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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