hypertension: new concepts, guidelines, and clinical management hypertension: new concepts,...
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Hypertension: New Concepts, Guidelines, and Clinical
Management
Nathan D. Wong, PhD, FACC
Associate Professor and Director
Heart Disease Prevention Program
Division of Cardiology, Department of Medicine
College of Medicine, University of California, Irvine
•Prevalence of Cardiovascular Disease
10 20 30 40 50 60
High BP
CAD
CHF
Stroke
Other
50,000,000
12,200,000
4,600,000
4,400,000
2,800,000
Prevalence (millions)
BP=blood pressure, CAD=coronary artery disease, CHF=congestive heart failure
•Estimated Number of Persons With Cardiovascular Disease in the US
•American Heart Association® . 2000 Heart and Stroke Statistical Update. 1999.
(24%)
Age Distribution of Hypertensives in US Population
(NHANES III and the 1991 Census)
3.7
9.5
13
21.323.7
19.2
9.6
0
5
10
15
20
25
30
18-29 30-39 40-49 50-59 60-69 70-79 80+
Hyp
erte
nsiv
es W
ithi
n Ag
e G
roup
(%
)
Franklin SS. J Hypertension. 1999;17(suppl 5):S29-S36.
Age Groups (y)
47.4 million 47.4 million hypertensiveshypertensives26.0% of US 26.0% of US populationpopulation
26% 74%
<40 40-49 50-59 60-69 70-79 80+Age (y)
17% 16% 16% 20% 20% 11%
Distribution of Hypertension Subtype in the untreated Distribution of Hypertension Subtype in the untreated Hypertensive Population in NHANES III by AgeHypertensive Population in NHANES III by Age
ISH (SBP 140 mm Hg and DBP <90 mm Hg) SDH (SBP 140 mm Hg and DBP 90 mm Hg)IDH (SBP <140 mm Hg and DBP 90 mm Hg)
0
20
40
60
80
100
Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age. Franklin et al. Hypertension 2001;37: 869-874.
Frequency of hypertension
subtypes in all untreated
hypertensives (%)
Peripheral vascular disease
Morbidity
Disability
Renal disease
CADCHFLVHStroke
Hypertension
National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186-208.
Hypertension: A Significant CV and Renal Disease Risk Factor
Benefits of Lowering BP
Average Percent Reduction
Stroke incidence 35–40%
Myocardial infarction 20–25%
Heart failure 50%
Preventable CHD Events from Control of Hypertension in US Adults(Wong et al., Am Heart J 2003; 145: 888-95)
19
37
31
56
21
11
39
21
0
10
20
30
40
50
60
PAR
% /
NNT
Men PAR% Women PAR% Men NNT Women NNT
Treatment to <140/90 mmHg Treatment to <120/80 mmHg
PAR% = population attributable risk (proportion of CHD events preventable), NNT = number needed to treat to prevent 1 CHD event ; <0.01 comparing men and women for PAR%
Preventable CHD Events from Control of Hypertension in US Adults
(Wong et al., Am Heart J 2003; 145: 888-95) (cont.)
• The greatest impact (absolute numbers) from control of hypertension occurs in men, older persons, and those with isolated systolic hypertension
• The greatest proportion of preventable CHD events from control of hypertension occurs in women
• Optimal control of blood pressure could prevent more than one third of CHD events in men and more than half of CHD events in women
BP Control RatesTrends in awareness, treatment, and control of high
blood pressure in adults ages 18–74National Health and Nutrition Examination Survey, Percent
II1976–80
II(Phase 1)1988–91
II(Phase 2)1991–94 1999–2000
Awareness 51 73 68 70
Treatment 31 55 54 59Control 10 29 27 34
Sources: Unpublished data for 1999–2000 computed by M. Wolz, National Heart, Lung, and Blood Institute; JNC 6.
U.S. Department of Health and Human
Services
National Institutes of Health
National Heart, Lung, and Blood Institute
The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)
National Heart, Lung, and Blood InstituteNational High Blood Pressure Education Program
Blood Pressure Classification
Normal <120 and <80
Prehypertension 120–139 or 80–89Stage 1 Hypertension 140–159 or 90–99Stage 2 Hypertension >160 or >100
BP Classification SBP mmHg DBP mmHg
For persons over age 50, SBP is a more important than DBP as CVD risk factor
Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range.
Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN.
Those with SBP 120–139 mmHg or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD.
New Features and Key Messages
4-Year Progression To Hypertension: The Framingham Heart Study
5
18
37
0
10
20
30
40
50
Optimal Normal High-Normal
Patie
nts
(%)
(<120/80 mm Hg) (130/85 mm Hg)(130-139/85-89 mm Hg)
Vasan, et al. Lancet 2001;358:1682-86
Participants age 36 and older
HOT Study: Significant Benefit FromHOT Study: Significant Benefit From
Intensive Treatment in the Diabetic SubgroupIntensive Treatment in the Diabetic Subgroup
Hansson L et al. Lancet. 1998;351:1755-1762.
0
5
10
15
20
25
90 85 80
Major cardiovascular events/1,000 patient-years
p=0.005 for trend
mm Hg
Target Diastolic Blood Pressure
SBP-Associated Risks: MRFIT
Adapted from Neaton JD et al. Arch Intern Med. 1992;152:56-64.
SBP versus DBP in Risk of CHD Mortality
Diastolic BP(mm Hg)
Systolic BP(mm Hg)
CHD Death Rate
100+90–99
80–8975–79
70–74<70 <120
120–139
140–159
160+
48.3
20.6
10.3 11.88.8
8.59.2
23.8
16.913.9
12.812.6 11.8
31.0
25.524.6 25.3
25.224.9
37.434.7
43.8
38.1
80.6
Disease Relative Risk
Kidney failure (ESRD) 2.8Stroke 2.7Heart failure 1.5Peripheral vascular disease 1.8Myocardial infarction* =1.6Coronary artery disease 1.5
ESRD = end-stage renal disease; SBP 165 mm Hg.*Men only.
Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S; Perry HM Jr et al. Hypertension. 1995;25(part 1):587-594; Klag MJ et al. N Engl J Med. 1996;334:13-18; Nielsen WB et al. Ugeskr Laeger. 1996;158:3779-3783; Neaton JD et al. Arch Intern Med. 1992;152:56-64.
Elevated SBP Alone Is Associated With Increased Risk of Cardiovascular and
Renal Disease
Lowering SBP Benefits Older Patients
Clinical trials document importance of controlling elevated SBP to prevent cardiovascular disease– SHEP (Systolic Hypertension in the Elderly
Program)– Syst-Eur (Systolic Hypertension in Europe)
Adapted from SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264; Staessen JA et al. Lancet. 1997;350:757-764.
SHEP: Outcomes
*P=.0003 vs placebo.
Adapted from SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264.
Risk ReductionR
isk
Red
uctio
n (%
)
0
–10
–20
–30
–40
–50
–36*
Total Mortality
–13
Stroke
Systolic Hypertension in Europe (Syst-Eur)
Objective: To determine whether antihypertensive treatment reduces cardiovascular complications in older patients with elevated SBP
Patients: 4695 patients, 60 years of age, with SBP 160–219 mm Hg and DBP <95 mm Hg
Treatments: Nitrendipine (10–40 mg/day) with possible addition or substitution of:
– Enalapril (5–20 mg/day)– Hydrochlorothiazide (12.5–25 mg/day)
Placebo
Follow-up: 2 years (median)
Endpoint: Total strokeMyocardial infarction
Adapted from Staessen JA et al. Lancet. 1997;350:757-764.
Syst-Eur: Outcomes
*P=.003; †P=.03; ‡P=.12; §P<.001.Adapted from Staessen JA et al. Lancet. 1997;350:757-764.
Perc
ent R
educ
tion
0
–5
–10
–15
–20
–25
–30
–35
–40
–45 –42*Heart
FailureStrokeAll CardiacEndpoints
All Fatal/NonfatalCardiac EndpointsMI
–26†
–29‡ –30‡–31§
Risk Reduction
Pulse Pressure
• Increase in pulse pressure (PP) indicates greater stiffness in large conduit arteries, primarily the thoracic aorta.
• PP, therefore, is a surrogate measure of dynamic, cyclic stress during systole.
• PP may be a better marker of increased CV risk than either systolic BP or diastolic BP alone in older persons.
PP = SBP – DBPPP = SBP – DBP
ATP III: The Metabolic Syndrome*
*Diagnosis is established when 3 of these risk factors are present.†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡Some men develop metabolic risk factors when circumference is only marginally increased.Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
<40 mg/dL<50 mg/dL
MenWomen
>102 cm (>40 in)>88 cm (>35 in)
MenWomen
110 mg/dLFasting glucose130/85 mm HgBlood pressure
HDL-C150 mg/dLTG
Abdominal obesity† (Waist circumference‡)
Defining LevelRisk Factor
© 2001, Professional Postgraduate Services®
www.lipidhealth.org
Prevalence of Selected Risk Factors in US Adults with the Metabolic Syndrome (without Diabetes)
(Wong et al., Am J Cardiol 2003, in press)
80.584.2
76.784.6
73.2
82.986.5
57.662.6
22.216.7
95.1
0102030405060708090
100
Men Women
Perc
ent (
%) o
f Met
abol
ic S
yndr
ome
Subj
ects
Waist Cir >40cm M/>35 cm W Blood Pressure >=130/85 or RxFasting Trig. >=150 mg/dl HDL-C <40 mg/dl M/<50 mg/dl WLDL-C >=130 mg/dl Fasting Glucose 110-125 mg/dl
Estimated Proportion of CHD Events Preventable by Control of Blood Pressure, HDL-C, LDL-C, and All 3 Factors to “Optimal”
Levels in Persons with the Metabolic Syndrome (Wong et al., Am J Cardiol 2003, in press)
28.2
51.2 50.646.2
38.1
80.5 82.1
45.1
0
10
20
30
40
50
60
70
80
90
Men Women
Prop
ortio
n of
CH
D E
vent
s Pr
even
ted
(PA
R%
)
BP only HDL-C only LDL-C only All 3 factors
***
* p<0.05, ** p<0.01 compared to men
Antihypertensive
Trial Design
• Randomized, double-blind, multi-center clinical trial
• Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic
• 42,418 high-risk hypertensive patients ≥ 55 years
ALLHAT
Years to CHD Event0 1 2 3 4 5 6 7
Cumulative CHD Event Rate
0
.04
.08
.12
.16
.2
Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209 Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195
Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group
RR (95% CI) p value
A/C 0.98 (0.90-1.07) 0.65
L/C 0.99 (0.91-1.08) 0.81
ALLHAT
ChlorthalidoneAmlodipineLisinopril
Cumulative Stroke Rate
Years to Stroke0 1 2 3 4 5 6 7
0
.02
.04
.06
.08
.1
Number at risk: Chlor 15,255 14,515 13,934 13,309 11,570 6,385 3,217 567 Amlo 9,048 8,617 8,271 7,949 6,937 3,845 1,813 506 Lisin 9,054 8,543 8,172 7,784 6,765 3,891 1,828 949
Cumulative Event Rates for Stroke by ALLHAT Treatment Group
RR (95% CI) p value
A/C 0.93 (0.81-1.06) 0.28
L/C 1.15 (1.02-1.30) 0.02
ALLHAT
ChlorthalidoneAmlodipineLisinopril
Cumulative CHF Rate
Years to HF0 1 2 3 4 5 6 7
0
.03
.06
.09
.12
.15
Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group
HR (95% CI) p value
A/C 1.38 (1.25-1.52) <.001
L/C 1.19 (1.07-1.31) <.001
ALLHAT
ChlorthalidoneAmlodipineLisinopril
Number at risk: Chlor 15,255 14,528 13,898 13,224 11,511 6,369 3,016 384 Amlo 9,048 8,535 8,185 7,801 6,785 3,775 1,780 210 Lisin 9,054 8,496 8,096 7,689 6,698 3,789 1,837 313
Overall ConclusionsALLHAT
Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy.
JNC-VII New Features and Key Messages (Continued)
Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes.
Certain high-risk conditions are compelling indications for other drug classes.
Most patients will require two or more antihypertensive drugs to achieve goal BP.
If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.
JNC-VII New Features and Key Messages (Continued)
The most effective therapy prescribed by the careful clinician will control HTN only if patients are motivated.
Motivation improves when patients have positive experiences with, and trust in, the clinician.
Empathy builds trust and is a potent motivator.
The responsible physician’s judgment remains paramount.
Patient EvaluationEvaluation of patients with documented HTN has three
objectives:
1. Assess lifestyle and identify other CV risk factors or concomitant disorders that affects prognosis and guides treatment.
2. Reveal identifiable causes of high BP.
3. Assess the presence or absence of target organ damage and CVD.
BP Measurement Techniques
Method Brief DescriptionIn-office Two readings, 5 minutes apart, sitting in
chair. Confirm elevated reading in contralateral arm.
Ambulatory BP monitoring
Indicated for evaluation of “white-coat” HTN. Absence of 10–20% BP decrease during sleep may indicate increased CVD risk.
Self-measurement Provides information on response to therapy. May help improve adherence to therapy and evaluate “white-coat” HTN.
CVD Risk Factors Hypertension* Cigarette smoking Obesity* (BMI >30 kg/m2) Physical inactivity Dyslipidemia* Diabetes mellitus* Microalbuminuria or estimated GFR <60 ml/min Age (older than 55 for men, 65 for women) Family history of premature CVD
(men under age 55 or women under age 65)
*Components of the metabolic syndrome.
JNC VI. Arch Intern Med 1997;157:2413.
JNC VI: BP Risk Stratification• Risk Group A
– No CV risk factors– No diabetes, target-organ damage, or clinical CVD
• Risk Group B– At least one other risk factor: age >60, male gender or
postmenopausal status, dyslipidemia, smoking, +FH– (No diabetes, target-organ damage, or clinical CVD)
• Risk Group C– Diabetes or target-organ damage or clinical CVD
with or without other risk factors
Target Organ Damage Heart
• Left ventricular hypertrophy• Angina or prior myocardial infarction• Prior coronary revascularization• Heart failure
Brain• Stroke or transient ischemic attack
Chronic kidney disease
Peripheral arterial disease Retinopathy
Laboratory Tests Routine Tests
• Electrocardiogram • Urinalysis • Blood glucose, and hematocrit • Serum potassium, creatinine, or the corresponding estimated GFR,
and calcium• Lipid profile, after 9- to 12-hour fast, that includes high-density and
low-density lipoprotein cholesterol, and triglycerides
Optional tests • Measurement of urinary albumin excretion or albumin/creatinine ratio
More extensive testing for identifiable causes is not generally indicated unless BP control is not achieved
Lifestyle ModificationModification Approximate SBP reduction
(range)Weight reduction 5–20 mmHg/10 kg weight loss
Adopt DASH eating plan 8–14 mmHg
Dietary sodium reduction 2–8 mmHg
Physical activity 4–9 mmHg
Moderation of alcohol consumption
2–4 mmHg
For Prevention and Management
Lifestyle Modifications
• Lose weight if overweight• Limit alcohol intake• Increase aerobic physical
activity• Reduce sodium intake• Maintain adequate intake
of potassium
• Maintain adequate intake of calcium and magnesium
• Stop smoking• Reduce dietary saturated
fat and cholesterol
For Overall and Cardiovascular Health
Dietary Approaches to Stop Hypertension (DASH)
• Diet high in fruits and vegetables and low-fat dairy products lowers blood pressure (11 mmHg SBP/ 5 mmHg DBP lower than traditional US diet), including more than a sodium-restricted diet
• Recommends 7-8 servings/day of grain/grain products, 4-5 vegetable, 4-5 fruit, 2-3 low- or non-fat dairy products, 2 or less meat, poultry, and fish.
• NEJM 1997; 366: 1117-24.
Algorithm for Treatment of Hypertension
Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)
Initial Drug Choices
Drug(s) for the compelling indications
Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)
as needed.
With Compelling Indications
Lifestyle Modifications
Stage 2 Hypertension (SBP >160 or DBP >100 mmHg)
2-drug combination for most (usually thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB,
or combination.
Without Compelling Indications
Not at Goal Blood Pressure
Optimize dosages or add additional drugs until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
Classification and Management
of BP for adultsBP
classification
SBP* mmHg
DBP* mmHg
Lifestyle modificati
on
Initial drug therapy Without compelling
indication With compelling
indications
Normal <120 & <80 Encourage Prehypertension
120–139
or 80–89
Yes No antihypertensive drug indicated.
Drug(s) for compelling indications. ‡
Stage 1 Hypertension
140–159
or 90–99
Yes Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.
Drug(s) for the compelling indications.‡
Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.
Stage 2 Hypertension
>160 or >100 Yes Two-drug combination for most† (usually thiazide-type diuretic and ACEI or ARB or BB or CCB).
*Treatment determined by highest BP category.†Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.
Followup and Monitoring
Patients should return for followup and adjustment of medications until the BP goal is reached.
More frequent visits for stage 2 HTN or with complicating comorbid conditions.
Serum potassium and creatinine monitored 1–2 times per year.
Followup and Monitoring
(continued)
After BP at goal and stable, followup visits at 3- to 6-month intervals.
Comorbidities, such as heart failure, associated diseases, such as diabetes, and the need for laboratory tests influence the frequency of visits.
Special Considerations
Compelling Indications
Other Special Situations
• Minority populations• Obesity and the metabolic syndrome• Left ventricular hypertrophy• Peripheral arterial disease• Hypertension in older persons• Postural hypotension• Dementia• Hypertension in women• Hypertension in children and adolescents• Hypertension urgencies and emergencies
Compelling Indications for Individual Drug Classes
Compelling Indication Initial Therapy Clinical Trial BasisACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES
ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS
ALLHAT, HOPE, ANBP2, LIFE, CONVINCE
THIAZ, BB, ACEI, ARB, ALDO ANT
BB, ACEI, ALDO ANT
THIAZ, BB, ACE, CCB
Heart failure
Postmyocardialinfarction
High CAD risk
Diabetes
Chronic kidney disease
Recurrent stroke prevention
Compelling Indications for Individual Drug Classes
Compelling Indication Initial Therapy Options
Clinical Trial Basis
NKF-ADA Guideline, UKPDS, ALLHAT
NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
PROGRESS
THIAZ, BB, ACE, ARB,
CCB ACEI, ARB
THIAZ, ACEI
Cardiovascular Diseases
• Cerebrovascular disease–Indication for treatment, except immediately after
ischemic cerebral infarction.
• Coronary artery disease–Benefits of therapy well established.
• Left ventricular hypertrophy–Antihypertensive agents (except direct vasodilators)
indicated.–Reduced weight and decreased sodium intake
beneficial.
Cardiovascular Diseases (continued)
• Cardiac failure–ACE inhibitors, especially with digoxin or
diuretics, shown to prevent subsequent heart failure.
• Peripheral arterial disease–Limited or no data available.
CCBs, calcium channel blockers. CHD, coronary heart disease.* Includes INSIGHT, NICS-EH, STOP-2, NORDIL, and VHAS. Diamonds represent the 95% CI for pooled estimates of effect and are centered on pooled relative risk. Adapted from Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2000;356:1955-1964.
Stroke 456 529 0.87 (0.77-0.98)CHD 567 510 1.12 (1.00-1.26)Heart Failure 278 250 1.12 (0.95-1.33)Major CV Events 1,251 1,234 1.02 (0.95-1.10)CV Death 425 405 1.05 (0.92-1.20)Total Mortality 776 776 1.01 (0.92-1.11)
Relative RiskFavors CCBs Favors diuretics or beta blockers
CCBs(n=11,685)
Diuretics or Beta Blockers
(n=11,769)
0.5 1.0 2.0
No. of Events*
Relative Risk(95% CI)
Relative Risk of CV Events and Mortality:CCBs vs Diuretics or Beta Blockers
-22(P<.001)
MI, Stroke,CV Death(primary
end point)
-26(P<.001)
CV Death
-20(P<.001)
MI
-32(P<.001)
Stroke
-16(P=.005)
All-causeDeath
-35
-30
-25
-20
-15
-10
-5
0
Ris
k R
educ
tion
(%)
HOPE: Risk Reduction of CV EventsAssociated with ACEI (RAS Inhibition) Treatment
Adapted from The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.
CHD, coronary heart disease.* Includes STOP-2, UKPDS-HDS, and CAPPP. Diamonds represent the 95% CI for pooled estimates of effect and are centered on pooled relative risk. Adapted from Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2000;356:1955-1964.
Stroke 425 402 1.05 (0.92-1.19)CHD 423 420 1.00 (0.88-1.14)Heart Failure 223 250 0.92 (0.77-1.09)Major CV Events 1,018 1,004 1.00 (0.93-1.08)CV Death 350 348 1.00 (0.87-1.15)Total Mortality 639 618 1.03 (0.93-1.14)
Relative RiskFavors ACE inhibitors Favors diuretics or beta blockers
No. of Events*
ACE Inhibitors(n=8,097)
Diuretics or Beta Blockers
(n=8,064)
0.5 1.0 2.0
Relative Risk(95% CI)
Relative Risk of CV Events and Mortality:ACE Inhibitors vs Diuretics or Beta Blockers
Reversal of LV Hypertrophy By Antihypertensive Treatment
Schmieder RE et al. JAMA. 1996;275:1507-1513.
Cha
nge
in L
V m
ass
inde
x(%
)
0
-5
-10
-15
-20
-25
Diuretics -blockers
Calciumchannelblockers
ACEinhibitors
p<.01
p<.01
7%6%
9%
13%
Regression of LV HypertrophyPredicts Prognosis
LV, left ventricular.Nonregressors defined as baseline and follow-up left ventricular mass index (LVMI) >125 g/m2;regressors defined as baseline LVMI >125 g/m2 and follow-up LVMI <125 g/m2.Adapted from Verdecchia P et al. Circulation. 1998;97:48-54.
Prob
abili
ty o
f eve
nt-fr
ee s
urvi
val
(%)
Rat
e of
eve
nts
(per
100
pat
ient
-yrs
)
Time to event (wk)0 100 200 300 400 500
P=.002
Regressors (n=285)Nonregressors (n=145)
100
90
80
70
0
60
50
7
6
5
4
1
3
2
0
Regressors (n=52)
Nonregressors (n=50)
Irbesartan and Atenolol in Hypertension and LVH
Study Design
Single-blindPlacebo
Irbesartan 150-300 mg
Atenolol50-100 mg
Addition of HCTZ12.5-25 mgif SeDBP
90 mm Hg
Addition of Felodipine5-10 mgif SeDBP
90 mm Hg
Wk: -4 0 12 2448
* BP, echocardiography, neurohormone measurements.
Malmqvist K et al. J Hypertens. 2001;19:1167-1176.
*
DoubleBlind
* * *
Irbesartan vs Atenolol in Hypertension and LVH: SeDBP Reduction
-20
-15
-10
-5
012 wk 24 wk 48 wk
% re
duct
ion
in S
eDB
P
Irbesartan Atenolol
**
† * *
**
* p<.001 vs baseline.† p<.028 irbesartan vs atenolol.Malmqvist K et al. J Hypertens. 2001;19:1167-1176.
Irbesartan vs Atenolol in Hypertension and LVH: LVMI Reduction
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
% c
hang
e in
LVM
I (g/
m2 )
*p<.001 vs baseline; †p=.024 irbesartan vs atenolol.
12 wk
*
24 wk
*
*
48 wk
*
*
†
Malmqvist K et al. J Hypertens. 2001;19:1167-1176.
Irbesartan Atenolol
LIFE: Inclusion Criteria
• Age 55-80 years
• Previously treated or untreated hypertension
• Systolic BP 160-200 mmHg or
Diastolic BP 95-115 mmHg
• ECG LVH
Adapted from Dahlöf B et al. Am J Hypertens. 1997;10:705-13.
* Other antihypertensives excluding ACEIs, AII antagonists, beta-blockers. Adapted from Dahlöf B et al. Am J Hypertens. 1997;10:705-713.
LIFE: DosingTitration to target blood pressure: <140 / <90 mmHg
PlaceboRun-in
Losartan 50 mg Atenolol 50 mg
Losartan 50 mg + HCTZ 12.5 mg
Losartan 100 mg + HCTZ 12.5 mg
Losartan 100 mg + HCTZ 12.5-25 mg + others*
Atenolol 50 mg + HCTZ 12.5 mg
Atenolol 100 mg + HCTZ 12.5 mg
Atenolol 100 mg + HCTZ 12.5-25 mg + others*
Average follow up 4.7 years
LIFE: Blood Pressure Results – Follow-up
0 6 12 18 24 30 36 42 48 54Study Month
40
60
80
100
120
140
160
180
Systolic
Diastolic
Mean Arterialmm
Hg
AtenololLosartan
Atenolol 145.4 mmHg
Losartan 144.1 mmHg
Atenolol 80.9 mmHg
Losartan 81.3 mmHg
B Dahlöf et al. Lancet. 2002;359:995-1003.
LosartanAtenolol (n=4,605) (n=4,588) RR (%) p-value
Primary composite† 508 588 -13 .021
CV mortality 204 234 -11 .21
Stroke 232 309 -25 .001
MI 198 188 +7 .49
Total mortality 383 431 -10 .13
New onset DM‡ 241 319 -25 <.001
LIFE: Primary and Select Secondary Outcomes
Adjusted*
* For degree of LVH and Framingham risk score at randomization† Number of patients with a first primary event‡ In patients without diabetes at randomization (losartan, n=4,019; atenolol, n=3,979)Adapted from B Dahlöf et al. Lancet. 2002;359:995-1003.
Valsartan Heart Failure Trial(Val-HeFT)
Study Characteristics: • 5,010 total patients randomized with NYHA class II, III, or IV
HF • Two groups: valsartan (target dose 160 mg BID) plus
standard therapy vs placebo plus standard therapy • Mean duration of follow-up: 23 months (range 0-38)• Two primary end points:
– Mortality– Combined mortality and morbidity (morbidity defined as cardiac
arrest with resuscitation, hospitalization for HF, or administration of IV inotropic or vasodilator drugs for > 4 hours without hospitalization)
Val-HeFTResults • Overall mortality was similar in the two groups• 13% RRR (p=.009) in combined end point• Predominantly because of a 27% decrease in hospitalization for
HF in the valsartan group• Subgroup analyses:
– Valsartan had a favorable effect in patients receiving neither an ACE inhibitor nor a beta-blocker
– Valsartan had a favorable effect in patients receiving an ACE inhibitor or a beta blocker
– Valsartan demonstrated a statistically non-significant trend towards an adverse outcome in patients receiving an ACE inhibitor and a beta blocker
Web sitewww.nhlbi.nih.gov/
DASH Fact Sheet
Your Guide to Lowering Blood Pressure
Reference Card
Diabetes Mellitus
• Drug therapy should begin along with lifestyle modifications to reduce blood pressure to < 130/85 mm Hg.
• ACE inhibitors, -blockers, calcium antagonists, and low-dose diuretics are preferred.
• Insulin resistance or high peripheral insulin levels may cause hypertension, which can be treated with lifestyle changes, insulin-sensitizing agents, vasodilating antihypertensive drugs, and lipid-lowering agents.
Renal Disease
• Hypertension may result from renal disease that reduces functioning nephrons.
• Evidence shows a clear relationship between high blood pressure and end-stage renal disease.
• Blood pressure should be controlled to < 130/85 mm Hg or lower (< 125/75 mm Hg) in patients with proteinuria in excess of 1 gram per 24 hours.
• ACE inhibitors work well to control blood pressure and slow progression of renal failure.
ADA Guidelines on Management of Diabetic Nephropathy
Hypertensive Type 2 Diabetic Patients*ARBs are the initial agents of choice
Type 1 Diabetics with or without hypertension*
ACEIs are the initial agents of choice If one class is not tolerated the other should
be substituted* With microalbuminuria and clinical proteinuria. Adapted from American Diabetes Association. Diabetes Care. 2002;25:S85-S89.
MRFIT: Association of Systolic BP and MRFIT: Association of Systolic BP and Cardiovascular Death in Type 2 DiabetesCardiovascular Death in Type 2 Diabetes
250
225
200
175
150
125
100
75
50
0
25
< 120 120–139 140–159 160–179 180–199 200Systolic blood pressure (mm Hg)
Cardiovascular mortality
rate/10,000 person-yr
Nondiabetic
Diabetic
Stamler J et al. Diabetes Care. 1993;16:434-444.
Veterans Administration Hypertension and Screening Clinics
15-Year ESRD Rates and Risk Ratios by BaselineSystolic Blood Pressure
SBP (mm Hg) Risk Ratio
< 140> 140 but < 151> 151 but < 165> 165 but < 180> 180
1.001.001.082.075.62
Number of screenees: 11,912 (5,730 black; 6,182 white)Source: Perry HM, et al. Hypertension. 1995;25:587-594
Veterans Administration Hypertension and Screening
Clinics15-Year ESRD Rates and Risk Ratios by BaselineDiastolic Blood Pressure
DBP (mm Hg) Risk Ratio
< 94> 94 but < 100> 100 but < 106> 106 but < 118> 118
1.001.050.891.544.18
Number of screenees: 11,912 (5,730 black; 6,182 white)Source: Perry HM, et al. Hypertension. 1995;25:587-594
United Kingdom Prospective Diabetes United Kingdom Prospective Diabetes Study (UKPDS): ResultsStudy (UKPDS): Results
• Tight blood pressure control* with captopril- or atenolol-based therapy reduces risk of Risk reduction p-value
– Any diabetes-related endpoints 24%0.005– Diabetes-related deaths 32%0.019– Stroke 44%0.013– Microvascular endpoints 37%0.009
* Mean blood pressure achieved: 144/82 vs 154/87 mm Hg.UK Prospective Diabetes Study Group 38. BMJ. 1998;317:703-713.UK Prospective Diabetes Study Group 33. Lancet. 1998;352:837-853.
Diabetic NephropathyBurden of Illness
Incidence Approximately 40% of all new cases of ESRD in the U.S. are due to
diabetes1
Type 2 diabetes accounts for most cases of diabetic nephropathy2,3
Prevalence of nephropathy 57% after 25 years of type 2 diabetes4
Cost In U.S. alone, total annual spending for ESRD > $15 billion1
Cost/patient-year higher for diabetic ESRD ($51,000) than nondiabetic ESRD ($39,000)5
1. USRDS Coordinating Center. USRDS 1999 Annual Data Report. The Kidney Epidemiology and Cost Center of the 1. USRDS Coordinating Center. USRDS 1999 Annual Data Report. The Kidney Epidemiology and Cost Center of the University of Michigan; 1999. NIH Contract no. NO1-DK-3-2202.University of Michigan; 1999. NIH Contract no. NO1-DK-3-2202.
2. American Diabetes Association. Diabetes Care. 2001;24 (supp 1):S69-72.2. American Diabetes Association. Diabetes Care. 2001;24 (supp 1):S69-72.3. Ritz E, et al. Am J Kidney Dis. 1996;27:167-194.3. Ritz E, et al. Am J Kidney Dis. 1996;27:167-194.4. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.4. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.5. Ruggenenti P et al. J Am Soc Nephrol. 1998;9:2336-2343.5. Ruggenenti P et al. J Am Soc Nephrol. 1998;9:2336-2343.
Diabetic NephropathyBurden of Illness (continued)
Mortality1.5-2.5x greater mortality among diabetics with
ESRD than nondiabetics1
< 20% of diabetics with ESRD survive 5 years after initiation of dialysis1
Cardiovascular complications the most common cause of death2,3
1. Koch M et al. Diabetologia. 1993;36:1113-1117.1. Koch M et al. Diabetologia. 1993;36:1113-1117.2. Bakris GL. Diabetes Res Clin Pract. 1998;39:S35-S42. 2. Bakris GL. Diabetes Res Clin Pract. 1998;39:S35-S42. 3. Grundy SM et al. Circulation. 1999;100:1134-1146.3. Grundy SM et al. Circulation. 1999;100:1134-1146.
GFR, glomerular filtration rate; HTN, hypertension; MAP, mean arterial pressure.GFR, glomerular filtration rate; HTN, hypertension; MAP, mean arterial pressure.Adapted from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.Adapted from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.
Correlation Between MAP & Renal Function
GFR
Dec
line
(mL/
min
/y)
0
-2
-4
-6
-8
-10
-12
-14
MAP (mm Hg)95 98 101 107104 110 113 116 119
r=0.69; P<.05
UntreatedHTN
130/85 140/90
Microalbuminuria as a Risk Factor for Death in Type 2 Diabetes
UAC, urinary albumin concentration.Adapted from Schmitz A et al. Diabetes Med. 1988;5:126-134.
Years after Diagnosis
Sur
viva
l
UAC 15 g/mL
UAC 16-40 g/mL
UAC 41-200 g/mL
0.0
0.4
1.0
0.8
0.6
0.2
0 5 1021 3 4 76 8 9 11
Proteinuria & Risk of CV Mortality,Stroke, & CHD Events in
Type 2 Diabetes
CHD, coronary heart disease; UPC, urinary protein concentration.CHD, coronary heart disease; UPC, urinary protein concentration.* Defined as CHD death or nonfatal MI.* Defined as CHD death or nonfatal MI. Adapted from Miettinen H et al. Stroke. 1996;27:2033-2039.Adapted from Miettinen H et al. Stroke. 1996;27:2033-2039.
A: UPC <150 mg/L B: UPC 150-300 mg/L C: UPC >300 mg/L
1.0
0.9
0.8
0.7
0.6
0.5
00 10 20 30 40 50 60 70 80 90 Stroke CHD Events*
P<.001 for trends
Inci
denc
e (%
)
Red
uctio
n in
Sur
viva
l due
to
CV
Mor
talit
y
Months
A
B
C
P-values:Overall <.001A vs B =.013A vs C <.001B vs C <.001
0
10
20
30
40
* Death due to MI, sudden death, stroke, peripheral vascular disease, renal disease, hyperglycemia, or * Death due to MI, sudden death, stroke, peripheral vascular disease, renal disease, hyperglycemia, or hypoglycemia.hypoglycemia.† † Fatal or nonfatal.Fatal or nonfatal.‡ ‡ Retinopathy requiring photocoagulation, vitreous hemorrhage and fatal or nonfatal renal failure.Retinopathy requiring photocoagulation, vitreous hemorrhage and fatal or nonfatal renal failure. Mean BP achieved with captopril- or atenolol-based therapy: 144/82 mm Hg (tight BP control) vs Mean BP achieved with captopril- or atenolol-based therapy: 144/82 mm Hg (tight BP control) vs 154/87 mm Hg (less tight BP control).154/87 mm Hg (less tight BP control). Adapted from UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.Adapted from UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.
Risk Reduction of Diabetes-RelatedEnd Points with Tight BP Control
Ris
k R
educ
tion
(%)
Diabetes-related Mortality* Stroke†
Microvascular End Points‡
Myocardial Infarction
0
10
20
30
40
50
32
44
37
21
HOT: Significant Benefit From Intensive Antihypertensive Treatment in Diabetes
* Defined as fatal and nonfatal MI, fatal and nonfatal stroke, and all other CV death.* Defined as fatal and nonfatal MI, fatal and nonfatal stroke, and all other CV death. Adapted from Hansson L et al. Lancet. 1998;351:1755-1762.Adapted from Hansson L et al. Lancet. 1998;351:1755-1762.
0
5
10
15
20
25
90 85 80
Maj
or C
V Ev
ents
*/100
0 Pa
tient
-yrs
in H
yper
tens
ive
Patie
nts
with
Dia
bete
s
P=.005 for trend
Target DBP (mm Hg)
Effect of ACE Inhibition on Nephropathy in Type 1 Diabetes
* P=.006 vs placebo.* P=.006 vs placebo. Adapted from Lewis EJ et al. N Engl J Med. 1993;329:1456-1462.Adapted from Lewis EJ et al. N Engl J Med. 1993;329:1456-1462.
Prog
ress
ion
to D
eath
, Dia
lysi
s,Pr
ogre
ssio
n to
Dea
th, D
ialy
sis,
or T
rans
plan
t (%
)or
Tra
nspl
ant (
%)
CaptoprilCaptopril
PlaceboPlacebo
Follow-up (y)Follow-up (y)00 11 22 33 44
00
1010
2020
3030
4040
**
SeSBP, seated systolic blood pressure; SeDBP, seated diastolic blood pressure.SeSBP, seated systolic blood pressure; SeDBP, seated diastolic blood pressure. Control defined as placebo.Control defined as placebo.* Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to to all groups to help achieve target BP levels.all groups to help achieve target BP levels. At the end of 2-year follow-up, 56% of patients in the control group, 45% in the irbesartan 150-mg group, and 43% At the end of 2-year follow-up, 56% of patients in the control group, 45% in the irbesartan 150-mg group, and 43% inin the irbesartan 300-mg group were receiving concomitant antihypertensive agents.the irbesartan 300-mg group were receiving concomitant antihypertensive agents. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.
IRMA 2: Blood Pressure Response
Control SeDBP*Irbesartan 150 mg SeDBP*Irbesartan 300 mg SeDBP*
Control SeSBP*Irbesartan 150 mg SeSBP*Irbesartan 300 mg SeSBP*
Mea
n Se
SBP
and
SeD
BP
(mm
Hg)
0 3 6 9 12 15 18 21 24 27Months
070
130
160
8090
100110120
140150
14
18
16
12
10
86
4
2
0
Subjects(%)
Control (n=201)
150 mg(n=195)
300 mg(n=194)
Irbesartan
9.7
5.2
14.9
RRR=39%P=0.08
RRR=70%P<0.001
IRMA 2 Primary EndpointDevelopment of Overt Proteinuria
Parving H-H, et al. N Engl J Med 2001;345:870-878.
IDNT: Systolic BP, Mean Arterial Pressure, & Diastolic BP Response
Control defined as placebo.Control defined as placebo.Patients received an average of 3.0 concomitant antihypertensive agents in the irbesartan and amlodipine groups, Patients received an average of 3.0 concomitant antihypertensive agents in the irbesartan and amlodipine groups, and 3.3 concomitant agents in the control group.and 3.3 concomitant agents in the control group.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.
IrbesartanIrbesartanAmlodipineAmlodipineControlControl
00 66 1212 1818 2424 3030 3636 4242 4848 5454
Follow-up Visit (mo)Follow-up Visit (mo)
8080
100100
120120
140140
160160
SBPSBP
MAPMAP
DBPDBP
BP
(mm
Hg)
BP
(mm
Hg)
Subjects (%)
0 6 12 18 24 30 36 42 48 54Follow-up (mo)
60
0
10
20
30
40
50
60
70
IDNT Primary Endpoint:Time to Doubling of Serum Creatinine, ESRD, or Death
Irbesartan
Amlodipine
Control
Lewis EJ et al. N Engl J Med 2001;345:851-860.
RRR 20%P=0.02
P=NS
RRR 23%P=0.006
IDNT & RENAAL: Study Design
SeCr, serum creatinine; ESRD, end-stage renal disease.SeCr, serum creatinine; ESRD, end-stage renal disease.† † Lewis EJ et al. N Engl J Med. 2001;345:851-860.Lewis EJ et al. N Engl J Med. 2001;345:851-860.‡ ‡ Brenner BM et al. N Engl J Med. 2001;345:861-869.Brenner BM et al. N Engl J Med. 2001;345:861-869.
Patients:Patients: 1,715 HTN patients with type 2 1,715 HTN patients with type 2 1,513 HTN patients with 1,513 HTN patients with diabetes & nephropathydiabetes & nephropathy type 2 diabetes & type 2 diabetes & nephropathynephropathy
Treatment arms:Treatment arms: irbesartan, amlodipine,irbesartan, amlodipine, losartan, placebolosartan, placeboplaceboplacebo
Target BP:Target BP: 135/85 mm Hg135/85 mm Hg 140/90 mm Hg140/90 mm HgAdjunctive therapy:Adjunctive therapy: Permitted except ARBs, Permitted except ARBs, Permitted including Permitted including ACE ACE
inhibitors, or CCBs inhibitors, or CCBs CCBs, except ARBs or CCBs, except ARBs or ACE inhibitorsACE inhibitorsPrimary outcome:Primary outcome: Composite of doubling ofComposite of doubling of Composite of doubling of Composite of doubling of SeCr, SeCr,
ESRD, or deathESRD, or death SeCr, ESRD, or deathSeCr, ESRD, or deathSecondary outcomes: Secondary outcomes: CV events CV events CV eventsCV events
Mean Follow-up:Mean Follow-up: 2.6 years2.6 years 3.4 years3.4 years
RENAALRENAAL‡‡IDNTIDNT††
IDNT and RENAAL Trial Results
Doubling of Creat, 16 (P=0.02) 20 (P=0.02) 23 (P=0.006) -4 (P=0.69) ESRD, or death
Doubling of Creat 25 (P=0.006) 33 (P=0.003) 37 (P<0.001) -6 (P=0.60)
ESRD 28 (P=0.002) 23 (P=0.07) 23 (P=0.07) 0 (P=0.99)
Death -2 (P=0.88) 8 (P=0.57) -4 (P=0.8) 12 (P=0.4)
CV Morbidity 10 (P=0.26) 9 (P=0.4) -3 (P=0.79) 12 (P=0.29) & Mortality
Losartan vs control
Irbesartan vs control
Irbesartan vs amlodipine
Amlodipine vs control
RRR (%)
Comparison of Major Endpoints
RENAAL IDNT
Lewis EJ et al. N Engl J Med 2001;345:851-860.Brenner B et al. N Engl J Med 2001;345:861-869.
Minority Populations In general, treatment similar for all demographic groups.
Socioeconomic factors and lifestyle important barriers to BP control.
Prevalence, severity of HTN increased in African Americans.
African Americans demonstrate somewhat reduced BP responses to monotherapy with BBs, ACEIs, or ARBs compared to diuretics or CCBs.
These differences usually eliminated by adding adequate doses of a diuretic.
Left Ventricular Hypertrophy
LVH is an independent risk factor that increases the risk of CVD.
Regression of LVH occurs with aggressive BP management: weight loss, sodium restriction, and treatment with all classes of drugs except the direct vasodilators hydralazine and minoxidil.
Peripheral Arterial Disease(PAD)
PAD is equivalent in risk to ischemic heart disease.
Any class of drugs can be used in most PAD patients.
Other risk factors should be managed aggressively.
Aspirin should be used.
Hypertension in OlderPersons
More than two-thirds of people over 65 have HTN.
This population has the lowest rates of BP control.
Treatment, including those who with isolated systolic HTN, should follow same principles outlined for general care of HTN.
Lower initial drug doses may be indicated to avoid symptoms; standard doses and multiple drugs will be needed to reach BP targets.
Postural Hypotension
Decrease in standing SBP >10 mmHg, when associated with dizziness/fainting, more frequent in older SBP patients with diabetes, taking diuretics, venodilators, and some psychotropic drugs.
BP in these individuals should be monitored in the upright position.
Avoid volume depletion and excessively rapid dose titration of drugs.
Dementia
Dementia and cognitive impairment occur more commonly in people with HTN.
Reduced progression of cognitive impairment occurs with effective antihypertensive therapy.
Hypertension in Women
Oral contraceptives may increase BP, and BP should be checked regularly. In contrast, HRT does not raise BP.
Development of HTN—consider other forms of contraception.
Pregnant women with HTN should be followed carefully. Methyldopa, BBs, and vasodilators, preferred for the safety of the fetus. ACEI and ARBs contraindicated in pregnancy.
Strategies for Improving Adherence to Regimens
Clinician empathy increases patient trust, motivation, and adherence to therapy.
Physicians should consider their patients’ cultural beliefs and individual attitudes in formulating therapy.
Causes of Resistant Hypertension
Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication
• Inadequate doses• Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)• Over-the-counter (OTC) drugs and herbal supplements
Excess alcohol intake Identifiable causes of HTN
Public Health Challenges and Community Programs
Public health approaches (e.g. reducing calories, saturated fat, and salt in processed foods and increasing community/school opportunities for physical activity) can achieve a downward shift in the distribution of a population’s BP, thus potentially reducing morbidity, mortality, and the lifetime risk of an individual’s becoming hypertensive.
These public health approaches can provide an attractive opportunity to interrupt and prevent the continuing costly cycle of managing HTN and its complications.
Supporting Materials
Web site www.nhlbi.nih.gov/
For patients and the general public
• “Facts About the DASH Eating Plan” (Revised May 2003)
• “Your Guide to Lowering Blood Pressure”
For health professionals
• Reference Card
• Slide Show
Back-up Slides: Special Populations
• Racial and ethnic groups
• Children and adolescents
• Women
• Older persons
Heart
– Myocardial hypertrophy
– Interstitial fibrosis Coronary Arteries
– Endothelial dysfunction with decreased release of nitric oxide
– Coronary constriction via release of norepinephrine
– Formation of oxygen-derived free radicals via NADH (nicotinamide adenine dinucleotide) oxidase
– Promotion of inflammatory response and plaque instability
– Promotion of low-density lipoprotein cholesterol uptake
Adapted from Opie and Gersh. Drugs for the Heart, 2001.
Potential Pathogenic Propertiesof Angiotensin II
Kidneys– Increased intraglomerular pressure– Increased protein leak– Glomerular growth and fibrosis– Increased sodium reabsorption– Decreased renal blood flow
Adrenal Glands– Increased formation of aldosterone
Coagulation System– Increased fibrinogen– Increased PAI-1 (plasminogen activator inhibitor-1) relative to tissue
plasminogen factorAdapted from Opie and Gersh. Drugs for the Heart, 2001.
Potential Pathogenic Propertiesof Angiotensin II (continued)
Summary of Chapter 3 (continued)
• Management strategies can improve adherence through the use of multidisciplinary teams.
• The reductions in cardiovascular events demonstrated in randomized controlled trials have important implications for managed care organizations.
• Management of hypertensive emergencies requires immediate action, whereas urgencies benefit from reducing blood pressure within a few hours.
Drug Therapy
• A low dose of initial drug should be used, slowly titrating upward.
• Optimal formulation should provide 24-hour efficacy with once-daily dose with at least 50% of peak effect remaining at end of 24 hours.
• Combination therapies may provide additional efficacy with fewer adverse effects.
Classes ofAntihypertensive Drugs
• ACE inhibitors
• Adrenergic inhibitors
• Angiotensin II receptor blockers
• Calcium antagonists
• Direct vasodilators
• Diuretics
Combination Therapies
-adrenergic blockers and diuretics
• ACE inhibitors and diuretics
• Angiotensin II receptor antagonists and diuretics
• Calcium antagonists and ACE inhibitors
• Other combinations
Followup
• Followup within 1 to 2 months after initiating therapy.• Recognize that high-risk patients often require high
dose or combination therapies and shorter intervals between changes in medications.
• Consider reasons for lack of responsiveness if blood pressure is uncontrolled after reaching full dose.
• Consider reducing dose and number of agents after 1 year at or below goal.
Guidelines for ImprovingAdherence to Therapy
• Be aware of signs of nonadherence.• Establish goal of therapy.• Encourage a positive attitude about achieving
goals.• Educate patients about the disease and therapy.• Maintain contact with patients.• Encourage lifestyle modifications.• Keep care inexpensive and simple.
Guidelines for ImprovingAdherence to Therapy (continued)
• Integrate therapy into daily routine.• Prescribe long-acting drugs.• Adjust therapy to minimize adverse effects.• Continue to add drugs systematically to meet
goal.• Consider using nurse case management.• Utilize other health professionals.• Try a new approach if current regime is
inadequate.
African Americans • Among the highest prevalence• Early onset • Delayed treatment
Hispanics • Generally low prevalence• Lowest control rate in Mexican Americans
Asian and Pacific Islanders
• May be more responsive to treatment than other groups
American Indians • Similar prevalence to general population• High prevalence of diabetes and obesity
Racial and Ethnic Groups
Women
• Clinical trials have not demonstrated significant differences between men and women in treatment response and outcomes.
• Some women using oral contraceptives may have significant increases in blood pressure.
• High blood pressure is not a contraindication to hormone replacement therapy.
Pregnant Women
• Chronic hypertension is high blood pressure present before pregnancy or diagnosed before the 20th week of gestation.
• Preeclampsia is increased blood pressure that occurs in pregnancy (generally after the 20th week) and is accompanied by edema, proteinuria, or both.
• ACE inhibitors and angiotensin II receptor blockers are contraindicated for pregnant women.
• Methyldopa is recommended for women diagnosed during pregnancy.
These agents* may be used with chronic hypertension (DBP > 100 mm Hg) or acute hypertension (DBP > 105 mm Hg).
Central -agonists Methyldopa is the drug of choice.
-blockers and --blockers
Atenolol, metoprolol, and labetalol appear safe and effective in late pregnancy.
Calcium antagonists
Potential synergism with magnesium sulfate may lead to precipitous hypotension.
*Limited or no controlled trials in pregnant women.
Antihypertensive Drugs Used in Pregnancy
These agents* may be used with chronic hypertension (DBP > 100 mm Hg) or acute hypertension (DBP > 105).
Diuretics Diuretics are recommended for chronic hypertension if prescribed before gestation, but they are not recommended for preeclampsia.
Direct vasodilators
Hydralazine is the parenteral drug of choice based on its long history of safety and efficacy.
*Limited or no controlled trials in pregnant women.
ACE inhibitors and angiotensin II receptor blockers are contraindicated.
Antihypertensive Drugs Used in Pregnancy (continued)
Older Persons
• Hypertension is common.• SBP is a better predictor of events than DBP.• Pseudohypertension and “white-coat
hypertension” may indicate a need for readings outside the office.
• Primary hypertension is the most common cause, but common identifiable causes (e.g., renovascular hypertension) should be considered.
Older Persons (continued)
• Therapy should begin with lifestyle modifications.
• Starting doses for drug therapy should be lower than those used in younger adults.
• Goal of therapy is the same (< 140/90 mm Hg), although an interim goal of SBP < 160 mm Hg may be necessary.
Combined Results of FiveRandomized Trials of Antihypertensive
Treatment in the Elderly
Stroke0
100
200
300
400
500
600
78
288
T
T = TreatmentC = Control
= Fatal events
120
438
C
CHD
208
346
T 279
438
C
Vascular deaths
Tota
l num
bers
of i
ndiv
idua
ls a
ffect
ed
383
T
494
C
All other deaths
34% (6)2P <0.0001
% (SD) reductionin odds
19% (7)2P <0.05
23% (6)2P <0.001
–7% (8) 2P >0.5
344362
TC
SHEP STOP-HTN MRC SYST-EUR(1991) (Dahlöf, 1991) (1992) (1997)
Mean BP 170/77 195/102 185/91 174/85at entry (mm Hg)
Effects of Therapy in Elderly Hypertensive Patients
Double-blind Treatment
Up to 5 weeks
Screening/EnrollmentIrbesartan 150 mg*
Irbesartan 300 mg*
Follow-up: 2 years
Placebo/Control group*
IRMA 2: Study Design
• 590 patients with hypertension, type 2 diabetes, microalbuminuria (albumin excretion rate 20–200 µg/min), and normal renal function
* Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and dihydropyridine calcium channel blockers) could be added to all groups to help achieve equal blood pressure levels.
Parving H-H, et al. N Engl J Med 2001;345:870-878.
Mechanism of Action ofMechanism of Action ofAngiotensin II Receptor AntagonistsAngiotensin II Receptor Antagonists
Angiotensinogen
Angiotensin I
Angiotensin II
AT2 receptor AT1 receptor Other ATreceptors
Bradykinin
Inactivepeptides
VasodilationAttenuate growth anddisease progression
ACEinhibitors
Alternatepathways
AIIRAs
?
?
IRMA 2: Clinical Outcome Measures
• Primary outcome:– Time to occurrence of overt proteinuria (AER > 200
g/min)
• Secondary outcomes:– Change in AER– Regression to normoalbuminuria (AER < 20 g/min)– Change in creatinine clearance– Clotting factors and lipid profile
Parving H-H, et al. N Engl J Med 2001;345:870-878.
IDNT: Study Design• 1,715 patients with hypertension, type 2 diabetes, and
proteinuria 900 mg/day
Double-blind Treatment
Up to 5 weeks
Screening/EnrollmentPlacebo/Control group*
Amlodipine*
Minimum follow-up: approximately 2 years
(average follow-up 2.6 years)
Irbesartan*
* Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and calcium channel blockers) could be added to all groups to help achieve equal blood pressure levels.
Lewis EJ et al. N Engl J Med 2001;345:851-860.
IDNTClinical Outcome Measures
• Primary outcome is time to a composite endpoint consisting of:
– Doubling of baseline serum creatinine
– End-stage renal disease (dialysis, renal transplant, or serum creatinine 6 mg/dL)
– Death (all-cause mortality)
• Secondary outcome is time to a composite endpoint of fatal or nonfatal cardiovascular events
Lewis EJ et al. N Engl J Med 2001;345:851-860.
KidneysKidneys Increased intraglomerular pressureIncreased intraglomerular pressure Increased protein leakIncreased protein leakGlomerular growth and fibrosisGlomerular growth and fibrosis Increased sodium reabsorptionIncreased sodium reabsorptionDecreased renal blood flowDecreased renal blood flow
Adapted from Opie and Gersh. Drugs for the Heart, 2001.
Potential Pathogenic Propertiesof Angiotensin II
Double-blind treatment
3 weeks
Screening/enrollment
Irbesartan 150 mg/d†
Irbesartan 300 mg/d†
Follow-up: 2 years
Control†
IRMA 2: Study Design 590 patients with hypertension, type 2 diabetes,
microalbuminuria,* and normal renal function
Control defined as placebo.Control defined as placebo.* Defined as albumin excretion rate 20-200 µg/min.* Defined as albumin excretion rate 20-200 µg/min.† † Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels.could be added to all groups to help achieve target BP levels. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.
IRMA 2: Clinical Outcome Measures
Primary outcome:Time to occurrence of overt proteinuria
(UAER >200 mg/min)Secondary outcomes:
Change in UAERRegression to normoalbuminuria
(UAER <20 mg/min)Change in creatinine clearance
UAER, urinary albumin excretion rate.UAER, urinary albumin excretion rate.Parving H-H et al. N Engl J Med. 2001;345:870-878.Parving H-H et al. N Engl J Med. 2001;345:870-878.
NAge (y)Male (%)BMI (kg/m2)
BP (mm Hg)
HbA1c (%)
SeCr (mg/dL)
Irbesartan 150 mg/d
1955866
29.9
153/90
7.3
1.0
Irbesartan 300 mg/d
19457 71
30.0
153/91
7.1
1.1
Control
20158 69
30.3
153/90
7.1
1.0
IRMA 2: Mean Baseline Characteristics
UAER (µg/min) 58 53 55
Duration of diabetes (y) 9.5 9.2 10.4
Control defined as placebo.Control defined as placebo.BMI, body mass index; SeCr, serum creatinine; UAER, urinary albumin excretion rate; HbABMI, body mass index; SeCr, serum creatinine; UAER, urinary albumin excretion rate; HbA1c1c, glycosylated , glycosylated hemoglobin.hemoglobin.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.
IRMA 2 Primary End Point:Time to Overt Proteinuria
RRR, relative risk reduction. RRR, relative risk reduction. Control defined as placebo. Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)* Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels.could be added to all groups to help achieve target BP levels. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.
00 33 66 1212 1818 2222 242400
55
1010
1515
2020
Follow-up (mo)Follow-up (mo)
Control (n=201)*Control (n=201)*Irbesartan 150 mg/d (n=195)*Irbesartan 150 mg/d (n=195)*Irbesartan 300 mg/d (n=194)*Irbesartan 300 mg/d (n=194)* RRR=39%RRR=39%
PP=.08=.08
RRR=70%RRR=70%PP<.001<.001
Patie
nts
(%)
Patie
nts
(%)
IRMA 2: Normalization* of UAER
UAER, urinary albumin excretion rate.UAER, urinary albumin excretion rate. Control defined as placebo. Control defined as placebo. * Normoalbuminuria defined as UAER of <20 mg/min.* Normoalbuminuria defined as UAER of <20 mg/min.† † Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels.could be added to all groups to help achieve target BP levels. Parving H-H et al. N Engl J Med. 2001;345:870-878.Parving H-H et al. N Engl J Med. 2001;345:870-878.
35
45
40
30
25
20
15
10
5
0Control†(n=201)
150 mg/d†
(n=195)300 mg/d†
(n=194)Irbesartan
24
34
21
P=.006P
atie
nts
(%)
IRMA 2: Adverse Events
Cardiovascular eventsCardiovascular events 18 (8.7)18 (8.7)11 14 (6.9)14 (6.9)22 9 (4.5)9 (4.5)11
Serious AESerious AE 47 (22.8)47 (22.8)11 32 (15.8)32 (15.8)22 30 (15.0)30 (15.0)22
Discontinuations due to AEDiscontinuations due to AE 19 (9.2)19 (9.2)22 18 (8.9)18 (8.9)22 11 (5.5)11 (5.5)22
Control group* Control group* (n=201)(n=201)
IrbesartanIrbesartan150 mg* (n=195)150 mg* (n=195)
IrbesartanIrbesartan300 mg* (n=194)300 mg* (n=194)
No. of Adverse Events (%)No. of Adverse Events (%)
Control defined as placebo. Control defined as placebo. * * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels.could be added to all groups to help achieve target BP levels.1. Parving H-H, et al. 1. Parving H-H, et al. N Engl J Med.N Engl J Med. 2001;345:870-878. 2001;345:870-878.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.
IRMA 2: Summary The renal benefits of irbesartan are independent of its
BP-lowering effects1
70% risk reduction in the progression from microalbuminuria to overt diabetic nephropathywith irbesartan 300 mg/d vs control (P<.001)1
More frequent restoration of normoalbuminuria with irbesartan 300 mg/d vs control (P=.006)1
Irbesartan is safe & well tolerated2
Fewer nonfatal CV events, serious AEs, and discontinuations due to AEs in the irbesartan groups2 AE, adverse event.AE, adverse event.
1. Parving H-H et al. N Engl J Med. 2001;345:870-878.1. Parving H-H et al. N Engl J Med. 2001;345:870-878.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.
IDNT: Study Design1,715 patients with hypertension, type 2 diabetes, & 1,715 patients with hypertension, type 2 diabetes, &
proteinuria proteinuria 900 mg/d900 mg/d
Double-blind treatmentDouble-blind treatment
Up to 5 weeksUp to 5 weeks
Screening/enrollmentScreening/enrollment
Control*Control*
Amlodipine*Amlodipine*
Minimum follow-up: Minimum follow-up: approximately 2 years approximately 2 years
(average follow-up, 2.6 years)(average follow-up, 2.6 years)
Irbesartan*Irbesartan*
Control defined as placebo. Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and CCBs) could be added to all groups to * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and CCBs) could be added to all groups to help achieve target BP.help achieve target BP. Lewis EJ et al. N Engl J Med. 2001;345:851-860.Lewis EJ et al. N Engl J Med. 2001;345:851-860.
IDNT: Clinical Outcome Measures
Primary outcome: time to composite end point ofDoubling of baseline SeCrESRD (dialysis, renal transplant, or SeCr ³6 mg/dL)Death (all-cause mortality)
Secondary outcome: time to composite end point offatal or nonfatal CV events
SeCr, serum creatinine; ESRD, end-stage renal disease.SeCr, serum creatinine; ESRD, end-stage renal disease.Lewis EJ et al. N Engl J Med. 2001;345:851-860.Lewis EJ et al. N Engl J Med. 2001;345:851-860.
NN
Age (y)Age (y)
Male (%)Male (%)
Non-white (%)Non-white (%)
BMI (kg/mBMI (kg/m22))
History of CV disease (%)History of CV disease (%)
Retinopathy (%)Retinopathy (%)
IrbesartanIrbesartan
579579
5959
6565
2424
31.0 31.0
2727
6969
AmlodipineAmlodipine
567567
59 59
6363
3131
30.9 30.9
3030
6464
ControlControl
569569
58 58
7171
2828
30.5 30.5
2929
6767
IDNT: Mean Baseline Demographics
Control defined as placebo.Control defined as placebo.BMI, body mass index.BMI, body mass index.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.
Duration of diabetes (y)Duration of diabetes (y) 1515 1414 1515
IDNT: Baseline Exam & Laboratory Characteristics
IrbesartanIrbesartan AmlodipineAmlodipine
DBP (mm Hg)*DBP (mm Hg)* 87 87 8787 8787
SeCr (mg/dL)*SeCr (mg/dL)* 1.671.67 1.651.65 1.691.69
Urine protein (g/24 h)Urine protein (g/24 h)†† 2.92.9 2.92.9 2.92.9
HbAHbA1c1c (%)* (%)* 8.18.1 8.28.2 8.28.2
ControlControl
SBP (mm Hg)*SBP (mm Hg)* 160 160 159159 158158
Control defined as placebo.Control defined as placebo. SeCr, serum creatinine; HbASeCr, serum creatinine; HbA1c1c, glycosylated hemoglobin., glycosylated hemoglobin.* Mean.* Mean.† † Median.Median. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.
IDNT Primary End Point:Time to Doubling of SeCr, ESRD, or
Death
Control defined as placebo.Control defined as placebo.SeCr, serum creatinine; ESRD, end-stage renal disease; RRR, relative risk reduction.SeCr, serum creatinine; ESRD, end-stage renal disease; RRR, relative risk reduction.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.
Irbesartan (n=579)Irbesartan (n=579)
Amlodipine (n=565)Amlodipine (n=565)
Control (n=568)Control (n=568)
RRR=20%RRR=20%PP=.02=.02
PP=NS=NS
RRR=23%RRR=23%PP=.006=.006
00 66 1212 1818 2424 3030 3636 4242 4848 5454Follow-up (mo)Follow-up (mo)
00
1010
2020
3030
4040
5050
6060
7070Pa
tient
s (%
)Pa
tient
s (%
)
IDNT: Time to Doubling of SeCr
Control defined as placebo.Control defined as placebo.SeCr, serum creatinine; RRR, relative risk reduction.SeCr, serum creatinine; RRR, relative risk reduction.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.
Patie
nts
(%)
Patie
nts
(%)
Follow-up (mo)Follow-up (mo)00 66 1212 1818 2424 3030 3636 4242 4848 5454
00
1010
2020
3030
4040
5050
6060
7070Irbesartan (n=579)Irbesartan (n=579)
Amlodipine (n=567)Amlodipine (n=567)
Control (n=569)Control (n=569)
RRR=33%RRR=33%PP=.003=.003
PP=NS=NS
RRR=37%RRR=37%PP<.001<.001
IDNT Secondary End Point:IDNT Secondary End Point:CV EventsCV Events**
No significant differences between groups.No significant differences between groups. Control defined as placebo.Control defined as placebo.* Defined as death from cardiovascular causes, nonfatal myocardial infarction, heart failure resulting in * Defined as death from cardiovascular causes, nonfatal myocardial infarction, heart failure resulting in hospitalization,hospitalization, a permanent neurologic deficit caused by a cerebrovascular event, or lower limb amputation above the ankle.a permanent neurologic deficit caused by a cerebrovascular event, or lower limb amputation above the ankle. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.
ControlControl(n=569)(n=569)
IrbesartanIrbesartan(n=579)(n=579)
AmlodipineAmlodipine(n=567)(n=567)
25.325.323.823.8 22.622.6
00
1010
2020
3030
55
1515
2525Pa
tient
s (%
)Pa
tient
s (%
)
Early SeCr rise (n)Early SeCr rise (n)22 00 00 11
Discontinuations dueDiscontinuations dueto hyperkalemia [n (%)]to hyperkalemia [n (%)]11 11 (1.9) 11 (1.9) 3 (0.5) 3 (0.5) 2 (0.4) 2 (0.4)
Stopped study medicine [n (%)]Stopped study medicine [n (%)]22 134 (23)134 (23) 133 (23)133 (23) 140 (25)140 (25)
SAEs/1000 days on drug (%)SAEs/1000 days on drug (%)22 2.02.0 2.52.5 2.32.3
IrbesartanIrbesartan AmlodipineAmlodipine ControlControl
No. of AEsNo. of AEs
AE, adverse event; SAE, serious adverse event.AE, adverse event; SAE, serious adverse event.Control defined as placebo.Control defined as placebo.1. Lewis EJ et al. N Engl J Med. 2001;345:851-860.1. Lewis EJ et al. N Engl J Med. 2001;345:851-860.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.
IDNT: Adverse Events
IDNT: SummaryIrbesartan reduced the composite risk of progression of renal
disease or total mortality, independent of its BP-lowering effects
20% RRR vs control (P=.02) 23% RRR vs amlodipine (P=.006)
No significant differences among groups for CV outcomes Size and duration of study was insufficient to detect any
differencesIrbesartan was generally safe and well tolerated
Lower rate of SAEs in the irbesartan groupSAE, serious adverse event; RRR, relative risk reduction.SAE, serious adverse event; RRR, relative risk reduction.Lewis EJ et al. N Engl J Med. 2001;345:851-860.Lewis EJ et al. N Engl J Med. 2001;345:851-860.