE

Lancet. 1999;353:611-616. Lancet. 2003;362:759-766. JAMA. 2003;290:2805-2816. Lancet. 2000;356:366-372. Lancet. 2002;359:995-1003. JAMA. 2002;288:2981-2997. N Engl J Med. 2000;342:145-153.

Trandolapril: Reduces Mortality in Patients with LV Dysfunction Post-MI

In the TRACE Study, the mortality curves diverged early on, favoring trandolapril, and remained distinct for 10 years of follow-up.

Years since randomization

Placebo

Trandolapril

0 1 5 6 72 3 4 8 9 10

70

60

40

30

20

0

50

10Mo

rtal

ity

rate

(%

)

No. pts at risk

Trandolapril Placebo

876 677 475 434 385615 576 524 351 310 265

873 647 417 398 338564 497 463 299 273 245

Log rank P=0.04

Relative Risk 0.89, 95% Cl 0.80-0.99

Buch P. et al. JACC 2004;1012-128:159A. 50

Gustafsson I et al. J Am Coll Cardiol. 1999;34:83-9.

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

-44%

-54%-62%

Cardiovascular Death

Progression to Heart Failure

Sudden Death

% O

dd

s R

edu

ctio

n

TRACE StudyPost-MI Diabetic Patient Long-term Survival Benefits (n=237)

Trandolapril: Survival Benefits Among Post-MI Diabetics

P<0.001

P=0.01

P=0.01

51

Key Points for Optimal Hypertension Management

JNC 7 Report. Hypertension. 2003;42(6):1206-1252.

JNC 7 recommends:

If SBP >20 mm Hg, DBP >10 mm Hg over goal,

consider initiating with 2-drug combination

<130/80 mm Hg in diabetes or renal

disease

<140/90mm Hg

JNC 7BP

Goals

HTNis one of the few diseases

in which we make the MAJOR therapeutic drug decisions

based on comorbidity

Classes of Anti-Hypertensives(1999 PDR)

Adrenergic blockersAlpha/Beta adrenergic blockersACE inhibitorsACE + Ca blockersACE + diureticsARB’sARB’s with diureticsBeta blockersBeta blockers with diureticsCalcium blockersDiureticsRauwolfia derivativesVasodilators

Preparations of Anti-Hypertensives by Class(1999 PDR)

Adrenergic blockersAlpha/Beta adrenergic blockersACE inhibitorsACE + Ca blockersACE + diureticsARB’sARB’s with diureticsBeta blockersBeta blockers with diureticsCalcium blockersDiureticsRauwolfia derivativesVasodilators

65

114572

186

25242

18

Total = 133

Compelling Indications* for Antihypertensive Drugs

High-risk Condition† ACEI

Aldosterone Antagonist ARB

-Blocker CCB Diuretic

CAD * * * *Post-MI * * *Heart failure * * * * *Diabetes * * * * *Chronic kidney disease

* *

Recurrent stroke prevention

* *

*Compelling indications are based on benefits from outcomes studies or existing clinical guidelines. †The high-risk condition is managed simultaneously with the BP. A combination of agents may be required.Adapted from JNC 7. Guidelines. JAMA. 2003;289(19):2560.

JNC 7 Algorithm for Treatment of HTN

JNC 7 Report. Hypertension. 2003;42(6):1206-1252.

Goal BP Not Reached

Optimize dose/add drugs to reach goal BP Consultation with HTN

specialist

Initial drug choices

Lifestyle modifications

Without Compelling Indications

Stage 2 HTN SBP ≥160, DBP ≥100 mm

Hg2-drug combo for most (thiazide-type diuretic and ACEI, or ARB, or BB, or

CCB)

Stage 1 HTNSBP 140–159, DBP 90–99

mm Hg Thiazide-type diuretics for most. Consider

ACEI, ARB, BB, CCB, or combination

Goal BP (<140/90 mm Hg)Not Attained

(<130/80 mm Hg for those with diabetes or chronic

kidney disease)

Compelling Indications Other antihypertensives

as needed (diuretics, ACEI, ARB, BB, CCB)

as needed

With Compelling Indications

When BP >20/10 mm Hg above goal, consider initiating with 2

drugs, separate or in fixed combinations

Prevalence of Microalbuminuria in the US Population

Patient Type Prevalence

Diabetes 29%

Hypertension 16%

Normal Population* 5%

Microalbuminuria defined as urinary albumin concentration 30 mg/g to 299 mg/g*No hypertension, CVD, diabetes, elevated serum creatinineJones CA et al. Am J Kidney Dis. 2002;39(3):445-459. 28

Definitions of Proteinuria

JNC 7 Report. Hypertension. 2003;42(6):1206-1252. Eknoyan G et al. Am J Kidney Dis. 2003;42:617-622.

JNC 7Definition

(albumin/creatinine ratio on spot urine)

Levelsof

Proteinuria

NKFDefinition

(albumin/creatinine ratio on spot urine)

<20 mg/g Normal <30 mg/g

20-200 mg/g Microalbuminuria 30-300 mg/g

>200 mg/g Macroalbuminuria >300 mg/g

N orm oalb u m in u r ia

Microalb u m in u ria 0123456

B orch-Johnsen e t a l. A rteriosc ler T hrom b V asc B io l. 1999;19:1992.

N =2,085 , 10 year fo llow -up

M icroalbum inuria andIschem ic H eart D isease R isk

M icroalbum inuria andIschem ic H eart D isease R isk

R Rof

IH D

S B P <140S B P 140–166

S B P >160

TRAndolapril Cardiac Evaluation Study:Reduction in All Cause Mortality at 6-Year Follow-Up

Torp-Pedersen et al, for the Trandolapril Cardiac Evaluation (TRACE) Study Group. Lancet. 1999;354:9-12.

873 647 564 497 463 416 373876 677 615 576 524 475 431

Time (years) Since Treatment

All-

Cau

se M

ort

alit

y

Placebo

Trandolapril

0 1 5 6 7

Number of Patients

0.7

0.6

0.4

0.3

0.2

0.0

0.5

0.1

2 3 4

PlaceboTrandolapril

C o m p a r is o n o f M e a n C h a n g e s inA lb u m in u r ia a n d M e a n A r te r ia l P r e s s u r e F r o m

S tu d ie s o f H y p e r te n s iv e P a t ie n ts W ith P r o te in u r ia

C o m p a r is o n o f M e a n C h a n g e s inA lb u m in u r ia a n d M e a n A r te r ia l P r e s s u r e F r o m

S tu d ie s o f H y p e r te n s iv e P a t ie n ts W ith P r o te in u r ia

-4 5

-3 5

-2 5

-1 5

-5

5

1 5 M A P (m m H g )

A lb u m in u ria

%

N ife d ip in e(N = 1 7 3 )

A l l D H P C C B s(N = 1 2 1 )

N o n D H P C C B s(N = 1 1 1 )

A C E In h ib ito r s(N = 7 2 3 )

K lo k e H e t a l. K id n e y In t . 1 9 9 8 ;5 3 :1 5 5 9 .

Properties of ACE Inhibitors Based on Pharmacology and Clinical Trial

Evidence

Sobel B, Bakris G. Hypertension–A Clinicians Guide. 1999;47.

ACE inhibitor

• Lowers blood pressure

• Lowers proteinuria

• Reduces mortality in patients with CHF (post-MI*)

CaptoprilEnalaprilLisinoprilRamipril*

Trandolapril*

II

ACE inhibitor

• Lowers blood pressure

• Lowers proteinuria

• Reduces mortality in patients with CHF (post-MI*)

• Tissue selectivity

Bioavailability >50%

Once-daily dosing

Dual mode of excretion*

Ramipril*Trandolapril*

III

BenazeprilCaptoprilCilazaprilEnalapril

FosinoprilLisinopril

Perindopril Quinapril Ramipril

Trandolapril

I

ACE inhibitor

• Lowers blood pressure

• Lowers proteinuria

ACE Inhibitor Metabolism

Generic Trade Active Compound Recommended Dosing

quinapril Accupril quinaprilat 1-2 x/day enalapril Vasotec enalaprilat 1-2 x/day benazapril Lotensin benazaprilat 1-2 x/day lisinopril Zestril

Prinivil lisinopril* 1 x/day

trandolapril Mavik trandolaprilat 1 x/day ramipril Altace ramiprilat 1-2 x/day perindopril Aceon perindoprilat 1-2 x/day captopril Capoten captopril* 2-3 x/day moexipril Univasc moexiprilat 1-2 x/day fosinopril Monopril fosinoprilat 1-2 x/day

ACE Inhibitor Half-Lives

Generic Trade ½ life - hours (accumulation)

Recommended Dosing

quinapril Accupril 3 1-2 x/day enalapril Vasotec 11 1-2 x/day benazapril Lotensin 10-11 1-2 x/day lisinopril Zestril

Prinivil 12 1 x/day

trandolapril Mavik 16-24 1 x/day ramipril Altace 13-17 1-2 x/day perindopril Aceon 3-10 (mean) 1-2 x/day captopril Capoten 4 (elimination) 2-3 x/day moexipril Univasc 2-9 1-2 x/day fosinopril Monopril 11.5 1-2 x/day

Trandolapril: True 24-Hour Blood Pressure Control

Cesarone et al. J Cardiovasc Pharmacol. 1994;23(suppl 4):S65-S72.

Systolic Pressure by Ambulatory Monitoring 24-48 Hours after Last Medication Dose after 2 Weeks of Treatment (Mean SEM)

Baseline

Placebo washout*

Active treatment

27 30 33 36 39 42 45 48

Trandolapril

= 2 mg OD

Blood Pressure-Lowering Effects Persist Even 24-48 Hours after Dosing (N=13)

Hours after dosing

3 6 9 12 15 18 21 24

mm

Hg

160

150

140

130

120

110

SBP0-24 Hours 24-48 Hours

Placebo Washout

48

ACE Inhibitor Pricing

www.drugstore.com (10/5/04)

Generic Trade Cost per Pill (low dose)

Cost per Pill (high dose)

quinapril Accupril Accupril 5 mg 1.17 40 mg 1.11

enalapril Vasotec Vasotec 2.5 mg enalapril 2.5 mg

0.84 0.19

20 mg 20 mg

1.53 0.19

benazapril Lotensin Lotensin 5 mg benazapril 5 mg

1.07 0.72

40 mg 40 mg

1.00 0.72

lisinopril Zestril Prinivil

Zestril 2.5 mg Prinivil 2.5 mg

lisinopril 2.5 mg

0.69 0.59 0.37

40 mg 40 mg 40 mg

1.49 1.47 0.74

trandolapril Mavik Mavik 1 mg 1.04 4 mg 1.12

ramipril Altace Altace 1.25 mg 0.97 10 mg 1.47

perindopril Aceon Aceon 2 mg 1.09 8 mg 1.63

captopril Capoten Capoten 12.5 mg captopril 12.5 mg

1.05 0.07

100 mg 100 mg

2.37 0.14

moexipril Univasc moexipril 7.5 mg Univasc 7.5 mg

0.67 1.13

15 mg 15 mg

0.67 0.82

fosinopril Monopril Monopril 10 mg fosinopril 10 mg

1.13 1.00

40 mg 40 mg

1.11 1.00

1 + 1 = 3

Combination Drugs:A Different Animal

• Beta blocker + diuretic• ACE + diuretic• ACE + calcium blocker• ARB + diuretic• Diuretic + diuretic• “other” + diuretic

Key Points for Optimal Hypertension Management

Fixed-combination agents recommended

• Improved tolerability

• Simpler dosing regimens may increase compliance

• 1 copay—may reduce prescription costs for combination drug vs separate agents

Ramsay LE et al. J Hum Hypertens. 1999;13:569-592Ruzicka M et al. Drugs. 2001;61:943-954Sica DA. Drugs. 2002;62:443-462Neutel JM et al. Am J Hypertens. 1999;12(8, pt 2):73S-79S. 

Combination Therapy Needed to Achieve Target SBP Goals

Updated from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

Number of BP meds

Trial/SBP Achieved

1 2 3 4

UKPDS (144 mm Hg)

RENAAL (141 mm Hg)

ALLHAT (138 mm Hg)

IDNT (138 mm Hg)

HOT (138 mm Hg)

INVEST (133 mm Hg)

ABCD (132 mm Hg)

MDRD (132 mm Hg)

AASK (128 mm Hg)

Benazepril HCl/ Amlodipine

Trandolapril/Verapamil SR

Blood Pressure Lowering

+++ +++

Proteinuria-25%*

(NS difference of B+A vs B alone)

-62%† (88% difference of T+V

vs T alone P<0.05)

Clinical Outcomes

No StudiesINVEST

(T+V equivalent to SOC in mortality in HTN+CAD)

Trandolapril/Verapamil SR vs Benazepril HCl/ Amlodipine in Complex Hypertension

A=amlodipine; B=benazepril; T=trandolapril; V=verapamil SR; NS=not significant; SOC=standard of care;

Fogari R, et al. Clin Drug Invest 1997;13(suppl 1):50-55Bakris et al. Kidney Int. 1998;54:1283-89Pepine CJ et al. JAMA. 2003;290:2805-16

* In patients with microalbuminuria; †in patients with macroalbuminuria

INternational VErapamil SR-Trandolapril STudy

(INVEST)

INVEST Relative Risk of New Onset Diabetes

The verapamil SR strategy reduced the risk of new onset diabetes by 15%

CI = confidence interval

Unadjusted hazard ratios with 95% CI

0.6 0.8 1 1.2

Verapamil SRStrategy

β-Blocker Strategy

Outcome Favors

Outcome

Verapamil SR Strategy

n = 8098 No. (%)

Atenolol Strategy n = 8078 No. (%)

HR

95% CI

New diabetes 569 (7.0) 665 (8.2) 0.85 0.76, 0.96

Primary outcome or new diabetes

1185 (14.6) 1313 (16.3) 0.90 0.83, 0.97

Cooper-DeHoff R et al. Circulation. 2003;108:IV-750.

-27%-33%

-62%-70

-50

-30

-10

Verapamil315 mg

n=11

Trandolapril5.5 mgn=12

Trandolapril +Verapamil3/220 mg

n=14

Ch

ang

es f

rom

bas

elin

e (%

)

Baseline=604Endpoint=421 Baseline=616

Endpoint=399

Baseline=672Endpoint=234

Proteinuria baseline and endpoint expressed in mg/d.Bakris et al. Kidney Int. 1998;54:1283-89.

Proteinuria Mean arterial pressure

Trandolapril/Verapamil SR: Proteinuria Reduction in Diabetics

P<0.05 vs T or V alone

63

Proteinuria Predicts Stroke andCHD Events in Type 2 Diabetes

Proteinuria Predicts Stroke andCHD Events in Type 2 Diabetes

P<0.001

40

30

20

10

0Stroke CHD Events80604020

0

0.5

0.6

0.7

0.8

0.9

1

Su

rviv

al C

urv

es F

or

CV

Mo

rtal

ity

Overall: P <0.001C

B

A

Inci

den

ce(%

)

Months

Miettinen H et al. Stroke. 1996;27:2033-2039.

B: U-Prot 150–300 mg/LA: U-Prot <150 mg/L C: U-Prot >300 mg/L

0

U-Prot = Urinary protein concentration.

100

Trandolapril/Verapamil SR Effects on Lipid Levels

Schneider M et al. J Hypertens. 1996;14:669-77.

N=2452-week treatment period

Trandolapril/verapamil SR(mean doses 1.6/180 mg OD)

Placebo Atenolol + chlorthalidone(mean doses 71/18 mg OD)

0

40

80

120

160

200

240

280

mg

/dL

TriglyceridesLDL Cholesterol

HDL Cholesterol

40 4333

148 140 140222

249

436500

400

300

200

100

0

P<0.05

40

How to Initiate Therapy

• Initial Evaluation• Good history and physical exam (note comorbidities)• Take BP in both arms• Take BP at least 2 min apart and average them• Take BP at least on two separate office visits• Look for end-organ damage• Stratify patient• Initiate drug therapy based on comorbidity and risk

The patient must becomeexpert on their own

blood pressure

Long-term Therapy

Take BP at home

Write each BP down in a log

Date Time BP Pulse

• 1x / day• 2x / day• 3x / day• 3x / week• etc…..

Summary

• HTN + comorbidity = poor prognosis• DM + HTN = more comorbidity• High risk = high benefit• Goals are BP, albuminuria• ACE inhibitors are cornerstone• Combination therapy is often

mandatory

The END

Clinical Trials and Renal Outcomes Based on Proteinuria Reduction

ACE Inhibitor or angiotensin II receptor blocker:

• Increased time to dialysis (30%–35% proteinuria reduction)

• IDNT1

• AASK2

• RENAAL3

• Captopril Trial4

Dihydropyridine calcium channel blocker:

• No change in time to dialysis(No proteinuria reduction)

• DHPCCB* arm-IDNT

• DHPCCB* arm-AASK

*Amlodipine used as DHPCCB.

1Lewis EJ et al. N Engl J Med. 2001;345:851-860.2Wright JT et al. JAMA. 2002;288:2421-2431.3Brenner BM et al. N Engl J Med. 2001;345:861-869.4Lewis EJ et al. N Engl J Med. 1993;329:1456-1462.

Hypertension (HTN)

• ≈50 million adults in the United States have HTN

• ≈66% of adults with HTN are not achieving BP reduction goals below 140/90 mm Hg

• Most will need ≥2 drugs to achieve target BPJNC 7 Report. JAMA. 2003;289:2560-2572.JNC VI. Arch Intern Med. 1997;157:2413-2446. WHO: www.who.int/whr/en/

Chronically elevated blood pressure (BP) is associated with the development of cardiovascular disease (CVD), congestive heart failure (CHF), stroke, and renal failure

JNC 7 Algorithm for Treatment of HTN

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB,

CCB) as needed

With Compelling Indications

Not at Goal BP (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Lifestyle Modifications

Stage 2 HTN (SBP ≥160 or DBP ≥100 mm Hg)

2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 HTN(SBP 140–159 or DBP 90–99 mm

Hg) thiazide-type diuretics for most. May consider ACEI, ARB,

BB, CCB, or combination

Without Compelling Indications

Not at Goal BP

Optimize dosages or add additional drugs until goal BP is achieved.

Consider consultation with HTN specialist

The JNC 7 Report. JAMA 2003;289:2560-2572

Increased Risk of Cardiovascular Events Per Standard Deviation Increase in BP Parameter:

Framingham Study 30y Follow-Up

Gender and Age

Incre

ase

d R

isk o

f C

V E

ven

ts

Systolic

41%

51%43%

23%

9%

33%30%35%

0%

10%

20%

30%

40%

50%

60%

Men (35-64 yr)*

Men (65-94 yr)*

Women (35-64 yr)*

Women (65-94 yr)

Diastolic

*P< 0.001Kannel WB. Am J Cardiol. 2000;85:251-255

Why do we need blood pressure?

• Get blood to the scalp• Distribute flow quickly