Transcript ISHIB2005 Slide Presentation P III

ISHIB 2007
Innovating Vascular Health: Practical Applications to Clinical Practice
Critical Challenges in
Cardiovascular Disease
Program Chairwoman
Shawna D. Nesbitt, MD, MS
Associate Professor
Department of Internal Medicine
Division of Hypertension
University of Southwestern Texas
Medical School
Dallas, TX
Welcome and Program Overview
CME-accredited symposium jointly sponsored by the American
Society of Hypertension and CMEducation Resources, LLC
Commercial Support: Sponsored by an independent educational
grant from Novartis Pharmaceuticals
Mission statement: Improve patient care through evidence-based
education, expert analysis, and case study-based management
Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies
COI: Full faculty disclosures provided in syllabus and at the
beginning of the program
Program Educational Objectives
As a result of this session, physicians will be able to:
►
Identify the importance of early treatment of patients with high blood
pressure, and the importance of treating both systolic and diastolic
blood pressure abnormalities.
►
Implement clinical strategies that help patients achieve blood
pressure goals as quickly as possible, using combination therapy,
when indicated.
►
Identify prescribing strategies that reduce side effects and increase
the likelihood of adherence to an antihypertensive drug regimen.
►
Characterize and distinguish among safety profiles of and efficacy
characteristics of antihypertensive agents used in the African
American population.
Program Educational Objectives
►
Recognize markers of target organ damage and learn which
antihypertensive agents are useful for preventing end organ
complications such as CV disease and diabetic renal disease.
►
Manage hypertension as a systematic disease, with multiple
manifestations, and associations, including metabolic syndrome
and associated risk factors.
►
Address complications linked to healthcare disparities observed in
specific patient populations, and the importance of providing
access, treatment, and monitoring of patients with multiple risk CV
risk factors.
►
Manage African American patients with features of the metabolic
syndrome, and its implications for multiple risk factor
management
Program Faculty
Program Chairwoman
Shawna D. Nesbitt, MD, MS
Associate Professor
Department of Internal Medicine
Division of Hypertension
University of Southwestern Texas
Medical School
Dallas, Texas
Ken Jamerson, MD
Professor of Medicine
Cardiovascular Medicine
University of Michigan Health
System
Ann Arbor, Michigan
Jackson T. Wright, Jr., MD, PhD, FACP
Professor of Medicine
Program Director, General Clinical
Research Center
Case Western Reserve University
Director, Clinical Hypertension Program
University Hospitals of Cleveland
Chief, Case Western Reserve
University Hypertension Section
(Louis Stokes VAMC)
Cleveland, Ohio
Faculty Disclosures
Shawna D. Nesbitt, MD, MS
Grant/Research Support: Pfizer
Consultant: Novartis, BMS
Speakers Bureau: Boerhinger Ingelheim, Novartis, AstraZeneca
Ken Jamerson, MD
Research Support: NIH, NHLBI, NIH, NIDDK, Novartis, King
Pharmaceuticals
Consultant: MSD, Pfizer, Novartis, Speedel
Jackson T. Wright, Jr., MD, PhD, FACP
Research Support: Glaxo Smith Kline, Novartis
Consultant: Novartis, MSD, Sanofi, BMS, Pfizer, NIH
Honoraria: Novartis, Biovail, Sanofi, Pfizer
Program Agenda
7:15 – 7:30 PM
Introduction and Overview
The Current Landscape of Cardiovascular Risk
Management in African Americans—
Where Co-morbidity Matters: The Evolving
Relationship Between Risk Factors, Diabetes,
Hypertension, and Vascular Complications
Shawna D. Nesbitt, MD, MS
7:30 – 8:00 PM
Are We in Control? An Epidemiological
Examination of How Well We Are Managing
Hypertension in Ethnic Minority Populations:
The Importance of Early Risk Identification and
Intervention—Getting to Goal and Staying There
Ken Jamerson, MD
Program Agenda
8:00 – 8:25 PM
Hypertension—A Systemic Disease Requiring
Systematic Approaches to Therapy:
Recent Clinical Practice Recommendations
Focusing on Combination Therapy in Difficultto-Treat Patient Populations with High Blood
Pressure and Compelling Conditions
Jackson T. Wright, Jr., MD, PhD, FACP
8:25 – 8:55 PM
The Evolving Landscape of Antihypertensive
Therapy: Direct Renin Inhibition, Combination
Therapy, and Implications for African American
and Other Ethnic Populations
Shawna D. Nesbitt, MD, MS
8:55 PM
Questions and Interactions with the Faculty
Introduction and Overview
The Current Landscape of Cardiovascular
Risk Management in African Americans—
Where Co-morbidity Matters
The Evolving Relationship
Between Risk Factors, Diabetes, Hypertension, And
Vascular Complications
Shawna D. Nesbitt MD, MS
Associate Professor of Internal Medicine
University of Texas Southwestern
Dallas, Texas
The U.S. Population is Becoming
Increasingly Diverse
Changing Trends
Hispanics are the fastestgrowing segment of the
population, and now account
for 13% U.S., as do African
Americans.
The U.S. Asian population
currently consists of 10.6
million people, and represents
4% U.S.,; however, this
population group is expected
to triple in size by 2050.
120
100
80
60
40
20
0
2000
White
2010
2020
African American
2030
2040
Hispanic (any race)
Adapted from U.S. Census Bureau, 2004. Table 1a. Accessed Dec. 1, 2006.
2050
Asian
Southern U.S. Has the Highest Concentration
of African-Americans
25.0 to 60.0
12.3 to 24.9
5.0 to 12.2
0.3 to 4.9
People indicating exactly one race, Black or African
American, as a percent of total population by state
Adapted from U.S. Census Bureau, 2002 Redistricting Data (PL 94-171) Summary File
Estimated Rates of US Adults With
Hypertension by Sex, Race, and Ethnicity
NHANES 1988-1994 to 1999-2000
1988-1994
45
1999-2000
1.8% age adj. increase
Hypertensive Adults
(Rate, Percent ± SE)
40
7.2% age adj. increase
35
30
25
20
15
10
5
0
M
All
F
Non-Hispanic
Black
Fields et al. Hypertension. 2004;44:398-404.
Hajjar and Kotchen. JAMA. 2003;290:199–206
M
F
Non-Hispanic
White
M
F
Mexican
American
Hypertension Treatment and Control
Rates by Race/Ethnicity: NHANES 2000
70
63
60.1
60
Treatment
55.6
Control
%
50
44.6
40.3
44
40
30
20
10
7.2
0.9
6.2
8.2
6.2
3.7
0
African
Americans*
Whites*
*Non-Hispanic.
Hajjar and Kotchen. JAMA. 2003;290:199–206.
Mexican
Americans
Percentage
increase from
1988 to 2000
Mortality From High Blood Pressure
Higher in African Americans
Overall Mortality Rates From Causes Related to Hypertension, 2003*
Mortality Rate, %
60
50
40
49.7
40.8
30
14.9
20
14.5
10
0
Male
Female
African American
Male
Female
White
In hypertensive African Americans, 30% and 20% of all deaths in
men and women, respectively, may be due to high blood pressure.
*High blood pressure listed as a primary or contributing cause of death.
High blood pressure=systolic ≥140 mmHg or diastolic ≥90 mmHg, taking
antihypertensive medicine, being told ≥2 times by a physician that you have high
blood pressure.
Adapted from Thom T et al. Circulation. 2006;113:e85–e151.
Patients Not at JNC VI BP Goals
NHANES (1999-2000)
% Not at Goal BP
Systolic
Diastolic
Patient Type
Total hypertensives
African American
Mexican American/
Hispanic
Older patients (60 years)
Symptomatic CHD
Patients with diabetes†
(mm Hg)
BP
BP
<140/90
<140/90
57%
60%
26%
32%
<140/90
<140/90
<140/90
<130/85
63%
71%
47%
81%
30%
9%
4%
24%
*Includes those 17 years of age with diagnosed and undiagnosed hypertension. National
Center for Health Statistics. NHANES 1999-2000 (CD-ROM); †NHANES III.
Risk-Factor Clustering by Race and Sex
70
Percentage
60
50
40
30
20
10
0
0
White women
1
African-American women
Stone et al JAMA. 1996;275:1104-1112.
≥2
White men
≥3
African-American men
Obesity and Diabetes Among US Adults:
Growing prevalence
Obesity (BMI ≥30 kg/m2)
Diagnosed diabetes
30
8
6.4
25
21.8
Population
(%)
23.0
23.9
23.7
24.3
6
20
4
15
2
0
0
2000 2001 2002 2003 2004*
*Jan–June
6.5
6.6
6.6
5.9
2000 2001 2002 2003 2004*
CDC. 2004 NHIS; www.cdc.gov/nchs/nhis.htm.
Age-Adjusted Prevalence of Diabetes*
by Race/Ethnicity in the US
19%
15%
14%
7%
0
*In people 20+ years old
5
10
15
20
25
Percent
Sources: 1997-1999 National Health Interview Survey and 1988-1994 National Health and Nutrition
Examination Survey (NHANES) estimates projected to year 2000. 1998 outpatient database of the Indian
Health Service
CDC. National Diabetes Fact Sheet. 2002.
Percent of Population
Estimated Percentage of Americans Age 18 and Older Who
Report No Leisure-Time Physical Activity by Race and Sex
50
40
30
20
10
0
Afr
His
Ca
Ca
Afr
His
uca
uca
ica
ica
pan
p
ani
nA
nA
sia
sia
ic w
cm
me
nm
nw
me
om
en
rica
rica
om
en
en
nw
en
nm
om
en
en
Source: Physical Activity and Health: A Report of the Surgeon General, United States Department of
HHS
The Rising Tide of ESRD
Diabetes: The Number One Cause of ESRD
Other
Glomerulonephritis
No. of ESRD Patients (x 1000)
10%
700
13%
Hypertension
27%
Diabetes
50.1%
600
No of Patients
Projection
500
400
661,330
300
372,407
200
326,217
100
0
R2 = 99.8%
1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
Year
USRDS. Annual data report. 2000.
Years of Potential Life Lost to Total Heart
Disease Before Age 75 by Race and Gender
4000
3000
2000
1000
0
1980
White women
1985
African-American women
1990
White men
1995
African-American men
Clark et al Heart Dis. 2001;3:97-108; National Vital Statistics System, Health, United States, 1996–97.
Failure to Reach Treatment Goals
Carries Costly Burden
N = 1000 managed-care patients with treated hypertension
Greater medication costs
More physician visits
600
12
Mean
drug 400
cost per
patient
per year*
($ US) 200
Mean 8
visits
per
year 4
0
0
<130/85
130/85 –
139/89
Controlled
140/90 –
159/99
≥160/100
Uncontrolled
9.7
4.1
<120 mm Hg
≥180 mm Hg
Maximum SBP
Severity of hypertension (mm Hg)
*Based on 1999 average wholesale price
Paramore LC et al. Am J Manag Care. 2001;7:389-398.
Challenges and Solutions in
Minority Populations
Are We in Control?
The Importance of Early Risk
Identification and Treatment
Getting To Goal and Staying There in
Ethnic Minority Populations
Kenneth A. Jamerson, M.D.
Professor of Cardiovascular Medicine
University of Michigan
Medical Director, Program for Multi-cultural Health
Ann Arbor, Michigan
The Tecumseh Blood Pressure Study
A prospective epidemiological study of the antecedents of hypertension
and cardiovascular disease in 1,100 young men and women
Ann Arbor
Tecumseh
Tecumseh BP Study: Association of
DBP and Other CHD Risk Factors
Cholesterol
Triglycerides
Hematocrit
DBP
Insulin
Overweight
Heart Rate
N=124 (aged 18-28 years)
Adapted from Julius et al. JAMA 1990;264:354-358
P<0.001
P<0.01
P<0.05
Blood Pressure Trends
in Tecumseh, Michigan
140
*
Blood Pressure mmHg
130
120
*
*
110
100
**
90
80
*
*
70
60
6.4
21.5
31.3
Hypertensive and Normotensive at 31 Years of Age
Hypertensive
Normotensive
* P< .01
** P<.001
S. Julius, et al: JAMA 264:354-358, 1990
Causes and Causes for Concern
Is There a Unique Etiology for
Hypertension in African Americans?
Deciphering The Etiology and Associations
The Association of Skin Color with
Blood pressure in US blacks with
Low Socioeconomic Status
Klag, M J. Whelton, P K. Coresh, J. Grim, C E. Kuller, L H.
JAMA. 1991 Feb 6;265(5):639-40;
Abstract
To determine the association of skin color, measured by a reflectometer, with blood pressure in US blacks,
we studied a community sample of 457 blacks from three US cities. Persons taking antihypertensive medications
were excluded. Both systolic and diastolic blood pressure were higher in darker persons and increased by 2 mm
Hg for every 1-SD increase in skin darkness. However, the association was dependent on socioeconomic status,
whether measured by education or an index consisting of education, occupation, and ethnicity, being present
only in person with lower levels of either indicator. Using multiple linear regression, both systolic and diastolic
blood pressure remained significantly associated with darker skin color in the lower levels of socioeconomic
status, independent of age, body mass index, and concentrations of blood glucose, serum urea nitrogen, serum
uric acid, and urinary sodium and potassium. The association of skin color with blood pressure only in low
socioeconomic strata may be due to the lesser ability of such groups to deal with the psychosocial stress
associated with darker skin color. However, these findings also are consistent with an interaction between an
environmental factor associated with low socioeconomic status and a susceptible gene that has a higher
prevalence in persons with darker skin color.
Response to Therapy
A Critical Issue for Drug Selection and Care
Do African Americans respond to
antihypertensive therapy differently
than other races or ethnic groups?
Blood Pressure Response to
Quinapril: The ATIME Study
White,
%
20.0
15.0
10.0
Mean
–15.3
SD
12.2
Lower Quartile
–7.3
Upper Quartile
–23.5
Interquartile Range 16.2
5.0
African American,
%
0
20.0
15.0
10.0
Mean
–10.5
SD
13.4
Lower Quartile
–2.2
Upper Quartile
–20.0
Interquartile Range 17.8
5.0
0
39
27
15
3
–9
–21 –33
SBP (average change)
SD = standard deviation.
Mokwe E et al. Hypertension. 2004;43(6):1202–7.
–45
–57
Is It Important To Block The RAS
In African Americans?
Landmark Trials That Give Us Data,
Guidance, and Perspective
►
HOPE
►
PROGRESS
►
SOLVD
►
ValHeft
►
V-Heft
►
LIFE
►
OCTAVE
►
ALLHAT
Landmark and Longitudinal Studies
African American Study of
Kidney Disease and Hypertension
Achieved Blood Pressure in AASK
ACE
CCB
BB
LOW
USUAL
SBP
133.6
131.4
134.2
126.9
140.0
DBP
81.1
80.7
80.9
76.6
85.2
NEED FOR
28%
24%
32%
35%
23%
STEP 5
Cumulative Incidence of Confirmed Declining GFR Event,
Dialysis or Death by Drug Group
(Data as of 10/19/01)
Analysis Censored on 9/22/00 for the CCB Group
40
35
30
p-value
adjusted
25
A vs B
.042
C vs B*
.19
A vs C*
.005
20
15
10
5
0
0
6
12
18
24
30
36
42
Follow-up Time (Months)
.
Beta
ACE
CCB
48
54
60
Implications Of The AASK Study
►
Aggressive control of blood pressure can
eliminate ethnic differences in ESRD
►
Inadequate treatment of hypertension may
cause excess risk of target organ disease
►
Cultural, rather than genetic differences,
may underlay the excess risk of
hypertensive ESRD
International Society of
Hypertension in Blacks
IMPACT Campaign
Science
Guidelines
Behavioral Change
Vascular Matrix Summit
►
Dr. Gary Gibbons
►
Dr. Abraham Aviv
►
Rick Kittles, MD
►
Charles Rotimi, MD
►
David Harrison, MD
►
Willa Hsueh, MD
►
Helmy Siragy, MD
►
Douglas Vaughan, MD
►
Dr. Brent Egan
►
Ken Jamerson, MD
The Problem
Does Being African American
Modify the Problem?
Models to Explain Health Disparities
►
Racial Genetic Model
Cause of HD: Population differences in the distribution
of genetic variants
►
Health-behavior Model
Cause of HD: Differences between R/E groups in the
distribution of individual behaviors related to health
such as diet, exercise, and tobacco use
►
SES Model
Cause of HD: Over-representation of some R/E groups
within lower SES
►
Psychosocial Stress Model
Cause of HD: Stresses associated with minority group
status, especially the experience of racism and
discrimination
Critical Relationships
Race
(Social)
Disease
Ancestry
(Genetic)
Ancestry Informative Markers (AIMs)
Although much genetic variation (8590%) is shared among all human
populations, about 5% of SNPs have
high levels of allele frequency
differential (d>50%).
We call these markers Ancestry
Informative Markers (AIMs).
Ancestry Can Be Estimated Across
Chromosomal Regions
Seldin et al. Genome Res. 14:1076 -1084, 2004
Smith et al. AJHG 74:1001-1013, 2004
European Genetic Contribution in African-American
Populations Living in Different Areas of the U.S.
Parra et al. AJHG 1998; Parra et al. AJPA 2002; Kittles et al. unpublished
Era of Genomic Ancestry and
Challenges Related to Health
1. Group definition and membership.
2. Can we accurately assess genomic
ancestry?
3. How does genomic ancestry relate to
skin color and possibly SES?
4. How useful is genomic ancestry for
informing us about disease risk?
5. Health Disparities: are they due to
biological differences?
6. How do we prevent repeating the
negative past abuses of “race”.
Accomplishing Something
RESULTS
BP Control at 18 Months
ACCOMPLISH: Hypothesis
► ACCOMPLISH will test a new strategy for the
treatment of hypertension: Dual therapy
provided in a single tablet.
► The combination of benazepril and
amlodipine will reduce cardiovascular
morbidity and mortality in patients with highrisk hypertension by 15% when compared to
the combination of benazepril and HCTZ.
Jamerson KA et al. Am J Hypertens. 2004;17:793–801.
ACCOMPLISH: Primary Endpoint
Time to first event of composite
cardiovascular morbidity and mortality
CV MORBIDITY
►
Nonfatal MI
►
Nonfatal stroke
►
Hospitalization for unstable angina
►
Resuscitated sudden cardiac death
►
Coronary revascularization procedures
CV MORTALITY
►
Sudden cardiac death
►
Fatal MI
►
Fatal stroke
►
Death due to coronary intervention, congestive heart
failure, or other cardiovascular causes
Jamerson KA et al. Am J Hypertens. 2004;17:793–801.
ACCOMPLISH: Statistical Power
►
1,642 primary endpoints needed (~5 years)
►
90% power to detect a 15% risk reduction for
the primary endpoint at a two-sided overall
significance level of 5%
►
Four (4) interim analyses and 1 final analysis
►
Allow for lost-to-follow-up rate of less than 5%
Jamerson KA et al. Am J Hypertens. 2004;17:793–801.
ACCOMPLISH: Design
Titrated to achieve BP <140/90 mmHg;
<130/80 mmHg in patients with diabetes or
renal insufficiency
Free add-on
antihypertensive
agents*
Amlodipine/
benazepril 10/40 mg
Screening
(N=12,600)
Randomization
Amlodipine/
benazepril 5/40 mg
Amlodipine/
benazepril 5/20 mg
Benazepril 20 mg +
HCTZ 12.5 mg
Benazepril 40 mg +
HCTZ 12.5 mg
Benazepril 40 mg +
HCTZ 25 mg
Free add-on
antihypertensive
agents*
Forced titration
14 Days
Day 1
Month 1
Month 2
Month 3
Year 5
*Beta blockers; alpha blockers; clonidine; loop diuretics. Patients were seen at 6 months after the
start of study and thereafter at 6-month intervals until the end of the 5 year trial.
Jamerson KA et al. Am J Hypertens. 2004;17:793–801.
Targeted Population for Recruitment
into the ACCOMPLISH Trial
►
Men or women of any racial background, age
≥55 years
►
SBP ≥160 mmHg or currently on
antihypertensive therapy
►
Evidence of cardiovascular or renal disease
or target organ damage
ACCOMPLISH: Key Demographic Data
Race:
Caucasian
83.9%
Black
11.9%
Oriental
0.4%
Other
3.8%
Ethnicity:
Hispanic
% of
Population
Baseline
BP
(mmHg)
Control
Rate at
Baseline+
All
Patients*
40%
145.4/80
37.5%
Diabetic
SubPopulation
60%
145.2/79.
3
16.3%
5.4%
Gender
Male
60.7%
Mean Age,
years
Female
39.3%
% of Pts >70
• +BP<140/90 for non-diabetics and <130/80 for diabetics
• * including 6.8% of CKD based on Serum Creatinine
68.4
40.9%
Baseline Traits of ACCOMPLISH Cohort May Reflect
New Secular Trends in Disease Management
►
Patient enrollment completed.




►
50% of patients are obese
60% of patients have Diabetes Mellitus
97% of patients were treated previously for
hypertension.
74% of patients were treated with > 2 Hypertensive
Agents
Only 37.5% of patients were controlled to
<140/90 mmHg
ACCOMPLISH: Effect of Initial
Combination Therapy on SBP Over Time
160
All Patients
SBP (mmHg)
155
150
145.4
(18.3)
145
140
132.5
135
132.7
(16.0)
(16.0)
131.8
(16.0)
130
125
120
Baseline
N=11,400
Month 6
N=10,736
Month 12
N=10,335
(sd)
Data on file. Novartis Pharmaceuticals Corporation.
Month 18
N=9,898
ACCOMPLISH: Significant Reduction
in SBP in All Patient Populations
All
155
SBP (mmHg)
U.S.
152.6
(N=3,333)
150
145
Nordic
African
American
145.4
145.1
142.4
(N=11,400)
(N=1,361)
JNC-7 Goal:
SBP
140 mmHg
(N=8,067)
140
135
136.8
133.6
130
131.8
129.4
125
120
P<0.05
Neither age nor gender appeared to influence the effects on SBP.
Data on file. Novartis Pharmaceuticals Corporation.
Baseline
Range
ACCOMPLISH: Exceptional Control Rates
with Initial Combination Therapy
90
80
80.5
75.6
65.1
70
Control rate (%)
71.8
60
50
N=8,067
N=1,361
N=11,400
40
30
44.4
37.6
38.6
N=3,333
20
21.0
10
All
Nordic
U.S.
Data on file. Novartis Pharmaceuticals Corporation.
African
American
Baseline
Control Rates
Conclusions
►
Millions of Americans take anti-hypertension
medication, but do not achieve blood pressure
control. Initial therapy with single-tablet, dualmechanism drugs is highly effective (>80%
control) and safe.
►
We find substantial evidence to broaden the use
of combination therapy as an initial strategy for
the treatment of hypertension.
Considering Combination Therapy
Hypertension – A Systemic Disease
Requiring Systematic
Approaches To Therapy
Recent Clinical Practice Recommendations
Focusing on Combination Therapy in Difficult-to-Treat
Patient Populations with High Blood Pressure
and Compelling Conditions
Jackson T. Wright, Jr. MD, PhD
Professor of Medicine
Case Western Reserve University
Program Director, General Clinical Research Center
Director, Clinical Hypertension Program
University Hospitals Case Medical Center and
the Louis Stokes Cleveland VAMC
Goals of This Presentation
►
Need for multi-drug therapy for BP control
►
Guideline recommendations for treatment
and rationale for these recommendations
►
Importance of BP vs. drug selection
►
Combination drug regimens—options and
strategies
Hypertension in African Americans
(versus Whites)
Epidemiology
• Higher prevalence &
incidence (esp.
women)
• Greater severity
• Earlier onset
• Higher hospitalization
rates (~8 x  )
• More target-organ
injury
• Renin more often
suppressed
Treatment
• Less intensively treated
• More factors linked to HTN Tx
resistance
− Diabetes
−  GFR
− Target-organ
− Obesity
injury
− Proteinuria − Living in SE
USA
− Female
sex
• Lesser BP response to ACEI
than whites
• Less likely to receive RAS drugs
Combination Therapy is Needed to
Achieve Target SBP Goals
Trial/SBP Achieved
UKPDS (144 mm Hg)
RENAAL (141 mm Hg)
ALLHAT (135 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)
1
2
3
Number of BP meds
Updated from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661
4
Number of Antihypertensive Drugs
Used and BP Control (<140/90 mm Hg)
Chlorthalidone
Amlodipine
100
1.8-2.0
1.9-2.1
2
1.7-1.8
Lisinopril
1.5-1.7
80
Percent
1.4-1.5
60
53
48
46
40
20
1.5
1.3
28
28
58
55
51
64
63
61
57
54
59
67
65
63
68
66
1
62
0.5
27
0
0
0
ALLHAT
6
12
24
36
Months of Follow-up
48
60
Percent Controlled (BP < 140/90) at Five
Years by Number of Drugs Prescribed
Chlorthalidone
Amlodipine
Lisinopril
80
70
68 66
61
Percent
60
50
40
30
28
24 24
24 26
18
20
11 11 12
10
3
4
6
0
1
2
3
4+
Number of Prescribed Drugs
ALLHAT
ALL
Number of Drugs Needed to Control BP
(<140/90 mm Hg) in ALLHAT After 5 Years
►
26% of participants were controlled on 1 drug
(another 2% were untreated):

►
49% were controlled on 1 or 2 drugs (12% more
were uncontrolled on 1 drug or untreated):

►
Therefore, at least 72% received or
needed ≥ 2 drugs
Therefore, at least 39% received or would have
needed ≥ 3 drugs to control BP
60% were controlled on 3 or fewer drugs:

Therefore, at least 16% received or needed ≥ 4
drugs to control BP
ALLHAT
JNC-7 Algorithm for Treatment
of Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney disease)
Initial Drug Choices
Without
Compelling
Indications
Stage 1 Hypertension
(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
With Compelling
Indications
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)
Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
Consensus Statement: Management of High BP in African
Americans
Uncomplicated
hypertension
Goal BP: <140/90 mm Hg
If BP <155/100 mm
Hg, monotherapy†
Patient with elevated
BP
If BP 155/100 mmHg,
combination therapy‡
Not at BP goal?
Intensify lifestyle changes
AND
Add a 2nd agent from
a different class or
increase dose
Increase dose
or add a 3rd agent
from a different class
Diabetes/nondiabetic renal disease
with proteinuria >1 g/24 h*
Goal BP: <130/80 mm Hg
If BP <145/90 mm Hg,
monotherapy or
combination therapy
including a RAS blocker§
If BP 145/90 mm Hg,
combination therapy
including a RAS
blocker§
Not at BP goal?
Intensify lifestyle changes
AND
Add a 2nd agent from a
different class or
increase dose
RAS, renin-angiotensin system
Increase dose
or add a 3rd agent
from a different
class
*Preferable BP goal for patients with renal disease with proteinuria >1 g/24 h is <125/75 mm Hg
†Initiate
monotherapy at the recommended starting dose with an agent from any of the following classes:
diuretics, beta blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors,
or angiotensin II receptor blockers (ARBs)
‡To
achieve BP goals more expeditiously, initiate low-dose combination therapy with any of the following
combinations: beta blocker/diuretic, ACE inhibitor/diuretic, ACE inhibitor/CCB, or ARB/diuretic
§Consider
specific clinical indications when selecting agents
Douglas J et al. Arch Intern Med. 2003;16:525-541
Black vs. Non-Black
Lisinopril versus Chlorthalidone
Relative Risk and 95% Confidence Intervals
Non-Black
Black
Nonfatal MI + CHD Death
1.10 (0.94 - 1.28)
0.94 (0.85 - 1.05)
All-Cause Mortality
1.06 (0.95 - 1.18)
0.97 (0.89 - 1.06)
Combined CHD
1.15 (1.02 - 1.30)
1.01 (0.93 - 1.09)
1.19 (1.09 - 1.30)
1.06 (1.00 - 1.13)
1.40 (1.17 - 1.68)
1.00 (0.85 - 1.17)
1.30 (0.94 - 1.75)
0.93 (0.67 - 1.30)
1.30 (1.10 - 1.54)
1.13 (1.00 - 1.28)
Combined CVD
Stroke
End Stage Renal Disease
Heart Failure
ALLHAT
0.50
Favors
Lisinopril
1
2
Favors
Chlorthalidone
0.50
Favors
Lisinopril
1
2
Favors
Chlorthalidone
Wright JT et al; JAMA 2005; 293:1593
Blood Pressure at 5 Years by Race
SBP – mean (sd)
DBP – mean (sd)
∆ BP compared
with
chlorthalidone
ALLHAT
Chlorthalidone
Amlodipine
Lisinopril
Black
135.0 (15.8)
136.1 (15.3)
139.1 (19.7)
Nonblack
133.3 (14.8)
133.8 (14.6)
134.2 (16.7)
Black
77.4 (10.0)
76.3 (10.1)
78.0 (11.4)
Nonblack
74.4 (9.5)
73.6 (9.6)
74.1 (10.1)
Black
---
+1.1 / -1.1*
+4.1* / +0.6
Nonblack
---
+0.5 / -0.8*
+0.9 / -0.3
* P < 0.005
05/15/03
Frequency Distribution: SBP in Response to
Quinapril in Black and White Participants
White,
%
20.0
15.0
10.0
Mean
–15.3
SD
12.2
Lower Quartile
–7.3
Upper Quartile
–23.5
Interquartile Range 16.2
Whites
n = 2046
5.0
African American,
%
0
20.0
15.0
10.0
Mean
–10.5
SD
13.4
Lower Quartile
–2.2
Upper Quartile
–20.0
Interquartile Range 17.8
Blacks
n = 533
5.0
0
39
27
E. Mokwe et. al., HTN 2004;43:1
15
3
–9
–21 –33
SBP (average change)
–45
–57
Angioedema
Chlorthalidone
Lisinopril
Total
Blacks
Nonblacks
8 / 15,255
2 / 5,369
6 / 9,886
0.1%
<0.1%
0.1%
38 / 9,054
23 / 3,210
15 / 5,844
0.4%
0.7%
0.3%
p<.001
p<.001
p=.002
There were 3 cases (<0.1%) of angioedema in the amlodipine group
(comparison to chlorthalidone not significant).
ALLHAT
Results Of Primary Composite End Point
in LIFE By Ethnic Group
Race N
25
Hazard Ratio
Blacks
White
8503
20
Black
533
15
Hispanic 100
10
Asian
0.1
Atenolol
Losartan
(23.36) 5
43
1
2 3 4
Non-Blacks
0
0
12 24 36 48 600
12 24 36 48 60
Time in Months
Results of primary composite end point by ethnic
group. The dots represent the hazard ratio; dot
size is proportional to the number of patients for
each ethnic group, as shown to the left. The line
through each dot corresponds to the 95%
confidence interval.
Julius et al. J Am Coll Cardiol 2004;43:1047-55
Results of primary composite end point by
ethnic group in the U.s.: blacks versus nonblacks.
AASK Clinical Endpoint Analysis
ACEI vs. CCB
% Risk
Outcome
GFR event,
% Risk
95 %
Reduction1
Confidence
Interval
Reduction
Confidence
Interval
38%
(+ 14 to + 55)
22%
(+ 1 to + 38)
p<0.005
ESRD or Death2
GFR event or ESRD3
95 %
ACEI vs. BB
40%
(+ 13 to + 59)
p< 0.042
22%
p<0.007
ESRD or Death4
48%
(+ 26 to + 65)
p< 0.066
21%
p<0.004
ESRD alone5
59%
(+ 34 to + 74)
p< 0.001
(- 1 to + 41)
(- 5 to + 40)
p< 0.11
23%
(- 10 to +
45)
p< 0.14
1. Adjusted for baseline proteinuria, MAP,gender, Hx CHF and age; 2) 179 declining
GFR, 84 ESRD, 77 death; 3) 170 declining GFR, 84 ESRD; 4) 171 ESRD, 79 deaths;
5 170 events, deaths censored.
Wright et al 2002; JAMA, 288:2421
ASCOT All-Cause Mortality —
Amlodipine versus Atenolol
10.0
%
Atenolol
(No. of events 820)
8.0
6.0
Amlodipine
(No. of events 738)
4.0
2.0
HR = 0.89 (0.810.99)
p = 0.0247
0.0
0.0
Number at risk
Amlodipine  perindopril 9639
Atenolol  thiazide
9618
1.0
2.0
3.0
4.0
5.0
9167
9085
8078
7975
Years
9544
9532
9441
9415
9332
9261
Black vs. Non-Black
Amlodipine versus Chlorthalidone
Relative Risk and 95% Confidence Intervals
Black
Nonfatal MI + CHD Death
All-Cause Mortality
Combined CHD
Combined CVD
Stroke
End Stage Renal Disease
Heart Failure
0.50
Favors
Amlodipine
ALLHAT
1
Non-Black
1.01 (0.86 - 1.18)
0.97 (0.87 - 1.08)
0.97 (0.87 - 1.09)
0.94 (0.87 - 1.03)
1.03 (0.91 - 1.17)
0.99 (0.92 - 1.07)
1.06 (0.96 - 1.16)
1.04 (0.97 - 1.10)
0.93 (0.76 - 1.14)
0.93 (0.79 - 1.10)
1.15 (0.84 - 1.58)
1.08 (0.79 - 1.48)
1.46 (1.24 - 1.73)
1.32 (1.17 - 1.49)
2
Favors
Chlorthalidone
0.50
Favors
Amlodipine
1
2
Favors
Chlorthalidon
e
Wright JT et al; JAMA 2005; 293:1593
VALUE Trial: Primary Composite
Cardiac Endpoint
Proportion of Patients
With First Event (%)
14
Valsartan-based regimen
12
Amlodipine-based regimen
10
8
6
4
0
Number at risk
HR = 1.03; 95% CI = 0.94–1.14; P = 0.49
2
0
6
12 18 24 30 36 42
48 54 60 66
Time (months)
Valsartan
7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3765 1474
Amlodipine
7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474
Julius S et al. Lancet. June 2004;363
VALUE Trial — Hazard Ratios
for Pre-specified Analyses
Hazard Ratio
Valsartan/Amlodipine
Primary cardiac composite endpoint
cardiac mortality
cardiac morbidity
All myocardial infarction
All congestive heart failure
All stroke
All-cause death
New-onset diabetes
0.5
1
2
Favours valsartan
Favours amlodipine
Julius S et al. Lancet. June 2004;363
Staessen Meta-Regression Analysis: Robust Correlation
Between Difference in SBP and Risk of CV Events
All Trials
Recent Trials
Odds Ratio
(experimental/control)
1.50 −
1.50 −
P < 0 .0001
VALUE?
UKPDS C vs A
1.25 −
1.00
0.75
1.25 −
ALLHAT
CAPPP
NORDIL MIDAS/NICS/VHAS
HOT M vs H
−STOP2/CCBs
INSIGHT
HOT L vs HPROGRESS/Per
STOP2/ACEIs RENAAL
MRC2
MRC1
ATMH
HOPE PATS
Syst-China
−
Syst-Eur
EWPHE
HEP
PART2/SCAT
SHEP
RCT70–80
UKPDS L vs H PROGRESS/Com
STOP1
0.50 −
1.00 −
0.75 −
•
ALLHAT/Lis Blacks
ALLHAT/Lis ≥ 65 y
ALLHAT/Lis
ALLHAT/Aml
CONVINCE
ABCD/NT L vs H
DIABHYCAR
ANBP2
IDNT2
LIFE/ALLSCOPE
AASK L vs H
ELSA
PREVENT
LIFE/DM
NICOLE
0.50 −
STONE
0.25 −
0.25 −
-5
0
5
10
15
20
25
-5
0
5
10
15
20
25
Difference in SBP
Difference in SBP
(control minus experimental) mm Hg (control minus experimental) mm Hg
Adapted from Staessen JA, Wan JG, Thijs L. J Hypertens. 2003;21:1055-1076
BP Reduction and Major
Cardiovascular Outcomes
1.50
1.25
Stroke
CVD
Heart Failure
CHD
1.00
0.75
0.50
0.25
1.50
1.25
1.00
0.75
0.50
0.25
-10
-8
-6
-4
-2
0
2
4
-10
-8
-6
-4
Systolic blood pressure difference between randomised groups (mmHg)
Blood Pressure Lowering Treatment Trialists’ Collaboration
Lancet. 2003;362:1527-1535
-2
0
2
4
Percent Controlled (BP < 140/90) at Five
Years by Number of Drugs Prescribed
Chlorthalidone
Amlodipine
80
70
68 66
Lisinopril
61
Percent
60
50
40
30
28
24 24
24 26
18
20
11 11 12
10
3
4
6
0
1
2
3
4+
Number of Prescribed Drugs
ALLHAT
ALL
Multi-Drug Therapy: Rule or Exception?
If most hypertensive patients
(especially Black hypertensives)
require 2-3 medications for BP
control, which agents should we
include in this mix?
CCB, DIURETICS, RAASI
Drug Treatment Standards
Initiate TX
Uncomplicated HTN
WHO/ISH
JNC 7
HAAWG
ISHIB
140/90
140/90
140/90
160/100
155/100
130/80
130/80
150/90
145/90
(previously 160/90;
currently 160/100 in UK)
Initiate Combination
TX- Uncomplicated
Initiate TX
Complicated HTN &
Goal
Initiate Combination
TX- Complicated HTN
SD Nesbitt 2004
130/80
(140/90 for women &
elderly and in UK)
Drug Choice Recommendations
Uncomplicated
HTN
Combination TXUncomplicated
Complicated HTN
SD Nesbitt 2004
WHO/ISH
JNC 7
HAAWG ISHIB
Thiazide as
initial agent
Thiazide as initial
agent
May use ACE,
ARB, Beta-B, CCB
May initiate
diuretic, ACE,
ARB, Beta-B,
CCB
Diuretic + (ACE,
Beta-B, ARB)
Diuretic + (ACE,
Beta-B, ARB)
or ACE/CCB
or ACE/CCB
Not uniformly
recommended
Treat according to the compelling condition similarly
according to all guidelines.
NKF Guideline 3 – Management of
Hypertension in Diabetes and CKD
► Hypertensive
people with diabetes and
CKD Stage 1-4 should be treated with
an ACE inhibitor or an ARB, usually in
combination with a diuretic (A)
► Target
blood pressure in diabetes and
CKD should be <130/80 mmHg (B)
Combination Therapies
► b-adrenergic blockers and diuretics
► ACE inhibitors and diuretics
► Angiotensin II receptor antagonists
(ARBs)
and diuretics
► Calcium antagonists and ACE
inhibitors
► Calcium antagonists and ARBs
► Renin inhibitors and diuretics
Combination Drug Therapy In
HTN — Advantages
►
Improved blood pressure control
 Uses different approaches
 Blocking counter-regulatory
mechanisms
 Ease of titration to BP goal
►
Reduce side effects
(less dosage requirement)
►
Improve protection of target organs
Combination Drug Therapy
In Hypertension
CONCLUSIONS
►
BP lowering reduces BP-related outcomes
►
To achieve BP goals will require at least 2, and
usually more, BP drugs, especially in Black
hypertensive patients
►
Clinical outcome data are available for CCBs,
diuretics (thiazide-type), and RAS inhibitors (ACEIs
and ARBs) as initial Rx
►
Differences between guideline recommendations for
treatment are minor and all focus on achieving BP
goal and need for multi-drug regimens
►
With available agents, BP goals can be achieved
Emerging Therapies— Focus on RAS
The Evolving Landscape of
Antihypertensive Therapy
Direct Renin Inhibition, Combination Therapy, and
Implications for African American and other
Ethnic Populations
Shawna D. Nesbitt MD, MS
Associate Professor of Internal Medicine
Department of Medicine
University of Texas Southwestern
Dallas, Texas
ISHIB Consensus Statement: Management
of Hypertension in African Americans
Patient with elevated BP
Diabetes/nondiabetic renal disease with
proteinuria >1 g/24 h*
Goal BP: <130/80 mmHg
Uncomplicated hypertension
Goal BP: <140/90 mmHg
If BP <155/100 mmHg,
monotherapy†
If BP 155/100 mmHg,
combination therapy‡
If BP <145/90 mmHg,
monotherapy or
combination therapy
including a RAS blocker§
Not at BP goal?
Intensify lifestyle changes AND
Add a 2nd agent from a
different class or
increase dose
Increase dose
or add a 3rd agent
from a different class
If BP 145/90 mmHg,
combination therapy
including a RAS blocker§
Not at BP goal?
Intensify lifestyle changes AND
Add a 2nd agent from a
different class or
increase dose
Increase dose
or add a 3rd agent
from a different class
*Preferable BP goal for patients with renal disease with proteinuria >1 gm/24 h is <125/75 mmHg. †Initiate
monotherapy at the recommended starting dose with an agent from any of the following classes: diuretics,
b-blockers, CCBs, ACEIs, or ARBs. ‡To achieve BP goals more expeditiously, initiate low-dose
combination therapy with any of the following combinations: b-blocker/diuretic, ACEI/diuretic, ACEI
inhibitor/CCB, or ARB/diuretic. §Consider specific clinical indications when selecting agents.
Douglas JG et al. Arch Intern Med. 2003;163:525–541
JNC 7 Algorithm for Treatment
of Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (<140/90 mm Hg)
(<130/80 mm Hg for those with diabetes or chronic kidney disease)
Initial Drug Choices
Without Compelling
Indications
Stage 1 Hypertension
(SBP 140-159 or DBP 90-99 mm Hg)
Thiazide-type diuretics for most
May consider ACEI, ARB, BB, CCB,
or combination
With Compelling
Indications
Stage 2 Hypertension
(SBP 160 or DBP 100 mm Hg)
2-drug combination for most
(usually thiazide-type diuretic and
ACEI, ARB, BB, or CCB)
Not at Goal
Blood Pressure
Optimize Dosages or Add Additional Drugs
Until Goal Blood Pressure Is Achieved
Consider consultation with hypertension specialist
Chobanian et al. JAMA. 2003;289:2560-2572
Drug(s) for the Compelling
Indications
Other antihypertensive drugs
(diuretic, ACEI, ARB, BB, CCB)
as needed
Published Guidelines Have Set
Lower Treatment Goals
JNC 7 / ADA / NKF / ISHIB Guidelines
for Hypertension and Patients at High Risk
Condition
mmHg
Essential hypertension
<140/90
Diabetes mellitus
<130/80
Chronic renal disease
<130/80
High-risk* hypertension
<130/80
ADA=American Diabetes Association.
NKF=National Kidney Foundation.
ISHIB=International Society on Hypertension in Blacks.
*History
of CVD event, stroke, transient ischemic attack, evidence of target-organ
damage (e.g., left ventricular hypertrophy, microalbuminuria), CHD, or high-risk for CHD
(e.g., metabolic syndrome).
Chobanian AV et al. JAMA. 2003;289:2560–2572. Arauz-Pacheco C et al. Diabetes Care.
2003;26(suppl):S80–S82. Douglas JG et al. Arch Intern Med. 2003;163:525–541. Bakris GL et al. Am J
Kidney Dis. 2000;36:646–661
JNC-7 Compelling Indications
CHF
Diuretic
BB
ACEI
ARB






Post MI



DM






2° stroke
prevention

AA


CAD risk
Chronic kidney
disease
CCB



BB=beta blocker; ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor
blocker; CCB=calcium channel blocker; AA=aldosterone antagonist; CHF=chronic heart
failure; MI=myocardial infarction; CAD=coronary artery disease; DM=diabetes mellitus
The JNC 7 Report. JAMA. 2003;289:2560
Mortality From High Blood Pressure
Higher in African Americans
Overall Mortality Rates From Causes Related to Hypertension, 2003*
Mortality Rate, %
60
50
40
49.7
40.8
30
14.9
20
14.5
10
0
Male
Female
African American
Male
Female
White
In hypertensive African Americans, 30% and 20% of all deaths in
men and women, respectively, may be due to high blood pressure.
*High blood pressure listed as a primary or contributing cause of death.
High blood pressure=systolic ≥140 mmHg or diastolic ≥90 mmHg, taking antihypertensive
medicine, being told ≥2 times by a physician that you have high blood pressure.
Adapted from Thom T et al. Circulation. 2006;113:e85–e151
RAS Blockade in
African-American Patients
►
Drugs that block the renin-angiotensin system
(RAS) provide less antihypertensive efficacy
than in white patients*
►
Physiologic basis for this proposition:




Lower levels of plasma renin activity (PRA)
Relative expansion of plasma volume
Higher prevalence of salt dependency
Higher Na+ and Ca+, may suppress PRA†
* Weir MR et al. Hypertension. 1995;26:124-130
†Douglas JG. Unpublished data
‡Agodoa LY et al. JAMA. 2001;285:2719-2728
Renin Angiotensin System
Benefits of Renin System (RS)
Suppression to Date
Clinical Trial Data
Relative Risk Reduction With
Ramipril vs Amlodipine Besylate: AASK
RRR=38%
P=0.005
0.08
0.07
Ramipril
Amlodipine besylate
0.06
Events
per
personyr
0.05
RRR=41%
P=0.03
RRR=44%
P=0.01
0.04
0.03
0.02
0.01
0
GFR
ESRD
GFR, glomerular filtration rate; ESRD, end-stage renal
disease Agodoa LY et al. JAMA. 2001;285:2719-2728
GFR, ESRD,
or death
ALLHAT: Lisinopril vs Chlorthalidone
Primary Endpoint (Nonfatal MI + CHD Death) Subgroups
Relative Risk (95% CI)
Total
0.99 (0.91-1.08)
Age <65
0.95 (0.81-1.12)
Age 65
1.01 (0.91-1.12)
Men
0.94 (0.85-1.05)
Women
1.06 (0.92-1.23)
Black
1.10 (0.94-1.28)
Nonblack
0.94 (0.85-1.05)
Diabetic
1.00 (0.87-1.14)
Nondiabetic
0.99 (0.88-1.11)
0.5
Favors
Lisinopril
1
1.5
Favors
Chlorthalidone
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997
ACEIs and ARBs Yield Reduction in
Cardiovascular Morbidity and Mortality
Relative Risk Reduction, %
ACEIs
HOPE1
Placebo (n=4652)
Ramipril (n=4645)
ARBs
CONSENSUS2
Placebo (n=126)
Enalapril (n=127)
SOLVD3
Placebo (n=1284)
Enalapril (n=1285)
CHARM-Alternative4
LIFE5
Placebo (n=1015)
Atenolol (n=4588)
Candesartan (n=1013) Losartan (n=4605)
0
-10
-20
-30
-40
22%
P<.001
MI, stroke, or
CV death in
high-risk
patients
16%
P=.003
27%
P=.003
Total mortality
in severe HF
Mortality in
chronic HF
23%
P=.0004
CV death or HF
hospitalization in
patients with
chronic HF and
intolerance of
ACEI
13%
P=.021
Death, MI, or
stroke in patients
aged 55-80 years
with hypertension
and LVH
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HOPE, Heart Outcomes Prevention
Evaluation; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; SOLVD, Studies of Left Ventricular
Dysfunction; CHARM, Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity; LIFE, Losartan
Intervention for Endpoint Reduction in Hypertension; MI, myocardial infarction;
CV, cardiovascular; HF, heart failure; LVH, left ventricular hypertrophy.
1. Yusuf S et al. N Engl J Med. 2000;342:145-153
2. The CONSENSUS Trial Study Group
3. N Engl J Med. 1987;316:1429-1435
3. SOLVD Investigators. N Engl J Med. 1991;325:293-302
4. Granger CB et al. Lancet. 2003;362:772-776
5. Dahlöf B et al. Lancet. 2002;359:995-1003
Reduction of Progressive
Nephropathy with ARB: IDNT
Irbesartan
vs Control
Irbesartan vs
Amlodipine
Doubling Cr,
ESRD, or
Death (%)
20
*
23
**
4
ns
Doubling of
Cr, (%)
33
**
37
***
6
ns
ESRD (%)
23
ns
23
ns
0
ns
*
**
***
Lewis EJ NEJM 2001;345:851
p< .05
p< .01
p<.001
Amlodipine
vs Control
Diabetics Exposed to Telmisartan and
Enalapril Study (DETAIL)
►
►
►
250 Type 2 diabetes, hypertension and
nephropathy
Forced titration of telmisartan (40-80 mg) and
enalapril (10-20 mg)
Primary outcome was a change in glomerular
filtration rate (GFR) after 5 years
Death Rate
p=ns
14.9
17.9
35-50%
Percent
mL/min
Decrease in GFR
5%
enalapril
telmisartan
Barnett A et al N Engl J Med 2004
enalapril
5%
telmisartan expected
rate over
5 years
TRial Of Preventing HYpertension
(TROPHY)
Kaplan-Meier Curves of Clinical Hypertension in the Two Groups
4 Years
RR ↓15.8
AR ↓ 9.6
% Cumulative incidence
1.0
0.9
Candesartan
0.8
Placebo
0.7
0.6
0.5
0.4
2 Years
RR ↓66%
AR ↓ 26%
0.3
0.2
0.1
0
0
Candesartan
Placebo
391
381
1
356
269
2
Years in study
309
184
3
4
191
118
128
85
Numbers under the graph refer to hypertension-free individuals
Julius S, Nesbitt SD et al NEJM 2006;354
Combination Therapy Delays but Does
Not Prevent End-Stage Renal Disease
COOPERATE Findings
Proportion Reaching
Endpoint, %
30
25
Trandolapril (N=86)
Losartan
(N=89)
20
P=.02
15
Combination (N=88)
10
5
0
0
Number at risk
Losartan
Trandolapril
Combination
6
12
18
24
30
36
Months After Randomization
89
86
88
88
85
87
84
83
86
79
75
83
65
72
76
59
63
73
47
58
67
COOPERATE, combination treatment of angiotensin-II receptor blocker and angiotensinconverting-enzyme inhibitor in non-diabetic renal disease
Nakao N et al. Lancet. 2003;361:117-124
ASCOT: Blood Pressure Results
Amlodipine Besylate/Perindopril vs Atenolol/Bendroflumethiazide
1°*
endpoint
All-cause
mortality
CV
mortality
All CV
events +
revasc
Fatal +
nonfatal
stroke
New cases
of diabetes
mellitus
0
‒10
Change
(%)
‒20
‒30
‒40
‒10
NS
‒15
‒16
P<0.005
P<0.0001
‒26
‒23
P=0.0007
P=0.0017
‒32
N=19,257
P<0.0001
*1° endpoint: nonfatal MI and fatal CHD
CHD, coronary heart disease; MI, myocardial infarction; NS, nonsignificant
Presented March 8, 2005 at the American College of Cardiology Annual Scientific Session, Orlando, Florida
Renin System Suppression by ACE
Inhibitors and ARBs
Summary
►
Renin System suppression with ACEIs and ARBs has
demonstrated significant clinical benefit
►
Renin System suppression with ACEIs, ARBs, and even
combinations of ACEI + ARB therapy may elevate key
components and processes; such as PRA, Ang I, and Ang II
with ARB usage and PRA and Ang I with ACEI usage

Increased peptide levels have not been shown to overcome the
blood pressure-lowering effect of these agents
►
Consequently, benefits have not been demonstrated for all
endpoints and in all patients
►
Could even greater clinical benefits be expected from more
complete Renin System suppression?
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker
Direct Renin Inhibition: What Do We Know?
Renin System (RS) Suppression
via
Direct Renin Inhibition
Renin Suppression
Development of Direct Renin Inhibitors
(DRIs)
Plasma Renin Activity (PRA)
► PRA

is a surrogate measure of renin activity
Indicates the capacity of circulating renin to form Ang I (and
ultimately Ang II)
► PRA
is independently associated with the occurrence
of cardiovascular disease among hypertensive
patients1

A 25% increase in the risk of myocardial infarction for every 2
ng/mL/h increase in PRA1
► Increased
PRA activates the RAAS leading to
increased generation of Ang II. Ang II is important in
the generation of hypertension and both the shortterm and long-term effects leading to organ damage2
1. Alderman MH, et al. 1997
2. Burnier M, et al. 2000
Crystal Structure of Renin
Renin Cleaves its Substrate, Angiotensinogen, to Form ANG I
Angiotensinogen
Ang I
Adapted from Rahuel J et al. J Struct Biol. 1991;107:227-236
Only Direct Renin Inhibition Inhibits
the Entire Renin System1-6
Class
PRA
Ang I
Ang II
Diuretic
ACEI
ARB
Direct Renin Inhibitor (DRI)
Increased peptide levels have not been shown to overcome the blood pressure-lowering effect of these agents.
PRA, plasma renin activity; Ang, angiotensin; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
4. Waybill MM et al. J Vasc Interv Radiol. 2003;14:961-975
1. Johnston CI. Blood Pressure. 2000;9(suppl 1):9-13
5. Reid IA. Adv Physiol Ed. 1998;20:S236-S245
2. Widdop RE et al. Hypertension. 2002;40:516-520
6. Lin C et al. Am Heart J. 1996;131:1024-1034
3. Fabiani ME et al. In: Angiotensin II Receptor Antagonists
2001:263-278
Renin System Suppression via Direct
Renin Inhibition1-3
►
Targets the point of activation in the Renin System
►
Binds to renin, neutralizing its ability to convert angiotensinogen
to Ang I
►
Reduces plasma renin activity


►
PRA is a marker for Renin System activity/stimulation
Elevated levels of prorenin have been shown with direct renin
inhibition; potential physiological effects are being investigated in
animal studies
Decreases formation of Ang I and Ang II



Ang I unavailable for ACE and non-ACE conversion to Ang II
Ang II unavailable to stimulate AT receptors
Ang II unavailable for conversion to Ang subtypes
[eg, Ang (2-8), also called Ang III]
Ang, angiotensin; ACE, angiotensin-converting enzyme; AT, angiotensin receptor
1. Stanton A. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10
2. Wood JM et al. Cardiovasc Drugs Ther. 1996;10:309-312
3. Nussberger J et al. Hypertension. 2002;39:e1-e8
An Efficient Strategy to Achieve Interruption of the
Renin System Is Direct Renin Inhibition1-3
Renin
Angiotensinogen
The Point of Activation
Feedback Loop
Feedback Loop
• ACEIs and ARBs
impact the
feedback loop,
resulting in
increased levels
of Ang I (ACEIs)
and Ang I and
Ang II (ARBs)*
Ang I
AT1 Receptor
ARBs
ACEIs
• Renin initiates a chain of
events within the system
• Cleaves angiotensinogen
to form Ang I
– Ang I is then converted
to Ang II
ACE
*Increased peptide levels have not been shown to overcome the blood pressure-lowering effect of these agents.
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Ang, angiotensin.
Adapted from:
Stanton A. J Renin Angiotensin Aldosterone Syst.
2003;4:6-10
Kelly DJ et al. Hypertension. 2005;46:471-472
Fisher NDL et al. J Am Soc Nephrol. 2005;16:592-599
Aliskiren Exhibits Dose-dependent Reductions In PRA
Compared With ACE Inhibitors In Healthy Volunteers
PRA (ng/mL/h)
100
Placebo
Enalapril 20 mg
Aliskiren 640 mg
Aliskiren 160 mg
Aliskiren 80 mg
Aliskiren 40 mg
10
1
0.1
0
Treatment day 8
2
4
6
8 10
Time (hours)
Nussberger J, et al. Hypertension. 2002;39:e1e8
24
Aliskiren Reduces PRA as
Compared to an ARB
PRA (ng Ang I/mL/h)
8
*†
Valsartan 160 mg
Aliskiren 150 mg + valsartan 80 mg
6
Placebo
*†
4
2
Aliskiren 300 mg
*†
* †‡
†‡
*
0
012 4 6
*
12
18
Time (hours)
24 30
*p<0.05 vs aliskiren 150 mg + valsartan 80 mg
†p<0.05 vs aliskiren 300 mg; ‡p<0.05 vs valsartan 160
mg
n=12 mildly sodium-depleted normotensive subjects
Azizi M, et al. J Am Soc Nephrol 2004;15:3126–3133
†‡
*
48
Aliskiren Offers Dose-dependent
Reductions In SeDBP
Placebo
Aliskiren
150 mg
0
n=165
n=172
−2
−4
−6
−4.9
−8
−10.3
−10
−12
*
−14
−16
Mean  SeDBP (mmHg)
Aliskiren
300 mg
Aliskiren
600 mg
n=169
n=166
−11.1
*
−12.5
*§
* p<0.0001 versus placebo
§ p<0.05 for aliskiren 600 mg
compared to aliskiren 150 mg
Hypertension
Mitchell J, et al. J Clin Hypertens 2006; suppl A, 8(5): A93
Monotherapy
Herron J, et al. J Clin Hypertens 2006; suppl A, 8(5): A86
Aliskiren Offers Dose-dependent
Reductions in SeSBP
Placebo
Aliskiren
150 mg
0
n=165
n=172
−2
−3.8
−4
−6
−8
−10
−13.0
−12
−14
*
−16
Mean  SeSBP (mmHg)
Aliskiren
300 mg
Aliskiren
600 mg
n=169
n=166
−14.7
−15.8
*
*
* p<0.0001 versus placebo
Hypertension
Mitchell J, et al. J Clin Hypertens 2006; suppl A, 8(5): A93
Monotherapy
Herron J, et al. J Clin Hypertens 2006; suppl A, 8(5): A86
Clinical Trials:
Aliskiren Combination
Change in SBP for Aliskiren, HCTZ, and Aliskiren + HCTZ
Mean Reductions from
Baseline in SBP (mm Hg)
0
Placebo
0 mg
HCTZ
6.25 mg
HCTZ
12.5 mg
HCTZ
25 mg
HCTZ
-5
-10
-15
-20
-25
Placebo
Aliskiren 150 mg
Aliskiren 0 mg
Aliskiren 300 mg
Aliskiren 75 mg
Clinical Trials:
Aliskerin in Combination
Change in DBP for Aliskiren, HCTZ, and Aliskiren + HCTZ
Mean Reductions from
Baseline in DBP (mm Hg)
0
Placebo
0 mg
HCTZ
6.25 mg
HCTZ
12.5 mg
HCTZ
25 mg
HCTZ
-5
-10
-15
-20
-25
Placebo
Aliskiren 150 mg
Aliskiren 0 mg
Aliskiren 300 mg
Aliskiren 75 mg
Clinical Trials:
Aliskiren in Combination
Change in SBP for Aliskiren, Valsartan, and Aliskiren + Valsartan
Week 4
Placebo
Mean Reductions from
Baseline in SBP (mm Hg)
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
Aliskiren
Aliskiren Valsartan 150 mg +
150 mg 160 mg Valsartan
160 mg
Week 8
Placebo
Aliskiren
Aliskiren Valsartan 300 mg +
300 mg 320 mg Valsartan
320 mg
Clinical Trials:
Aliskiren in Combination
Change in DBP for Aliskiren, Valsartan, and Aliskiren + Valsartan
Week 4
Placebo
Mean Reductions from
Baseline in DBP (mm Hg)
0
-2
-4
-6
-8
-10
-12
-14
Aliskiren
Aliskiren Valsartan 150 mg +
150 mg 160 mg Valsartan
160 mg
Week 8
Placebo
Aliskiren
Aliskiren Valsartan 300 mg +
300 mg 320 mg Valsartan
320 mg
Conclusions and Summary
►
Hypertension is prevalent, underdiagnosed, and
inadequately treated. Many patients don’t get to BP goal
►
Treating hypertension involves more than BP reduction;
sustained 24-hour control and end-organ protection are
important
►
Inappropriate activation of the Renin System is a central
component in the development of hypertension and
cardiovascular and renal disease
►
Some agents that suppress the Renin System have unique
end-organ protection benefits beyond BP reduction
►
Targeting the Renin System at the point of activation, by direct
renin inhibition, provides inhibition of the entire Renin System
►
Future clinical trials are needed to elucidate additional benefits
of direct renin inhibition