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Critical Challenges in Cardiovascular medicine

VIEWS: 117 PAGES: 120

									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 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

Ken Jamerson, MD Professor of Medicine Cardiovascular Medicine University of Michigan Health System Ann Arbor, Michigan

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

2030

2040

2050
Asian

African American

Hispanic (any race)

Adapted from U.S. Census Bureau, 2004. Table 1a. Accessed Dec. 1, 2006.

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

45

1988-1994

1999-2000

1.8% age adj. increase
40 35 30 25

7.2% age adj. increase

Hypertensive Adults (Rate, Percent ± SE)

20 15 10
5 0

M
All

F

M

F

M

F

Non-Hispanic Black

Non-Hispanic White

Mexican American

Fields et al. Hypertension. 2004;44:398-404. Hajjar and Kotchen. JAMA. 2003;290:199–206

Hypertension Treatment and Control Rates by Race/Ethnicity: NHANES 2000

70

63

60.1 44.6

60
50

55.6

Treatment Control
40.3
44

%

40
30 20 10 0

7.2

0.9

6.2

8.2

6.2

3.7

Percentage increase from 1988 to 2000

African Americans*

Whites*

Mexican Americans

*Non-Hispanic.
Hajjar and Kotchen. JAMA. 2003;290:199–206.

Mortality From High Blood Pressure Higher in African Americans
Overall Mortality Rates From Causes Related to Hypertension, 2003*
60

Mortality Rate, %

50 40 30 20

49.7

40.8

14.9

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)
Patient Type (mm Hg)

% Not at Goal BP Systolic Diastolic BP BP 57% 60%
63%

Total hypertensives African American Mexican American/ Hispanic Older patients (60 years) Symptomatic CHD Patients with diabetes†

<140/90 <140/90
<140/90

26% 32%
30%

<140/90 <140/90 <130/85

71% 47% 81%

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

60
Percentage 50 40 30

20
10

0

0
White women
Stone et al JAMA. 1996;275:1104-1112.

1
African-American women

≥2
White men

≥3
African-American men

Obesity and Diabetes Among US Adults: Growing prevalence
Obesity (BMI ≥30 kg/m2) Diagnosed diabetes

30
25
Population (%)

8
6.4 21.8
23.0 23.9 23.7 6.5 6.6 6.6

24.3

6 4 2

5.9

20
15 0

0 2000 2001 2002 2003 2004* 2000 2001 2002 2003 2004*

*Jan–June

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
Percent

20

25

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.

Estimated Percentage of Americans Age 18 and Older Who Report No Leisure-Time Physical Activity by Race and Sex

Percent of Population

50 40 30 20 10 0
Afr His Ca Ca Afr His uca uca ica ica pan pan nA nA sia sia ic w ic m 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 10% Glomerulonephritis

13% Hypertension 27% No of Patients Projection

No. of ESRD Patients (x 1000)

700 600 500 400 300

Diabetes 50.1%

661,330 372,407

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
600 12 Mean drug 400 cost per patient per year* 200 ($ US)

More physician visits

9.7

Mean 8 visits per year 4

4.1

0
<130/85 130/85 – 139/89 140/90 – 159/99 ≥160/100

0
<120 mm Hg ≥180 mm Hg

Controlled

Uncontrolled

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 DBP
Overweight Insulin

Hematocrit

Heart Rate

P<0.001 P<0.01 P<0.05

N=124 (aged 18-28 years) Adapted from Julius et al. JAMA 1990;264:354-358

Blood Pressure Trends in Tecumseh, Michigan
140 130

* *

*

Blood Pressure mmHg

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
20.0
White, %

15.0 10.0 5.0
0

Mean –15.3 SD 12.2 Lower Quartile –7.3 Upper Quartile –23.5 Interquartile Range 16.2

African American, %

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) –45 –57

SD = standard deviation.
Mokwe E et al. Hypertension. 2004;43(6):1202–7.

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 DBP
NEED FOR

133.6 81.1 28%

131.4 80.7 24%

134.2 80.9 32%

126.9 76.6 35%

140.0 85.2 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 25 20 15 10 5 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up Time (Months)
. p-value adjusted A vs B .042 C vs B* .19 A vs C* .005

Beta

ACE

CCB

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
Amlodipine/ benazepril 5/40 mg Free add-on antihypertensive agents*
Amlodipine/ benazepril 10/40 mg

Randomization

Screening (N=12,600)

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

Forced titration

Free add-on antihypertensive agents*

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 Black
Oriental Other

83.9% 11.9%
0.4% 3.8%

% of Population

Baseline BP (mmHg)

Control Rate at Baseline+

All Patients* Diabetic SubPopulation

40% 60%

145.4/80 145.2/79. 3

37.5% 16.3%

Ethnicity:
Hispanic Gender 5.4% 60.7%

Male Female

Mean Age, years % of Pts >70

68.4
40.9%

39.3%

• +BP<140/90 for non-diabetics and <130/80 for diabetics • * including 6.8% of CKD based on Serum Creatinine

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

155

All Patients
145.4
(18.3)

SBP (mmHg)

150 145 140
135

132.5
(16.0)

132.7
(16.0)

131.8
(16.0)

130
125 120 Baseline N=11,400
(sd)

Month 6 N=10,736

Month 12 N=10,335

Month 18 N=9,898

Data on file. Novartis Pharmaceuticals Corporation.

ACCOMPLISH: Significant Reduction in SBP in All Patient Populations
All Nordic 152.6
(N=3,333)

U.S.

African American

155 150

SBP (mmHg)

145 140 135 130 125 120

145.4
(N=11,400)

145.1

Baseline Range
JNC-7 Goal: SBP 140 mmHg

142.4
(N=8,067)

(N=1,361)

136.8

133.6
131.8

129.4

P<0.05 Neither age nor gender appeared to influence the effects on SBP.
Data on file. Novartis Pharmaceuticals Corporation.

ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy
90

80.5 75.6 65.1 71.8

80 70

Control rate (%)

60 50 40
N=8,067 N=11,400 N=1,361

30
20 10

37.6
N=3,333

44.4

38.6

Baseline Control Rates

21.0 All

Nordic

U.S.

African American

Data on file. Novartis Pharmaceuticals Corporation.

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

Treatment
• Less intensively treated • More factors linked to HTN Tx resistance − Diabetes −  GFR − Obesity − Target-organ injury − Proteinuria − Living in SE − Female USA sex

• Higher hospitalization rates (~8 x  )
• More target-organ injury • Renin more often suppressed

• 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 HOT (138 mm Hg) (138 mm Hg)

INVEST (133 mm Hg) ABCD MDRD AASK (132 mm Hg) (132 mm Hg) (128 mm Hg)
1 2 3 4

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

Number of Antihypertensive Drugs Used and BP Control (<140/90 mm Hg)
100 80
1.4-1.5

Chlorthalidone Amlodipine Lisinopril
1.5-1.7 1.3 58 55 51 61 57 54 64 63 59 1.7-1.8

1.8-2.0

1.9-2.1

2 1.5
67 65 63 68 66 62

Percent

60 40 20 0 0
28 28 27

53 48 46

1 0.5 0

6

12

24

36

48

60

ALLHAT

Months of Follow-up

Percent Controlled (BP < 140/90) at Five Years by Number of Drugs Prescribed
Chlorthalidone Amlodipine Lisinopril

80 70 60
Percent

68 66 61

50 40 30 20 10 0 1 2 3 4+ ALL Number of Prescribed Drugs
28 24 24 24 26 18 11 11 12 3 4 6

ALLHAT

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):


Therefore, at least 72% received or needed ≥ 2 drugs

►

49% were controlled on 1 or 2 drugs (12% more were uncontrolled on 1 drug or untreated):


Therefore, at least 39% received or would have needed ≥ 3 drugs to control BP Therefore, at least 16% received or needed ≥ 4 drugs to control BP

►

60% were controlled on 3 or fewer drugs:


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 Stage 2 Hypertension

With Compelling Indications

(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)

Drug(s) for the compelling indications
Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.

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 Diabetes/nondiabetic renal disease with proteinuria >1 g/24 h* Goal BP: <130/80 mm Hg

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

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
†Initiate

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
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
Black
Nonfatal MI + CHD Death

Non-Black
1.10 (0.94 - 1.28)
1.06 (0.95 - 1.18) 1.15 (1.02 - 1.30) 0.94 (0.85 - 1.05) 0.97 (0.89 - 1.06)

All-Cause Mortality Combined CHD Combined CVD Stroke

1.01 (0.93 - 1.09) 1.06 (1.00 - 1.13)
1.00 (0.85 - 1.17) 0.93 (0.67 - 1.30) 1.13 (1.00 - 1.28) 0.50 Favors Lisinopril 1 2 Favors Chlorthalidone

1.19 (1.09 - 1.30)
1.40 (1.17 - 1.68) 1.30 (0.94 - 1.75)

End Stage Renal Disease Heart Failure

1.30 (1.10 - 1.54)
1 2 Favors Chlorthalidone

ALLHAT

0.50 Favors Lisinopril

Wright JT et al; JAMA 2005; 293:1593

Blood Pressure at 5 Years by Race

Chlorthalidone Black SBP – mean (sd) Nonblack
Black DBP – mean (sd) Nonblack

Amlodipine 136.1 (15.3)
133.8 (14.6) 76.3 (10.1)

Lisinopril 139.1 (19.7)
134.2 (16.7) 78.0 (11.4)

135.0 (15.8)
133.3 (14.8) 77.4 (10.0)

74.4 (9.5) -----

73.6 (9.6) +1.1 / -1.1*
+0.5 / -0.8*

74.1 (10.1) +4.1* / +0.6
+0.9 / -0.3

∆ BP compared with chlorthalidone

Black Nonblack

ALLHAT

* P < 0.005
05/15/03

Frequency Distribution: SBP in Response to Quinapril in Black and White Participants
20.0
White, %

15.0 10.0 5.0
0

Mean –15.3 SD 12.2 Lower Quartile –7.3 Upper Quartile –23.5 Interquartile Range 16.2

Whites

n = 2046

African American, %

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 15 3 –9 –21 –33 SBP (average change) –45 –57

E. Mokwe et. al., HTN 2004;43:1

Angioedema
Total
Chlorthalidone 8 / 15,255

Blacks
2 / 5,369

Nonblacks 6 / 9,886

0.1% Lisinopril 38 / 9,054
0.4%
p<.001

<0.1% 23 / 3,210
0.7%
p<.001

0.1% 15 / 5,844
0.3%
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 Hazard Ratio
25

Blacks
20 15

Non-Blacks

White Black

8503 533

Hispanic 100 Asian 43
0.1 1

10 (23.36) 5
Atenolol Losartan

2 3 4

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.

Results of primary composite end point by ethnic group in the U.s.: blacks versus nonblacks.

Julius et al. J Am Coll Cardiol 2004;43:1047-55

AASK Clinical Endpoint Analysis
ACEI vs. CCB
% Risk 95 %
Confidence Interval (+ 14 to + 55)

ACEI vs. BB
% Risk
Reduction

95 %
Confidence Interval (+ 1 to + 38)

Outcome
GFR event,

Reduction1

38%

22%

ESRD or Death2 GFR event or ESRD3 ESRD or Death4 ESRD alone5
40% 48%
59%

p<0.005 (+ 13 to + 59)
p<0.007

p< 0.042 22% 21%
23%

(- 1 to + 41)
p< 0.066

(+ 26 to + 65)
p<0.004 (+ 34 to + 74) p< 0.001

(- 5 to + 40)
p< 0.11 (- 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

%

8.0

Atenolol (No. of events 820)

6.0

4.0

Amlodipine (No. of events 738)
HR = 0.89 (0.81-0.99) p = 0.0247
0.0 1.0 2.0 3.0 4.0 5.0

2.0

0.0

Number at risk Amlodipine  perindopril 9639 Atenolol  thiazide 9618

Years
9544 9532 9441 9415 9332 9261 9167 9085 8078 7975

Black vs. Non-Black Amlodipine versus Chlorthalidone
Relative Risk and 95% Confidence Intervals
Black
Nonfatal MI + CHD Death

Non-Black
1.01 (0.86 - 1.18)
0.97 (0.87 - 1.09)

0.97 (0.87 - 1.08) 0.94 (0.87 - 1.03)
0.99 (0.92 - 1.07) 1.04 (0.97 - 1.10) 0.93 (0.79 - 1.10) 1.08 (0.79 - 1.48)

All-Cause Mortality Combined CHD

1.03 (0.91 - 1.17)
1.06 (0.96 - 1.16) 0.93 (0.76 - 1.14) 1.15 (0.84 - 1.58)

Combined CVD Stroke
End Stage Renal Disease Heart Failure

1.46 (1.24 - 1.73)
1 2 Favors Chlorthalidone 0.50 Favors Amlodipine 1

1.32 (1.17 - 1.49)
2 Favors Chlorthalidon e

0.50 Favors Amlodipine

ALLHAT

Wright JT et al; JAMA 2005; 293:1593

VALUE Trial: Primary Composite Cardiac Endpoint
14
Proportion of Patients With First Event (%)

12 10 8 6
4 2 0

Valsartan-based regimen Amlodipine-based regimen

HR = 1.03; 95% CI = 0.94–1.14; P = 0.49

0

6

12 18 24 30 36 42 Time (months)

48 54 60 66

Number at risk Valsartan Amlodipine
7649 7459 7407

7250 7085

6906 6732 6536 6349 5911

3765 1474

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
1.50 − 1.50 −
P < 0 .0001

Recent Trials

Odds Ratio (experimental/control)

UKPDS C vs A

1.25 −
1.00 0.75

ALLHAT

1.25 −
1.00 − 0.75 −

VALUE?
ALLHAT/Lis Blacks ALLHAT/Lis ≥ 65 y ALLHAT/Lis ALLHAT/Aml CONVINCE ABCD/NT L vs H DIABHYCAR ANBP2 IDNT2 SCOPE LIFE/ALL AASK L vs H ELSA PREVENT LIFE/DM NICOLE

0.50 −
0.25 −

CAPPP NORDIL MIDAS/NICS/VHAS M vs H STOP2/CCBs − INSIGHT HOTPROGRESS/Per HOT L vs H STOP2/ACEIs RENAAL MRC2 MRC1 HOPE PATS ATMH Syst-China − Syst-Eur EWPHE HEP PART2/SCAT SHEP RCT70–80 UKPDS L vs H PROGRESS/Com STOP1

•

0.50 −
0.25 −

STONE

-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 1.00

Stroke

CVD

0.75
0.50 0.25 1.50

Heart Failure
1.25
1.00 0.75

CHD

0.50
0.25 -10

-8

-6

-4

-2

0

2

4

-10

-8

-6

-4

-2

0

2

4

Systolic blood pressure difference between randomised groups (mmHg) Blood Pressure Lowering Treatment Trialists’ Collaboration

Lancet. 2003;362:1527-1535

Percent Controlled (BP < 140/90) at Five Years by Number of Drugs Prescribed
Chlorthalidone Amlodipine Lisinopril

80 70 60
Percent

68 66 61

50 40 30 20 10 0 1 2 3 4+ ALL Number of Prescribed Drugs
28 24 24 24 26 18 11 11 12 3 4 6

ALLHAT

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
HAAWG ISHIB
140/90

WHO/ISH
Initiate TX Uncomplicated HTN 140/90
(previously 160/90; currently 160/100 in UK)

JNC 7
140/90

Initiate Combination TX- Uncomplicated Initiate TX Complicated HTN & Goal 130/80

160/100

155/100

130/80

130/80

(140/90 for women & elderly and in UK) 150/90 145/90

Initiate Combination TX- Complicated HTN

SD Nesbitt 2004

Drug Choice Recommendations

WHO/ISH
Uncomplicated HTN Thiazide as initial agent

JNC 7
Thiazide as initial agent May use ACE, ARB, Beta-B, CCB

HAAWG ISHIB
May initiate diuretic, ACE, ARB, Beta-B, CCB
Diuretic + (ACE, Beta-B, ARB) or ACE/CCB

Combination TXUncomplicated

Not uniformly recommended

Diuretic + (ACE, Beta-B, ARB) or ACE/CCB

Complicated HTN

Treat according to the compelling condition similarly according to all guidelines.

SD Nesbitt 2004

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) blood pressure in diabetes and CKD should be <130/80 mmHg (B)

► Target

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 Uncomplicated hypertension Goal BP: <140/90 mmHg
Diabetes/nondiabetic renal disease with proteinuria >1 g/24 h* Goal BP: <130/80 mmHg If BP <145/90 mmHg, monotherapy or combination therapy including a RAS blocker§ If BP 145/90 mmHg, combination therapy including a RAS blocker§

If BP <155/100 mmHg, monotherapy†

If BP 155/100 mmHg, combination therapy‡

Not at BP goal? Intensify lifestyle changes AND

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

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

With 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

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)

Drug(s) for the Compelling Indications Other antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB) as needed

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

Published Guidelines Have Set Lower Treatment Goals
JNC 7 / ADA / NKF / ISHIB Guidelines for Hypertension and Patients at High Risk
Condition Essential hypertension

mmHg
<140/90

Diabetes mellitus Chronic renal disease High-risk* hypertension
ADA=American Diabetes Association. NKF=National Kidney Foundation. ISHIB=International Society on Hypertension in Blacks.
*History

<130/80 <130/80 <130/80

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
Diuretic CHF Post MI CAD risk
DM BB ACEI ARB CCB AA



 

  




  











Chronic kidney disease
2° stroke prevention 






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*
60

Mortality Rate, %

50 40 30 20

49.7

40.8

14.9

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 0.06 Events per personyr Ramipril Amlodipine besylate RRR=44% P=0.01

0.05 0.04 0.03
0.02 0.01

RRR=41% P=0.03

0

GFR

ESRD

GFR, ESRD, or death

GFR, glomerular filtration rate; ESRD, end-stage renal disease Agodoa LY et al. JAMA. 2001;285:2719-2728

ALLHAT: Lisinopril vs Chlorthalidone
Primary Endpoint (Nonfatal MI + CHD Death) Subgroups
Relative Risk (95% CI) Total 0.99 (0.91-1.08)

Age <65 Age 65 Men Women Black
Nonblack Diabetic Nondiabetic
0.5 1

0.95 (0.81-1.12) 1.01 (0.91-1.12) 0.94 (0.85-1.05)
1.06 (0.92-1.23) 1.10 (0.94-1.28) 0.94 (0.85-1.05) 1.00 (0.87-1.14) 0.99 (0.88-1.11)
1.5

Favors Lisinopril

Favors Chlorthalidone

ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997

ACEIs and ARBs Yield Reduction in Cardiovascular Morbidity and Mortality
ACEIs
Relative Risk Reduction, %

ARBs
SOLVD3
CHARM-Alternative4 LIFE5
Placebo (n=1284) Enalapril (n=1285)

HOPE1
Placebo (n=4652) Ramipril (n=4645)

CONSENSUS2
Placebo (n=126) Enalapril (n=127)

Placebo (n=1015) Atenolol (n=4588) Candesartan (n=1013) Losartan (n=4605)

0 -10 -20 22% P<.001 16% P=.003 27% P=.003
Total mortality in severe HF Mortality in chronic HF

23% P=.0004

13% P=.021

-30 -40

MI, stroke, or CV death in high-risk patients

CV death or HF hospitalization in patients with chronic HF and intolerance of ACEI

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
Doubling Cr, ESRD, or Death (%) 20 *

Irbesartan vs Amlodipine
23 **

Amlodipine vs Control
4 ns

Doubling of Cr, (%) ESRD (%)

33 ** 23 ns
* ** ***

37 *** 23 ns
p< .05 p< .01 p<.001

6 ns 0 ns

Lewis EJ NEJM 2001;345:851

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

Decrease in GFR Percent
mL/min
p=ns

35-50%

14.9

17.9
enalapril telmisartan

5%
enalapril
Barnett A et al N Engl J Med 2004

5%
telmisartan expected rate over 5 years

TRial Of Preventing HYpertension (TROPHY)
Kaplan-Meier Curves of Clinical Hypertension in the Two Groups
1.0

% Cumulative incidence

0.9

Candesartan Placebo

4 Years RR ↓15.8 AR ↓ 9.6

0.8 0.7 0.6
0.5 0.4

0.3
0.2 0.1

2 Years RR ↓66% AR ↓ 26%
0 1 2 3 4

0

Candesartan Placebo

391 381

356 269

Years in study
309 184

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
30

Proportion Reaching Endpoint, %

25
20 15 10 5 0 0 6 12 18 24 30 36

Trandolapril (N=86) Losartan (N=89)

P=.02
Combination (N=88)

Number at risk Losartan Trandolapril Combination

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
P<0.005

‒16
P<0.0001

‒26
P=0.0017

‒23
P=0.0007

‒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

• Renin initiates a chain of events within the system

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

ACEIs
ACE

• Cleaves angiotensinogen to form Ang I – Ang I is then converted to Ang II

ARBs

*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

10

1

Placebo Enalapril 20 mg Aliskiren 640 mg Aliskiren 160 mg Aliskiren 80 mg Aliskiren 40 mg

0.1

0
Treatment day 8

2

4

6 8 10 Time (hours)

24

Nussberger J, et al. Hypertension. 2002;39:e1e8

Aliskiren Reduces PRA as Compared to an ARB
PRA (ng Ang I/mL/h) 8 *† 6 *†
Valsartan 160 mg

Aliskiren 150 mg + valsartan 80 mg Placebo
Aliskiren 300 mg

4
2

*† * †‡
†‡
†‡

* 0 012 4 6

* 12 18 Time (hours) 24 30

*

48

*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

Aliskiren Offers Dose-dependent Reductions In SeDBP
0 n=165 n=172 −2 −4 −6 −4.9 −8 −10.3 −10 −12 * −14 −16 Mean  SeDBP (mmHg) Placebo

Aliskiren 150 mg

Aliskiren 300 mg
n=169

Aliskiren 600 mg
n=166

−11.1

−12.5

*

*§

* p<0.0001 versus placebo § p<0.05 for aliskiren 600 mg compared to aliskiren 150 mg

Hypertension Monotherapy

Mitchell J, et al. J Clin Hypertens 2006; suppl A, 8(5): A93
Herron J, et al. J Clin Hypertens 2006; suppl A, 8(5): A86

Aliskiren Offers Dose-dependent Reductions in SeSBP
Placebo

Aliskiren 150 mg

Aliskiren 300 mg
n=169

Aliskiren 600 mg
n=166

0 n=165 n=172 −2 −3.8 −4 −6 −8 −10 −13.0 −12 −14 * −16 Mean  SeSBP (mmHg)

−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
0
Mean Reductions from Baseline in SBP (mm Hg)
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
0
Mean Reductions from Baseline in DBP (mm Hg)
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
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

0
Mean Reductions from Baseline in SBP (mm Hg)

-2 -4 -6 -8 -10 -12 -14 -16 -18

Clinical Trials: Aliskiren in Combination
Change in DBP for Aliskiren, Valsartan, and Aliskiren + Valsartan
Week 4
Placebo
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

0
Mean Reductions from Baseline in DBP (mm Hg)

-2 -4 -6 -8 -10 -12 -14

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

►

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