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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

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slide2

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

slide3

Welcome and Program Overview

CME-accredited symposium jointly sponsored by the American Society of Hypertension and CMEducation Resources, LLCCommercial Support: Sponsored by an independent educational grant from Novartis PharmaceuticalsMission statement: Improve patient care through evidence-based education, expert analysis, and case study-based managementProcesses: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studiesCOI: Full faculty disclosures provided in syllabus and at the beginning of the program

program educational objectives
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 objectives5
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
slide6

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

slide7

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

slide8

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

slide9

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 Difficult-to-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

slide10

Introduction and Overview

The Current Landscape of Cardiovascular Risk Management in African Americans—Where Co-morbidity MattersThe Evolving RelationshipBetween Risk Factors, Diabetes, Hypertension, And Vascular Complications

Shawna D. Nesbitt MD, MS

Associate Professor of Internal Medicine

University of Texas Southwestern

Dallas, Texas

slide11

The U.S. Population is Becoming Increasingly Diverse

Changing Trends

Hispanics are the fastest-growing 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.

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

slide12

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

slide13

1.8% age adj. increase

7.2% age adj. increase

M

F

Non-Hispanic Black

Estimated Rates of US Adults With Hypertension by Sex, Race, and EthnicityNHANES 1988-1994 to 1999-2000

1988-1994

1999-2000

45

40

35

30

Hypertensive Adults(Rate, Percent ± SE)

25

20

15

10

5

0

M

F

M

F

Non-Hispanic White

MexicanAmerican

All

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

Percentage increase from 1988 to 2000

7.2

0.9

6.2

8.2

6.2

3.7

70

63

60.1

Treatment

55.6

60

Control

50

44.6

44

40.3

40

%

30

20

10

0

AfricanAmericans*

Whites*

MexicanAmericans

*Non-Hispanic.

Hajjar and Kotchen. JAMA. 2003;290:199–206.

mortality from high blood pressure higher in african americans
Mortality From High Blood Pressure Higher in African Americans

Overall Mortality Rates From Causes Related to Hypertension, 2003*

60

49.7

50

40.8

40

Mortality Rate, %

30

14.9

14.5

20

10

0

Male

Female

Male

Female

African American

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
Patients Not at JNC VI BP Goals

% Not at Goal BP Systolic DiastolicPatient Type (mm Hg) BP BP

NHANES (1999-2000)

Total hypertensives <140/90 57% 26%

African American <140/90 60% 32%

Mexican American/ Hispanic <140/90 63%30%

Older patients (60 years) <140/90 71% 9%

Symptomatic CHD <140/90 47% 4%

Patients with diabetes† <130/85 81% 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

50

40

30

20

10

0

0

1

≥2

≥3

White women

African-American women

White men

African-American men

Risk-Factor Clustering by Race and Sex

Percentage

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

obesity and diabetes among us adults growing prevalence
Obesity and Diabetes Among US Adults:Growing prevalence

Obesity (BMI ≥30 kg/m2)

Diagnosed diabetes

+11.9%

30

+11.5%

8

6.5

6.6

6.6

6.4

24.3

5.9

25

6

23.9

23.7

23.0

Population

(%)

21.8

20

4

15

2

0

0

2000

2001

2002

2003

2004*

2000

2001

2002

2003

2004*

CDC. 2004 NHIS; www.cdc.gov/nchs/nhis.htm.

*Jan–June

age adjusted prevalence of diabetes by race ethnicity in the us
Age-Adjusted Prevalence of Diabetes* by Race/Ethnicity in the US

American Indians/Alaska Natives

Non-Hispanic Blacks

19%

Hispanic/LatinoAmericans

15%

Non-Hispanic Whites

14%

7%

Percent

*In people 20+ years old

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.

slide20
Estimated Percentage of Americans Age 18 and Older Who Report No Leisure-Time Physical Activity by Race and Sex

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 Patients

10%

13%

Projection

Diabetes

Hypertension

50.1%

27%

The Rising Tide of ESRD

700

600

500

400

661,330

No. of ESRD Patients (x 1000)

300

372,407

200

326,217

100

R2 = 99.8%

0

1986

1984

1988

1990

1992

1998

1996

2004

1994

2000

2002

2010

2006

2008

Year

USRDS. Annual data report. 2000.

years of potential life lost to total heart disease before age 75 by race and gender
Years of Potential Life Lost to Total Heart Disease Before Age 75 by Race and Gender

4000

3000

Years

2000

1000

0

1980

1980

1985

1985

1990

1990

1995

1995

White women

African-American women

White men

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
Failure to Reach Treatment GoalsCarries Costly Burden

N = 1000 managed-care patients with treated hypertension

Greater medication costs

More physician visits

600

12

9.7

Mean drugcost perpatient per year*

($ US)

400

Mean visits per year

8

4.1

200

4

0

0

<130/85

≥160/100

140/90 –159/99

<120 mm Hg

≥180 mm Hg

130/85 –139/89

Maximum SBP

Controlled

Uncontrolled

Severity of hypertension (mm Hg)

*Based on 1999 average wholesale price

Paramore LC et al. Am J Manag Care. 2001;7:389-398.

slide24

Challenges and Solutions in

Minority Populations

Kenneth A. Jamerson, M.D.Professor of Cardiovascular Medicine University of MichiganMedical Director, Program for Multi-cultural HealthAnn Arbor, Michigan

Are We in Control?

The Importance of Early Risk

Identification and Treatment

Getting To Goal and Staying There in

Ethnic Minority Populations

slide25

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

slide26

Tecumseh BP Study: Association of DBP and Other CHD Risk Factors

Overweight

Hematocrit

Heart Rate

Insulin

DBP

Cholesterol

Triglycerides

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
Blood Pressure Trends in Tecumseh, Michigan

*

*

*

**

*

*

P< .01

*

Hypertensive

Normotensive

S. Julius, et al: JAMA 264:354-358, 1990

P<.001

**

slide29

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.

slide30

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?

slide31

Blood Pressure Response to Quinapril: The ATIME Study

20.0

Mean –15.3

SD 12.2

Lower Quartile –7.3

Upper Quartile –23.5

Interquartile Range 16.2

15.0

White, %

10.0

5.0

0

20.0

Mean –10.5

SD 13.4

Lower Quartile –2.2

Upper Quartile –20.0

Interquartile Range 17.8

15.0

African American, %

10.0

5.0

0

39

27

15

3

–9

–21

–33

–45

–57

SBP (average change)

SD = standard deviation.

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

is it important to block the ras in african americans
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
slide35

Cumulative Incidence of Confirmed Declining GFR Event,Dialysis or Death by Drug Group(Data as of 10/19/01)

p-value A vs B C vs B* A vs C*

adjusted .042 .19 .005

Cumulative Incidence

.

implications of the aask study
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
slide37

International Society of Hypertension in Blacks

IMPACT Campaign

Science Guidelines Behavioral Change

vascular matrix summit
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
models to explain health disparities
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

slide42

Critical Relationships

Race

(Social)

Disease

Ancestry

(Genetic)

slide43

Ancestry Informative Markers (AIMs)

Although much genetic variation (85-90%) 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).

slide44

Ancestry Can Be Estimated Across Chromosomal Regions

Smith et al. AJHG 74:1001-1013, 2004

Seldin et al. Genome Res. 14:1076 -1084, 2004

slide45

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

slide46

Era of Genomic Ancestry and Challenges Related to Health

  • Group definition and membership.
  • Can we accurately assess genomic ancestry?
  • How does genomic ancestry relate to skin color and possibly SES?
  • How useful is genomic ancestry for informing us about disease risk?
  • Health Disparities: are they due to biological differences?
  • How do we prevent repeating the negative past abuses of “race”.
accomplish hypothesis
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 high-risk 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
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
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
ACCOMPLISH: Design

Free add-on antihypertensive agents*

Titrated to achieve BP <140/90 mmHg; <130/80 mmHg in patients with diabetes or renal insufficiency

Amlodipine/benazepril 10/40 mg

Amlodipine/benazepril 5/40 mg

Amlodipine/benazepril 5/20 mg

Screening(N=12,600)

Randomization

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*

Day 1

14 Days

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
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
ACCOMPLISH: Key Demographic Data
  • +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
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

145.4

(18.3)

132.7

(16.0)

132.5

(16.0)

131.8

(16.0)

Month 18

N=9,898

Baseline

N=11,400

Month 6

N=10,736

Month 12

N=10,335

ACCOMPLISH: Effect of Initial Combination Therapy on SBP Over Time

160

All Patients

155

150

145

SBP (mmHg)

140

135

130

125

120

(sd)

Data on file. Novartis Pharmaceuticals Corporation.

accomplish significant reduction in sbp in all patient populations

152.6

(N=3,333)

Baseline Range

145.4

145.1

142.4

(N=11,400)

(N=1,361)

136.8

133.6

131.8

ACCOMPLISH: Significant Reduction in SBP in All Patient Populations

African American

All

Nordic

U.S.

155

150

145

JNC-7 Goal:SBP

140 mmHg

140

(N=8,067)

SBP (mmHg)

135

130

129.4

125

120

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

80.5

71.8

75.6

65.1

N=8,067

N=1,361

N=11,400

44.4

38.6

37.6

Baseline Control Rates

N=3,333

21.0

ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy

90

80

70

60

50

Control rate (%)

40

30

20

10

African American

U.S.

Nordic

All

Data on file. Novartis Pharmaceuticals Corporation.

conclusions
Conclusions
  • Millions of Americans take anti-hypertension medication, but do not achieve blood pressure control. Initial therapy with single-tablet, dual-mechanism 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.
slide59

Considering Combination Therapy

Hypertension – A Systemic Disease Requiring SystematicApproaches To Therapy Recent Clinical Practice RecommendationsFocusing on Combination Therapy in Difficult-to-Treat Patient Populations with High Blood Pressureand 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
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
slide61

Hypertension in African Americans

(versus Whites)

Epidemiology

Treatment

  • Higher prevalence & incidence (esp. women)
  • Greater severity
  • Earlier onset
  • Higher hospitalization rates (~8 x  )
  • More target-organ injury
  • Renin more often suppressed
  • Less intensively treated
  • More factors linked to HTN Tx resistance
  • Diabetes
  • Obesity
  • Proteinuria
  • Female sex
  •  GFR
  • Target-organ injury
  • Living in SE USA
  • Lesser BP response to ACEIthan 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

4

Number of BP meds

Combination Therapy is Needed to Achieve Target SBP Goals

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

slide63

Number of Antihypertensive Drugs Used and BP Control (<140/90 mm Hg)

ALLHAT

Chlorthalidone

Amlodipine

Lisinopril

slide64

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

ALLHAT

Chlorthalidone

Amlodipine

Lisinopril

number of drugs needed to control bp 140 90 mm hg in allhat after 5 years

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
  • 60% were controlled on 3 or fewer drugs:
    • Therefore, at least 16% received or needed ≥ 4 drugs to control BP
jnc 7 algorithm for treatment of hypertension

Without Compelling Indications

With Compelling Indications

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

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.

JNC-7 Algorithm for Treatmentof 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

slide67

Consensus Statement: Management of High BP in African Americans

Patient with elevated BP

Uncomplicated hypertensionGoal BP: <140/90 mm Hg

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

If BP <155/100 mm Hg, monotherapy†

If BP 155/100 mmHg, combination therapy‡

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

Not at BP goal?Intensify lifestyle changes

AND

Add a 2nd agent from a different class orincrease dose

Increase doseor add a 3rd agentfrom a different class

Add a 2nd agent from a different class orincrease dose

Increase doseor add a 3rd agentfrom a different class

RAS, renin-angiotensin system

*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

slide68

Black vs. Non-Black

Lisinopril versus Chlorthalidone

ALLHAT

Non-Black

0.94 (0.85 - 1.05)

1.10 (0.94 - 1.28)

0.97 (0.89 - 1.06)

1.06 (0.95 - 1.18)

1.01 (0.93 - 1.09)

1.15 (1.02 - 1.30)

1.06 (1.00 - 1.13)

1.19 (1.09 - 1.30)

1.00 (0.85 - 1.17)

1.40 (1.17 - 1.68)

0.93 (0.67 - 1.30)

1.30 (0.94 - 1.75)

1.13 (1.00 - 1.28)

1.30 (1.10 - 1.54)

0.50

1

2

0.50

1

2

Favors

Chlorthalidone

Favors

Lisinopril

Relative Risk and 95% Confidence Intervals

Black

Favors

Chlorthalidone

Favors

Lisinopril

Wright JT et al; JAMA 2005; 293:1593

slide69

ALLHAT

Blood Pressure at 5 Years by Race

* P < 0.005

05/15/03

slide70

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

20.0

Mean –15.3

SD 12.2

Lower Quartile –7.3

Upper Quartile –23.5

Interquartile Range 16.2

Whites n = 2046

15.0

White, %

10.0

5.0

0

20.0

Mean –10.5

SD 13.4

Lower Quartile –2.2

Upper Quartile –20.0

Interquartile Range 17.8

Blacks n = 533

15.0

African American, %

10.0

5.0

0

39

27

15

3

–9

–21

–33

–45

–57

SBP (average change)

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

angioedema

ALLHAT

Angioedema

There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to chlorthalidone not significant).

results of primary composite end point in life by ethnic group
Results Of Primary Composite End Point in LIFE By Ethnic Group

25

20

15

10

5

0

Race N Hazard Ratio

White 8503

Black 533

Hispanic 100

Asian 43

Blacks

Non-Blacks

Atenolol

(23.36)

Losartan

0.1 1 2 3 4

0 12 24 36 48 60

0 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 non-blacks.

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

aask clinical endpoint analysis
AASK Clinical Endpoint Analysis

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
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

HR = 0.89 (0.81­0.99)p = 0.0247

2.0

0.0

0.0

1.0

2.0

3.0

4.0

5.0

Years

Number at risk

Amlodipine  perindopril 9639 9544 9441 9332 9167 8078

Atenolol  thiazide 9618 9532 9415 9261 9085 7975

slide75

Black vs. Non-Black

Amlodipine versus Chlorthalidone

ALLHAT

1.01 (0.86 - 1.18)

0.97 (0.87 - 1.09)

1.03 (0.91 - 1.17)

1.06 (0.96 - 1.16)

0.93 (0.76 - 1.14)

1.15 (0.84 - 1.58)

1.46 (1.24 - 1.73)

1

2

0.50

Favors

Amlodipine

Relative Risk and 95% Confidence Intervals

Black

Non-Black

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)

1.32 (1.17 - 1.49)

0.50

1

2

Favors

Chlorthalidone

Favors

Chlorthalidone

Favors

Amlodipine

Wright JT et al; JAMA 2005; 293:1593

slide76

VALUE Trial: Primary Composite Cardiac Endpoint

14

12

10

8

6

4

2

0

Valsartan-based regimen

Amlodipine-based regimen

Proportion of Patients With First Event (%)

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

0 6 12 18 24 30 36 42 48 54 60 66

Time (months)

Number at risk

7649

7459

7407

7250

7085

6906

6732

6536

6349

5911

3765

1474

Valsartan

Amlodipine

7596

7469

7424

7267

7117

6955

6772

6576

6391

5959

3725

1474

Julius S et al. Lancet. June 2004;363

slide77

VALUE Trial — Hazard Ratios

for Pre-specified Analyses

HazardRatio

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

slide78

VALUE?

ALLHAT/Lis Blacks

ALLHAT/Lis ≥ 65 y

UKPDS C vs A

ALLHAT/Lis

ALLHAT

ALLHAT/Aml

CONVINCE

ABCD/NT L vs H

CAPPP

DIABHYCAR

MIDAS/NICS/VHAS

ANBP2

NORDIL

HOT M vs H

STOP2/CCBs

IDNT2

INSIGHT

SCOPE

PROGRESS/Per

LIFE/ALL

AASK L vs H

HOT L vs H

RENAAL

STOP2/ACEIs

ELSA

PREVENT

HOPE

MRC2

MRC1

LIFE/DM

NICOLE

ATMH

PATS

Syst-China

Syst-Eur

EWPHE

HEP

PART2/SCAT

SHEP

RCT70–80

UKPDS L vs H

PROGRESS/Com

STOP1

STONE

Staessen Meta-Regression Analysis: Robust Correlation Between Difference in SBP and Risk of CV Events

All Trials

Recent Trials

1.50 −

1.50 −

P < 0 .0001

1.25 −

1.25 −

1.00 −

1.00 −

Odds Ratio (experimental/control)

0.75 −

0.75 −

0.50 −

0.50 −

0.25 −

0.25 −

-5

-5

0

5

15

25

0

5

15

25

10

20

10

20

Difference in SBP

(control minus experimental) mm Hg

Difference in SBP

(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

Relative risk of stroke

Stroke

CVD

Relative risk of CVD

1.25

1.00

0.75

0.50

0.25

Heart Failure

CHD

Relative risk of heart failure

1.50

Relative risk of CHD

1.25

1.00

0.75

0.50

0.25

-10

-8

-6

-4

-2

0

2

4

-10

-8

-6

-4

-2

0

2

4

BP Reduction and Major Cardiovascular Outcomes

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

Lancet. 2003;362:1527-1535

slide80

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

ALLHAT

Chlorthalidone

Amlodipine

Lisinopril

slide81

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

nkf guideline 3 management of hypertension in diabetes and ckd
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
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
Combination Drug Therapy InHTN — 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
conclusions88
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
slide89

Emerging Therapies— Focus on RAS

The Evolving Landscape ofAntihypertensive TherapyDirect Renin Inhibition, Combination Therapy, and Implications for African American and otherEthnic 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
ISHIB Consensus Statement: Management of Hypertension in African Americans

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

Uncomplicated hypertensionGoal 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§

If BP 145/90 mmHg, combination therapy including a RAS blocker§

Not at BP goal?Intensify lifestyle changes AND

Not at BP goal?Intensify lifestyle changes AND

Increase doseor add a 3rd agentfrom a different class

Add a 2nd agent from a different class orincrease dose

Increase doseor add a 3rd agentfrom a different class

Add a 2nd agent from a different class orincrease dose

Patient with elevated BP

*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 hypertension91
JNC 7 Algorithm for Treatmentof 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 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

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

Not at Goal Blood Pressure

Optimize Dosages or Add Additional Drugs Until Goal Blood Pressure Is AchievedConsider consultation with hypertension specialist

Chobanian et al. JAMA. 2003;289:2560-2572

published guidelines have set lower treatment goals
Published Guidelines Have SetLower Treatment Goals

mmHg

Condition

Essential hypertension

Diabetes mellitus

Chronic renal disease

High-risk* hypertension

<140/90

<130/80

<130/80

<130/80

JNC 7 / ADA / NKF / ISHIB Guidelinesfor Hypertension and Patients at High Risk

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

slide93

JNC-7 Compelling Indications

BB

ACEI

ARB

CCB

AA

Diuretic

CHF

Post MI

CAD risk

DM

Chronic kidneydisease

2° strokeprevention

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 americans94
Mortality From High Blood Pressure Higher in African Americans

Overall Mortality Rates From Causes Related to Hypertension, 2003*

60

49.7

50

40.8

40

Mortality Rate, %

30

14.9

14.5

20

10

0

Male

Female

Male

Female

African American

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
RAS Blockade inAfrican-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

slide97

Relative Risk Reduction With

Ramipril vs Amlodipine Besylate: AASK

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0

RRR=38%P=0.005

Ramipril

Amlodipine besylate

RRR=44%P=0.01

RRR=41%P=0.03

Eventsperperson-yr

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)

0.99 (0.91-1.08)

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)

Total

Age <65

Age 65

Men

Women

Black

Nonblack

Diabetic

Nondiabetic

Favors Chlorthalidone

Favors Lisinopril

ALLHAT: Lisinopril vs ChlorthalidonePrimary Endpoint (Nonfatal MI + CHD Death) Subgroups

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

aceis and arbs yield reduction in cardiovascular morbidity and mortality

ACEIs

ARBs

HOPE1

CONSENSUS2

SOLVD3

CHARM-Alternative4

LIFE5

Placebo (n=4652)

Ramipril (n=4645)

Placebo (n=126)

Enalapril (n=127)

Placebo (n=1284)

Enalapril (n=1285)

Placebo (n=1015)

Candesartan (n=1013)

Atenolol (n=4588)Losartan (n=4605)

13% P=.021

16%P=.003

22%P<.001

23% P=.0004

27% P=.003

Total mortalityin severe HF

Mortality in chronic HF

Death, MI, or stroke in patients aged 55-80 years with hypertension and LVH

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

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

ACEIs and ARBs Yield Reduction in Cardiovascular Morbidity and Mortality

0

-10

Relative Risk Reduction, %

-20

-30

-40

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.

  • Yusuf S et al. N Engl J Med. 2000;342:145-153
  • The CONSENSUS Trial Study Group
  • N Engl J Med. 1987;316:1429-1435
  • SOLVD Investigators. N Engl J Med. 1991;325:293-302
  • Granger CB et al. Lancet. 2003;362:772-776
  • Dahlöf B et al. Lancet. 2002;359:995-1003
reduction of progressive nephropathy with arb idnt
Reduction of Progressive Nephropathy with ARB: IDNT

* p< .05

** p< .01

*** p<.001

Lewis EJ NEJM 2001;345:851

d iabetics e xposed to t elmisartan a nd enalapr il study detail
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

Decrease in GFR

Death Rate

14.9

17.9

35-50%

p=ns

Percent

mL/min

5%

5%

enalapril

telmisartan

enalapril

telmisartan

expected

rate over

5 years

Barnett A et al N Engl J Med 2004

trial of preventing hypertension trophy

4 Years

RR ↓15.8

AR ↓ 9.6

2 Years

RR ↓66%

AR ↓ 26%

TRial Of Preventing HYpertension (TROPHY)

Kaplan-Meier Curves of Clinical Hypertension in the Two Groups

1.0

0.9

Candesartan

Placebo

0.8

0.7

0.6

% Cumulative incidence

0.5

0.4

0.3

0.2

0.1

0

0

1

2

3

4

Years in study

Candesartan 391 356 309 191 128

Placebo 381 269 184 118 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

30

25

Trandolapril (N=86)

Losartan (N=89)

20

Proportion ReachingEndpoint, %

P=.02

15

Combination (N=88)

10

5

0

0

6

12

18

24

30

36

Combination Therapy Delays but Does Not Prevent End-Stage Renal Disease

COOPERATE Findings

Months After Randomization

Number at riskLosartan 89 88 84 79 65 59 47Trandolapril 86 85 83 75 72 63 58Combination 88 87 86 83 76 73 67

COOPERATE, combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease

Nakao N et al. Lancet. 2003;361:117-124

slide104

ASCOT: Blood Pressure Results

Amlodipine Besylate/Perindopril vs Atenolol/Bendroflumethiazide

All CVevents +revasc

Fatal +nonfatalstroke

New cases

of diabetesmellitus

1°*endpoint

All-causemortality

CVmortality

0

‒10

‒10NS

Change(%)

‒15P<0.005

‒16P<0.0001

‒20

‒23P=0.0007

‒26P=0.0017

‒30

‒32P<0.0001

N=19,257*1° endpoint: nonfatal MI and fatal CHDCHD, coronary heart disease; MI, myocardial infarction; NS, nonsignificant

‒40

Presented March 8, 2005 at the American College of Cardiology Annual Scientific Session, Orlando, Florida

renin system suppression by ace inhibitors and arbs
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

plasma renin activity pra
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 short-term and long-term effects leading to organ damage2

1.Alderman MH, et al. 19972. Burnier M, et al. 2000

crystal structure of renin
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 system 1 6

Diuretic

ACEI

ARB

Direct Renin Inhibitor (DRI)

Only Direct Renin Inhibition Inhibits the Entire Renin System1-6

PRA

Ang I

Ang II

Class

  • 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.
  • Johnston CI. Blood Pressure. 2000;9(suppl 1):9-13
  • Widdop RE et al. Hypertension. 2002;40:516-520
  • Fabiani ME et al. In: Angiotensin II Receptor Antagonists2001:263-278
  • Waybill MM et al. J Vasc Interv Radiol. 2003;14:961-975
  • Reid IA. Adv Physiol Ed. 1998;20:S236-S245
  • Lin C et al. Am Heart J. 1996;131:1024-1034
renin system suppression via direct renin inhibition 1 3
Renin System Suppression via DirectRenin 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
  • Stanton A. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10
  • Wood JM et al. Cardiovasc Drugs Ther. 1996;10:309-312
  • Nussberger J et al. Hypertension. 2002;39:e1-e8
an efficient strategy to achieve interruption of the renin system is direct renin inhibition 1 3

Renin

Angiotensinogen

Feedback Loop

Ang I

ACE

AT1 Receptor

ACEIs

Ang II

ARBs

An Efficient Strategy to Achieve Interruption of the Renin System Is Direct Renin Inhibition1-3
  • The Point of Activation
  • Renin initiates a chain of events within the system
  • Cleaves angiotensinogen to form Ang I
    • Ang I is then converted to Ang II
  • Feedback Loop
  • ACEIs and ARBs impact the feedback loop, resulting in increased levels of Ang I (ACEIs) and Ang I and 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;4:6-10Kelly DJ et al. Hypertension. 2005;46:471-472Fisher NDL et al. J Am Soc Nephrol. 2005;16:592-599

slide112

100

10

1

0.1

0

6

4

2

8

10

24

Aliskiren Exhibits Dose-dependent Reductions In PRA Compared With ACE Inhibitors In Healthy Volunteers

PRA (ng/mL/h)

Placebo

Enalapril 20 mg

Aliskiren 640 mg

Aliskiren 160 mg

Aliskiren 80 mg

Aliskiren 40 mg

Time (hours)

Treatment day 8

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

aliskiren reduces pra as compared to an arb

8

4

2

6

0

30

1

12

4

6

2

18

48

0

24

Aliskiren Reduces PRA asCompared to an ARB

PRA (ng Ang I/mL/h)

* †

Valsartan 160 mg

Aliskiren 150 mg + valsartan 80 mg

Placebo

* †

Aliskiren 300 mg

* †

* † ‡

† ‡

† ‡

*

*

*

Time (hours)

*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

−2

−4

−6

−8

−10

−12

−14

−16

0

Aliskiren Offers Dose-dependent Reductions In SeDBP

Aliskiren150 mg

Aliskiren300 mg

Aliskiren600 mg

Placebo

n=165

n=172

n=169

n=166

−4.9

−10.3

−11.1

−12.5

*

*

*

§

Mean  SeDBP (mmHg)

* p<0.0001 versus placebo

§ p<0.05 for aliskiren 600 mgcompared to aliskiren 150 mg

Hypertension

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

Monotherapy

aliskiren offers dose dependent reductions in sesbp

−2

−4

−6

−8

−10

−12

−14

−16

0

Aliskiren Offers Dose-dependent Reductions in SeSBP

Aliskiren150 mg

Aliskiren300 mg

Aliskiren600 mg

Placebo

n=165

n=172

n=169

n=166

−3.8

−13.0

−14.7

−15.8

*

Mean  SeSBP (mmHg)

*

*

* p<0.0001 versus placebo

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

Hypertension

Monotherapy

clinical trials alisk iren combination
Clinical Trials: Aliskiren Combination

Change in SBP for Aliskiren, HCTZ, and Aliskiren + HCTZ

0 mg

HCTZ

6.25 mg

HCTZ

12.5 mg

HCTZ

25 mg

HCTZ

Placebo

Mean Reductions from Baseline in SBP (mm Hg)

clinical trials aliskerin in combination
Clinical Trials: Aliskerin in Combination

Change in DBP for Aliskiren, HCTZ, and Aliskiren + HCTZ

0 mg

HCTZ

6.25 mg

HCTZ

12.5 mg

HCTZ

25 mg

HCTZ

Placebo

Mean Reductions from Baseline in DBP (mm Hg)

clinical trials aliskire n in combination
Clinical Trials: Aliskiren in Combination

Change in SBP for Aliskiren, Valsartan, and Aliskiren + Valsartan

Week 4

Week 8

Aliskiren

150 mg +

Valsartan

160 mg

Aliskiren

300 mg +

Valsartan

320 mg

Aliskiren

150 mg

Valsartan

160 mg

Placebo

Aliskiren

300 mg

Valsartan

320 mg

Placebo

Mean Reductions from Baseline in SBP (mm Hg)

clinical trials aliskiren in combination
Clinical Trials: Aliskiren in Combination

Change in DBP for Aliskiren, Valsartan, and Aliskiren + Valsartan

Week 4

Week 8

Aliskiren

150 mg +

Valsartan

160 mg

Aliskiren

300 mg +

Valsartan

320 mg

Aliskiren

150 mg

Valsartan

160 mg

Placebo

Aliskiren

300 mg

Valsartan

320 mg

Placebo

Mean Reductions from Baseline in DBP (mm Hg)

conclusions and summary
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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