ishib 2007 innovating vascular health: practical applications to clinical practice critical...

ISHIB 2007Innovating Vascular Health: Practical Applications to Clinical PracticeInnovating Vascular Health: Practical Applications to Clinical Practice

Critical Challenges in Critical Challenges in Cardiovascular DiseaseCardiovascular Disease

Program ChairwomanProgram Chairwoman

Shawna D. Nesbitt, MD, MSShawna D. Nesbitt, MD, MSAssociate Professor Associate Professor

Department of Internal MedicineDepartment of Internal MedicineDivision of HypertensionDivision of Hypertension

University of Southwestern Texas University of Southwestern Texas Medical SchoolMedical School

Dallas, TXDallas, TX

CME-accredited symposiumCME-accredited symposium jointly sponsored by the American jointly sponsored by the American Society of Hypertension and CMEducation Resources, LLCSociety of Hypertension and CMEducation Resources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational Sponsored by an independent educational grant from Novartis Pharmaceuticalsgrant from Novartis Pharmaceuticals

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the Full faculty disclosures provided in syllabus and at the beginning of the programbeginning of the program

Welcome and Program OverviewWelcome and Program Overview

Program Educational ObjectivesProgram Educational Objectives

As a result of this session, physicians will be able to:As a result of this session, physicians will be able to: ► Identify the importance of early treatment of patients with high blood Identify the importance of early treatment of patients with high blood

pressure, and the importance of treating both systolic and diastolic pressure, and the importance of treating both systolic and diastolic blood pressure abnormalities.blood pressure abnormalities.

► Implement clinical strategies that help patients achieve blood Implement clinical strategies that help patients achieve blood pressure goals as quickly as possible, using combination therapy, pressure goals as quickly as possible, using combination therapy, when indicated.when indicated.

► Identify prescribing strategies that reduce side effects and increase Identify prescribing strategies that reduce side effects and increase the likelihood of adherence to an antihypertensive drug regimen.the likelihood of adherence to an antihypertensive drug regimen.

► Characterize and distinguish among safety profiles of and efficacy Characterize and distinguish among safety profiles of and efficacy characteristics of antihypertensive agents used in the African characteristics of antihypertensive agents used in the African American population.American population.

As a result of this session, physicians will be able to:As a result of this session, physicians will be able to: ► Identify the importance of early treatment of patients with high blood Identify the importance of early treatment of patients with high blood

pressure, and the importance of treating both systolic and diastolic pressure, and the importance of treating both systolic and diastolic blood pressure abnormalities.blood pressure abnormalities.

► Implement clinical strategies that help patients achieve blood Implement clinical strategies that help patients achieve blood pressure goals as quickly as possible, using combination therapy, pressure goals as quickly as possible, using combination therapy, when indicated.when indicated.

► Identify prescribing strategies that reduce side effects and increase Identify prescribing strategies that reduce side effects and increase the likelihood of adherence to an antihypertensive drug regimen.the likelihood of adherence to an antihypertensive drug regimen.

► Characterize and distinguish among safety profiles of and efficacy Characterize and distinguish among safety profiles of and efficacy characteristics of antihypertensive agents used in the African characteristics of antihypertensive agents used in the African American population.American population.

Program Educational ObjectivesProgram Educational Objectives

► Recognize markers of target organ damage and learn which Recognize markers of target organ damage and learn which antihypertensive agents are useful for preventing end organ antihypertensive agents are useful for preventing end organ complications such as CV disease and diabetic renal disease.complications such as CV disease and diabetic renal disease.

► Manage hypertension as a systematic disease, with multiple Manage hypertension as a systematic disease, with multiple manifestations, and associations, including metabolic syndrome manifestations, and associations, including metabolic syndrome and associated risk factors.and associated risk factors.

► Address complications linked to healthcare disparities observed Address complications linked to healthcare disparities observed in specific patient populations, and the importance of providing in specific patient populations, and the importance of providing access, treatment, and monitoring of patients with multiple risk CV access, treatment, and monitoring of patients with multiple risk CV risk factors.risk factors.

► Manage African American patients with features of the metabolic Manage African American patients with features of the metabolic syndrome, and its implications for multiple risk factor syndrome, and its implications for multiple risk factor managementmanagement

► Recognize markers of target organ damage and learn which Recognize markers of target organ damage and learn which antihypertensive agents are useful for preventing end organ antihypertensive agents are useful for preventing end organ complications such as CV disease and diabetic renal disease.complications such as CV disease and diabetic renal disease.

► Manage hypertension as a systematic disease, with multiple Manage hypertension as a systematic disease, with multiple manifestations, and associations, including metabolic syndrome manifestations, and associations, including metabolic syndrome and associated risk factors.and associated risk factors.

► Address complications linked to healthcare disparities observed Address complications linked to healthcare disparities observed in specific patient populations, and the importance of providing in specific patient populations, and the importance of providing access, treatment, and monitoring of patients with multiple risk CV access, treatment, and monitoring of patients with multiple risk CV risk factors.risk factors.

► Manage African American patients with features of the metabolic Manage African American patients with features of the metabolic syndrome, and its implications for multiple risk factor syndrome, and its implications for multiple risk factor managementmanagement

Program FacultyProgram Faculty

Program ChairwomanProgram ChairwomanShawna D. Nesbitt, MD, MSShawna D. Nesbitt, MD, MSAssociate Professor Associate Professor Department of Internal MedicineDepartment of Internal MedicineDivision of HypertensionDivision of HypertensionUniversity of Southwestern Texas University of Southwestern Texas Medical SchoolMedical SchoolDallas, TexasDallas, Texas

Ken Jamerson, MDKen Jamerson, MDProfessor of MedicineProfessor of MedicineCardiovascular MedicineCardiovascular MedicineUniversity of Michigan Health University of Michigan Health SystemSystemAnn Arbor, MichiganAnn Arbor, Michigan

Program ChairwomanProgram ChairwomanShawna D. Nesbitt, MD, MSShawna D. Nesbitt, MD, MSAssociate Professor Associate Professor Department of Internal MedicineDepartment of Internal MedicineDivision of HypertensionDivision of HypertensionUniversity of Southwestern Texas University of Southwestern Texas Medical SchoolMedical SchoolDallas, TexasDallas, Texas

Ken Jamerson, MDKen Jamerson, MDProfessor of MedicineProfessor of MedicineCardiovascular MedicineCardiovascular MedicineUniversity of Michigan Health University of Michigan Health SystemSystemAnn Arbor, MichiganAnn Arbor, Michigan

Jackson T. Wright, Jr., MD, PhD, FACPJackson T. Wright, Jr., MD, PhD, FACPProfessor of MedicineProfessor of MedicineProgram Director, General Clinical Program Director, General Clinical Research CenterResearch CenterCase Western Reserve UniversityCase Western Reserve UniversityDirector, Clinical Hypertension ProgramDirector, Clinical Hypertension ProgramUniversity Hospitals of ClevelandUniversity Hospitals of ClevelandChief, Case Western Reserve Chief, Case Western Reserve University Hypertension SectionUniversity Hypertension Section (Louis Stokes VAMC)(Louis Stokes VAMC)Cleveland, OhioCleveland, Ohio

Jackson T. Wright, Jr., MD, PhD, FACPJackson T. Wright, Jr., MD, PhD, FACPProfessor of MedicineProfessor of MedicineProgram Director, General Clinical Program Director, General Clinical Research CenterResearch CenterCase Western Reserve UniversityCase Western Reserve UniversityDirector, Clinical Hypertension ProgramDirector, Clinical Hypertension ProgramUniversity Hospitals of ClevelandUniversity Hospitals of ClevelandChief, Case Western Reserve Chief, Case Western Reserve University Hypertension SectionUniversity Hypertension Section (Louis Stokes VAMC)(Louis Stokes VAMC)Cleveland, OhioCleveland, Ohio

Faculty DisclosuresFaculty Disclosures

Shawna D. Nesbitt, MD, MSShawna D. Nesbitt, MD, MSGrant/Research Support: PfizerGrant/Research Support: PfizerConsultant: Novartis, BMSConsultant: Novartis, BMSSpeakers Bureau: Boerhinger Ingelheim, Novartis, AstraZenecaSpeakers Bureau: Boerhinger Ingelheim, Novartis, AstraZeneca

Ken Jamerson, MDKen Jamerson, MDResearch Support: NIH, NHLBI, NIH, NIDDK, Novartis, King Research Support: NIH, NHLBI, NIH, NIDDK, Novartis, King PharmaceuticalsPharmaceuticalsConsultant: MSD, Pfizer, Novartis, SpeedelConsultant: MSD, Pfizer, Novartis, Speedel

Jackson T. Wright, Jr., MD, PhD, FACPJackson T. Wright, Jr., MD, PhD, FACPResearch Support: Glaxo Smith Kline, NovartisResearch Support: Glaxo Smith Kline, NovartisConsultant: Novartis, MSD, Sanofi, BMS, Pfizer, NIHConsultant: Novartis, MSD, Sanofi, BMS, Pfizer, NIHHonoraria: Novartis, Biovail, Sanofi, PfizerHonoraria: Novartis, Biovail, Sanofi, Pfizer

Shawna D. Nesbitt, MD, MSShawna D. Nesbitt, MD, MSGrant/Research Support: PfizerGrant/Research Support: PfizerConsultant: Novartis, BMSConsultant: Novartis, BMSSpeakers Bureau: Boerhinger Ingelheim, Novartis, AstraZenecaSpeakers Bureau: Boerhinger Ingelheim, Novartis, AstraZeneca

Ken Jamerson, MDKen Jamerson, MDResearch Support: NIH, NHLBI, NIH, NIDDK, Novartis, King Research Support: NIH, NHLBI, NIH, NIDDK, Novartis, King PharmaceuticalsPharmaceuticalsConsultant: MSD, Pfizer, Novartis, SpeedelConsultant: MSD, Pfizer, Novartis, Speedel

Jackson T. Wright, Jr., MD, PhD, FACPJackson T. Wright, Jr., MD, PhD, FACPResearch Support: Glaxo Smith Kline, NovartisResearch Support: Glaxo Smith Kline, NovartisConsultant: Novartis, MSD, Sanofi, BMS, Pfizer, NIHConsultant: Novartis, MSD, Sanofi, BMS, Pfizer, NIHHonoraria: Novartis, Biovail, Sanofi, PfizerHonoraria: Novartis, Biovail, Sanofi, Pfizer

Program AgendaProgram Agenda

7:15 – 7:30 PM7:15 – 7:30 PMIntroduction and OverviewIntroduction and Overview

The Current Landscape of Cardiovascular Risk The Current Landscape of Cardiovascular Risk Management in African AmericansManagement in African Americans——Where Co-morbidity Matters: The Evolving Where Co-morbidity Matters: The Evolving Relationship Between Risk Factors, Diabetes, Relationship Between Risk Factors, Diabetes, Hypertension, and Vascular ComplicationsHypertension, and Vascular ComplicationsShawna D. Nesbitt, MD, MSShawna D. Nesbitt, MD, MS 7:30 – 8:00 PM7:30 – 8:00 PMAre We in Control? An Epidemiological Are We in Control? An Epidemiological Examination of How Well We Are Managing Examination of How Well We Are Managing Hypertension in Ethnic Minority Populations:Hypertension in Ethnic Minority Populations: The Importance of Early Risk Identification and The Importance of Early Risk Identification and Intervention—Getting to Goal and Staying ThereIntervention—Getting to Goal and Staying ThereKen Jamerson, MDKen Jamerson, MD

Program AgendaProgram Agenda

8:00 – 8:25 PM8:00 – 8:25 PMHypertension—A Systemic Disease Requiring Hypertension—A Systemic Disease Requiring Systematic Approaches to Therapy:Systematic Approaches to Therapy:Recent Clinical Practice Recommendations Recent Clinical Practice Recommendations Focusing on Combination Therapy in Difficult-Focusing on Combination Therapy in Difficult-to-Treat Patient Populations with High Blood to-Treat Patient Populations with High Blood Pressure and Compelling ConditionsPressure and Compelling Conditions Jackson T. Wright, Jr., MD, PhD, FACPJackson T. Wright, Jr., MD, PhD, FACP 8:25 – 8:55 PM8:25 – 8:55 PMThe Evolving Landscape of Antihypertensive The Evolving Landscape of Antihypertensive Therapy:Therapy: Direct Renin Inhibition, Combination Direct Renin Inhibition, Combination Therapy, and Implications for African American Therapy, and Implications for African American and Other Ethnic Populationsand Other Ethnic PopulationsShawna D. Nesbitt, MD, MSShawna D. Nesbitt, MD, MS 8:55 PM8:55 PMQuestions and Interactions with the FacultyQuestions and Interactions with the Faculty

The Current Landscape of Cardiovascular The Current Landscape of Cardiovascular Risk Management in African Americans—Risk Management in African Americans—

Where Co-morbidity MattersWhere Co-morbidity Matters

The Evolving RelationshipThe Evolving RelationshipBetween Risk Factors, Diabetes, Hypertension, And Between Risk Factors, Diabetes, Hypertension, And

Vascular ComplicationsVascular Complications

Shawna D. Nesbitt MD, MSShawna D. Nesbitt MD, MSAssociate Professor of Internal MedicineAssociate Professor of Internal Medicine

University of Texas SouthwesternUniversity of Texas SouthwesternDallas, TexasDallas, Texas

Introduction and OverviewIntroduction and OverviewIntroduction and OverviewIntroduction and Overview

0

20

40

60

80

100

120

2000 2010 2020 2030 2040 2050

White African American Hispanic (any race) Asian

Changing TrendsChanging Trends

Hispanics are the fastest-Hispanics are the fastest-growing segment of the growing segment of the population, and now account population, and now account for 13% U.S., as do African for 13% U.S., as do African Americans.Americans.

The U.S. Asian population The U.S. Asian population currently consists of 10.6 currently consists of 10.6 million people, and represents million people, and represents 4% U.S.,; however, this 4% U.S.,; however, this population group is expected population group is expected to triple in size by 2050.to triple in size by 2050.

Changing TrendsChanging Trends

Hispanics are the fastest-Hispanics are the fastest-growing segment of the growing segment of the population, and now account population, and now account for 13% U.S., as do African for 13% U.S., as do African Americans.Americans.

The U.S. Asian population The U.S. Asian population currently consists of 10.6 currently consists of 10.6 million people, and represents million people, and represents 4% U.S.,; however, this 4% U.S.,; however, this population group is expected population group is expected to triple in size by 2050.to triple in size by 2050.

The U.S. Population is Becoming The U.S. Population is Becoming Increasingly DiverseIncreasingly Diverse

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

Southern U.S. Has the Highest Concentration of African-Americans

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

25.0 to 60.0

12.3 to 24.9

5.0 to 12.2

0.3 to 4.9People indicating exactly one race, Black or African American, as a percent of total population by statePeople 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 FileAdapted from U.S. Census Bureau, 2002 Redistricting Data (PL 94-171) Summary File

Non-Hispanic Non-Hispanic BlackBlack

FFMM

Estimated Rates of US Adults With Estimated Rates of US Adults With Hypertension by Sex, Race, and EthnicityHypertension by Sex, Race, and Ethnicity

NHANES 1988-1994 to 1999-2000NHANES 1988-1994 to 1999-2000

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

AllAll MexicanMexicanAmericanAmerican

Non-Hispanic Non-Hispanic WhiteWhite

Hyp

erte

nsi

ve A

du

lts

(Rat

e, P

erce

nt

± S

E)

4545

3030

2020

1515

00

1010

2525

4040

55

1999-20001999-20001988-19941988-1994

FFMM FFMM

3535

1.8% age adj. increase7.2% age adj. increase

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

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

%

63

44.6

60.155.6

40.344

0

10

20

30

40

50

60

70Treatment

Control

AfricanAmericans*

Whites* MexicanAmericans

Percentage increase from 1988 to 2000

Percentage increase from 1988 to 2000

7.2 0.9 6.2 8.2 6.2 3.7

*Non-Hispanic.*Non-Hispanic.

Mortality From High Blood Pressure Mortality From High Blood Pressure Higher in African Americans Higher in African Americans

Overall Mortality Rates From Causes Related to Hypertension, 2003*Overall Mortality Rates From Causes Related to Hypertension, 2003*

*High blood pressure listed as a primary or contributing cause of death.*High blood pressure listed as a primary or contributing cause of death.High blood pressure=systolic ≥140 mmHg or diastolic ≥90 mmHg, taking High blood pressure=systolic ≥140 mmHg or diastolic ≥90 mmHg, taking antihypertensive medicine, being told ≥2 times by a physician that you have high antihypertensive medicine, being told ≥2 times by a physician that you have high blood pressure.blood pressure.

Mo

rtal

ity

Rat

e, %

Mo

rtal

ity

Rat

e, %

African AmericanAfrican AmericanFemaleFemale MaleMale FemaleFemale

2020

1010

3030

40405050

49.749.7

14.914.9

40.840.8

14.514.5

00

6060

MaleMaleWhiteWhite

In hypertensive African Americans, In hypertensive African Americans, 30% and 30% and 20% of all deaths in20% of all deaths inmen and women, respectively, may be due to high blood pressure.men and women, respectively, may be due to high blood pressure.

Adapted from Thom T et al. Adapted from Thom T et al. Circulation. Circulation. 2006;113:e85–e151.2006;113:e85–e151.

*Includes those *Includes those 17 years of age with diagnosed and undiagnosed hypertension. National 17 years of age with diagnosed and undiagnosed hypertension. National Center for Health Statistics. NHANES 1999-2000 (CD-ROM); Center for Health Statistics. NHANES 1999-2000 (CD-ROM); ††NHANES III.NHANES III.

% Not at Goal BP% Not at Goal BP

SystolicSystolic

DiastolicDiastolic Patient Type Patient Type (mm Hg) (mm Hg) BP BP BP BP

Total hypertensivesTotal hypertensives <140/90<140/90 57%57%26%26%

African AmericanAfrican American <140/90<140/90 60%60%32%32%

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

30% 30%

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

Symptomatic CHDSymptomatic CHD <140/90 <140/90 47%47%4%4%

Patients with diabetesPatients with diabetes†† <130/85<130/85 81%81%24%24%

NHANES (1999-2000)NHANES (1999-2000)

Patients Not at JNC VI BP GoalsPatients Not at JNC VI BP Goals

Risk-Factor Clustering by Race and SexRisk-Factor Clustering by Race and Sex

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

0

10

20

30

40

50

60

70

0 1 ≥2 ≥3White women African-American women White men African-American men

Per

cen

tag

e

Obesity (BMI ≥30 kg/mObesity (BMI ≥30 kg/m22))

Population(%)

30

25

2000 2001 2002 2003

*Jan–June*Jan–June

20

15

02004*

8

6

4

2

02000 2001 2002 2003 2004*

Diagnosed diabetesDiagnosed diabetes

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

21.823.0

23.9 23.724.3 5.9

6.4 6.5 6.6 6.6

Obesity and Diabetes Among US Adults:Obesity and Diabetes Among US Adults:Growing prevalenceGrowing prevalence

+11.9%+11.9%

+11.5%+11.5%

0 5 10 15 20 25

American Indians/American Indians/Alaska NativesAlaska Natives

Age-Adjusted Prevalence of Diabetes* Age-Adjusted Prevalence of Diabetes* by Race/Ethnicity in the USby Race/Ethnicity in the US

PercentPercent

Hispanic/LatinoHispanic/LatinoAmericansAmericans

Non-Hispanic Non-Hispanic BlacksBlacks

Non-Hispanic Non-Hispanic WhitesWhites

*In people 20+ years old*In people 20+ years old

CDC. National Diabetes Fact Sheet. 2002.CDC. National Diabetes Fact Sheet. 2002.

Sources: 1997-1999 National Health Interview Survey and 1988-1994 National Health and Nutrition 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 Examination Survey (NHANES) estimates projected to year 2000. 1998 outpatient database of the Indian Health ServiceHealth Service

19%19%

15%15%

14%14%

7%7%

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

0

10

20

30

40

50

Per

cent

of P

opul

atio

n

Source: Physical Activity and Health: A Report of the Surgeon General, United States Department of Source: Physical Activity and Health: A Report of the Surgeon General, United States Department of HHSHHS

The Rising Tide of ESRDThe Rising Tide of ESRD

Diabetes: The Number One Cause of ESRDDiabetes: The Number One Cause of ESRD

DiabetesDiabetes50.1%50.1%

HypertensionHypertension27%27%

GlomerulonephritisGlomerulonephritis

13%13%

OtherOther

10%10%

USRDS. Annual data report. 2000.USRDS. Annual data report. 2000.

No of PatientsNo of PatientsProjectionProjection

1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 201000

100100

200200

300300

400400

500500

600600

700700

RR22 = 99.8% = 99.8%326,217

372,407

661,330

No

. o

f E

SR

D

Pat

ien

ts (

x 10

00)

YearYear

Years of Potential Life Lost to Total Heart Years of Potential Life Lost to Total Heart Disease Before Age 75 by Race and GenderDisease Before Age 75 by Race and Gender

Clark et al Clark et al Heart Dis.Heart Dis. 2001;3:97-108; National Vital Statistics System, Health, United States, 1996–97. 2001;3:97-108; National Vital Statistics System, Health, United States, 1996–97.

1980 1985 1990 19950

1000

2000

3000

4000

1980 1985 1990 1995

Yea

rs

White women African-American women White men African-American men

Failure to Reach Treatment GoalsFailure to Reach Treatment GoalsCarries Costly BurdenCarries Costly Burden

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

N = 1000 managed-care patients with treated hypertension

Greater medication costs More physician visitsMore physician visits

9.79.7

4.14.1

0

4

8

12

<120 mm Hg<120 mm Hg ≥≥180 mm Hg180 mm Hg

Mean Mean visits visits per per yearyear

Severity of hypertension (mm Hg)Severity of hypertension (mm Hg)

0

200

400

600

<130/85 140/90 –159/99

≥160/100 130/85 –139/89

Mean Mean drugdrug

cost percost perpatient patient

per year*per year*($ US)($ US)

ControlledControlled UncontrolledUncontrolled

*Based on 1999 average wholesale price *Based on 1999 average wholesale price

Maximum SBPMaximum SBP

Kenneth A. Jamerson, M.D.Kenneth A. Jamerson, M.D.Professor of Cardiovascular Medicine Professor of Cardiovascular Medicine

University of MichiganUniversity of MichiganMedical Director, Program for Multi-cultural HealthMedical Director, Program for Multi-cultural Health

Ann Arbor, MichiganAnn Arbor, Michigan

Are We in Control?Are We in Control? The Importance of Early Risk The Importance of Early Risk Identification and TreatmentIdentification and Treatment

Getting To Goal and Staying There in Getting To Goal and Staying There in Ethnic Minority PopulationsEthnic Minority Populations

Challenges and Solutions in Minority Populations

Challenges and Solutions in Minority Populations

The Tecumseh Blood Pressure StudyThe Tecumseh Blood Pressure Study

A prospective epidemiological study of the antecedents of hypertension A prospective epidemiological study of the antecedents of hypertension and cardiovascular disease in 1,100 young men and womenand cardiovascular disease in 1,100 young men and women

A prospective epidemiological study of the antecedents of hypertension A prospective epidemiological study of the antecedents of hypertension and cardiovascular disease in 1,100 young men and womenand cardiovascular disease in 1,100 young men and women

Ann ArborAnn ArborAnn ArborAnn Arbor

TecumsehTecumsehTecumsehTecumseh

HematocritHematocritHematocritHematocrit

CholesterolCholesterolCholesterolCholesterol

OverweightOverweightOverweightOverweight

Heart RateHeart RateHeart RateHeart Rate

InsulinInsulinInsulinInsulin

TriglyceridesTriglyceridesTriglyceridesTriglycerides

DBPDBPDBPDBP

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

P<0.001P<0.001

P<0.01P<0.01

P<0.05P<0.05

P<0.001P<0.001

P<0.01P<0.01

P<0.05P<0.05

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

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

Blood Pressure Trends Blood Pressure Trends in Tecumseh, Michiganin Tecumseh, Michigan

60

70

80

90

100

110

120

130

140

6.4 21.5 31.3

Hypertensive and Normotensive at 31 Years of Age

Blo

od P

ress

ure

mm

Hg

HypertensiveHypertensiveNormotensiveNormotensive

*

* *

*

**

** P< .01P< .01

**** P<.001P<.001

*

Is There a Unique Etiology for Is There a Unique Etiology for Hypertension in African Americans?Hypertension in African Americans?

Causes and Causes for ConcernCauses and Causes for Concern

The Association of Skin Color with The Association of Skin Color with Blood pressure in US blacks with Blood pressure in US blacks with Low Socioeconomic StatusLow Socioeconomic Status

Klag, M J. Whelton, P K. Coresh, J. Grim, C E. Kuller, L H.Klag, M J. Whelton, P K. Coresh, J. Grim, C E. Kuller, L H. JAMA. 1991 Feb 6;265(5):639-40;JAMA. 1991 Feb 6;265(5):639-40;AbstractAbstract To determine the association of skin color, measured by a reflectometer, with blood pressure in US blacks, 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 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 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 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 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, 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 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, 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 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 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 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 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.that has a higher prevalence in persons with darker skin color.

Deciphering The Etiology and AssociationsDeciphering The Etiology and Associations

Do African Americans respond to Do African Americans respond to antihypertensive therapy differently antihypertensive therapy differently than other races or ethnic groups?than other races or ethnic groups?

Response to Therapy A Critical Issue for Drug Selection and Care

Response to Therapy A Critical Issue for Drug Selection and Care

Afr

ican

Am

eric

an,

%W

hit

e, %

Blood Pressure Response to Blood Pressure Response to Quinapril: The ATIME StudyQuinapril: The ATIME Study

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

SBP (average change)

20.0 Mean –10.5SD 13.4Lower Quartile –2.2Upper Quartile –20.0Interquartile Range 17.8

39 27 15 3 –9 –21 –33 –45 –57

15.0

10.0

5.0

0

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

20.0

15.0

10.0

5.0

0

SD = standard deviation.SD = standard deviation.

Is It Important To Block The RAS Is It Important To Block The RAS In African Americans?In African Americans?

► HOPEHOPE

► PROGRESSPROGRESS

► SOLVDSOLVD

► ValHeftValHeft

► V-HeftV-Heft

► LIFELIFE

► OCTAVEOCTAVE

► ALLHATALLHAT

Landmark Trials That Give Us Data, Guidance, and Perspective

Landmark Trials That Give Us Data, Guidance, and Perspective

African American Study of African American Study of Kidney Disease and HypertensionKidney Disease and Hypertension

Landmark and Longitudinal StudiesLandmark and Longitudinal Studies

Achieved Blood Pressure in AASKAchieved Blood Pressure in AASK

ACEACE CCBCCB BBBB LOWLOW USUALUSUAL

SBPSBP 133.6133.6 131.4131.4 134.2134.2 126.9126.9 140.0140.0

DBPDBP 81.181.1 80.780.7 80.980.9 76.676.6 85.285.2

NEED FORNEED FOR STEP 5STEP 5

28%28% 24%24% 32%32% 35%35% 23%23%

Cumulative Incidence of Confirmed Declining GFR Event,Cumulative Incidence of Confirmed Declining GFR Event,Dialysis or Death by Drug GroupDialysis or Death by Drug Group

(Data as of 10/19/01)(Data as of 10/19/01)

Analysis Censored on 9/22/00 for the CCB Group

0

5

10

15

20

25

30

35

40

0 6 12 18 24 30 36 42 48 54 60

Follow-up Time (Months)

Beta ACE CCB

p-value A vs B C vs B* A vs C*adjusted .042.042 .19 .005.005

Cu

mu

lat i

ve I n

cid

ence

.

Implications Of The AASK StudyImplications Of The AASK Study

► Aggressive control of blood pressure can Aggressive control of blood pressure can eliminate ethnic differences in ESRDeliminate ethnic differences in ESRD

► Inadequate treatment of hypertension may Inadequate treatment of hypertension may cause excess risk of target organ diseasecause excess risk of target organ disease

► Cultural, rather than genetic differences, Cultural, rather than genetic differences, may underlay the excess risk of may underlay the excess risk of hypertensive ESRDhypertensive ESRD

International Society of International Society of Hypertension in BlacksHypertension in Blacks

IMPACT CampaignIMPACT Campaign

Science Guidelines Behavioral ChangeScience Guidelines Behavioral Change

Vascular Matrix SummitVascular Matrix Summit

► Dr. Gary Gibbons Dr. Gary Gibbons ► Dr. Abraham Aviv Dr. Abraham Aviv ► Rick Kittles, MD Rick Kittles, MD ► Charles Rotimi, MD Charles Rotimi, MD ► David Harrison, MDDavid Harrison, MD► Willa Hsueh, MDWilla Hsueh, MD► Helmy Siragy, MDHelmy Siragy, MD► Douglas Vaughan, MDDouglas Vaughan, MD► Dr. Brent EganDr. Brent Egan► Ken Jamerson, MDKen Jamerson, MD

The ProblemThe Problem

Does Being African American Does Being African American Modify the Problem?Modify the Problem?

Models to Explain Health DisparitiesModels to Explain Health Disparities

► Racial Genetic ModelRacial Genetic ModelCause of HD: Population differences in the distribution Cause of HD: Population differences in the distribution of of genetic variantsgenetic variants

► Health-behavior ModelHealth-behavior ModelCause of HD: Differences between R/E groups in the Cause of HD: Differences between R/E groups in the distribution of distribution of individual behaviorsindividual behaviors related to health related to health such as diet, exercise, and tobacco use such as diet, exercise, and tobacco use

► SES ModelSES ModelCause of HD: Over-representation of some R/E groups Cause of HD: Over-representation of some R/E groups within within lower SESlower SES

► Psychosocial Stress ModelPsychosocial Stress ModelCause of HD: Stresses associated with minority group Cause of HD: Stresses associated with minority group status, especially the experience of racism and status, especially the experience of racism and discriminationdiscrimination

RaceRace(Social)(Social)

AncestryAncestry(Genetic)(Genetic)

DiseaseDisease

Critical RelationshipsCritical Relationships

Although much genetic variation (85-Although much genetic variation (85-90%) is shared among all human 90%) is shared among all human populations, about 5% of SNPs have populations, about 5% of SNPs have high levels of allele frequency high levels of allele frequency differential (d>50%). differential (d>50%).

We call these markers Ancestry We call these markers Ancestry Informative Markers (AIMs).Informative Markers (AIMs).

Ancestry Informative Markers (AIMs)Ancestry Informative Markers (AIMs)

Ancestry Can Be Estimated Across Ancestry Can Be Estimated Across Chromosomal RegionsChromosomal Regions

Seldin et al. Seldin et al. Genome Res.Genome Res. 14:1076 -1084, 2004 14:1076 -1084, 2004 Smith et al. Smith et al. AJHGAJHG 74:1001-1013, 2004 74:1001-1013, 2004

European Genetic Contribution in African-American European Genetic Contribution in African-American Populations Living in Different Areas of the U.S.Populations Living in Different Areas of the U.S.

Parra et al. AJHG 1998; Parra et al. AJPA 2002; Kittles et al. unpublished Parra et al. AJHG 1998; Parra et al. AJPA 2002; Kittles et al. unpublished

1.1. Group definition and membership.Group definition and membership.

2.2. Can we accurately assess genomic Can we accurately assess genomic ancestry?ancestry?

3.3. How does genomic ancestry relate to How does genomic ancestry relate to skin color and possibly SES?skin color and possibly SES?

4.4. How useful is genomic ancestry for How useful is genomic ancestry for informing us about disease risk? informing us about disease risk?

5.5. Health Disparities: are they due to Health Disparities: are they due to biological differences?biological differences?

6.6. How do we prevent repeating the How do we prevent repeating the negative past abuses of “race”.negative past abuses of “race”.

Era of Genomic Ancestry and Era of Genomic Ancestry and Challenges Related to HealthChallenges Related to HealthEra of Genomic Ancestry and Era of Genomic Ancestry and Challenges Related to HealthChallenges Related to Health

RESULTSRESULTS BP Control at 18 Months BP Control at 18 Months

Accomplishing SomethingAccomplishing Something

ACCOMPLISH: HypothesisACCOMPLISH: Hypothesis

► ACCOMPLISH will test a new strategy for the ACCOMPLISH will test a new strategy for the treatment of hypertension: Dual therapy treatment of hypertension: Dual therapy provided in a single tablet. provided in a single tablet.

► The combination of benazepril and The combination of benazepril and amlodipine will reduce cardiovascular amlodipine will reduce cardiovascular morbidity and mortality in patients with high-morbidity and mortality in patients with high-risk hypertension by 15% when compared to risk hypertension by 15% when compared to the combination of benazepril and HCTZ.the combination of benazepril and HCTZ.

Jamerson KA et al. Jamerson KA et al. Am J HypertensAm J Hypertens. 2004;17:793–801.. 2004;17:793–801.

ACCOMPLISH: Primary EndpointACCOMPLISH: Primary Endpoint

CV MORBIDITYCV MORBIDITY► Nonfatal MINonfatal MI► Nonfatal strokeNonfatal stroke► Hospitalization for unstable anginaHospitalization for unstable angina► Resuscitated sudden cardiac deathResuscitated sudden cardiac death► Coronary revascularization proceduresCoronary revascularization procedures

CV MORTALITYCV MORTALITY► Sudden cardiac deathSudden cardiac death► Fatal MIFatal MI► Fatal strokeFatal stroke► Death due to coronary intervention, congestive heart Death due to coronary intervention, congestive heart

failure, or other cardiovascular causes failure, or other cardiovascular causes Jamerson KA et al. Jamerson KA et al. Am J HypertensAm J Hypertens. 2004;17:793–801.. 2004;17:793–801.

Time to first event of composite Time to first event of composite cardiovascular morbidity and mortalitycardiovascular morbidity and mortality

ACCOMPLISH: Statistical PowerACCOMPLISH: Statistical Power

► 1,642 primary endpoints needed (~5 years)1,642 primary endpoints needed (~5 years)

► 90% power to detect a 15% risk reduction for 90% power to detect a 15% risk reduction for the primary endpoint at a two-sided overall the primary endpoint at a two-sided overall significance level of 5% significance level of 5%

► Four (4) interim analyses and 1 final analysis Four (4) interim analyses and 1 final analysis

► Allow for lost-to-follow-up rate of less than 5%Allow for lost-to-follow-up rate of less than 5%


ACCOMPLISH: DesignACCOMPLISH: Design


*Beta blockers; alpha blockers; clonidine; loop diuretics. Patients were seen at 6 months after *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.the start of study and thereafter at 6-month intervals until the end of the 5 year trial.

14 Days14 Days Day 1Day 1 Month 1Month 1 Month 2Month 2 Year 5Year 5

ScreeningScreening(N=12,600)(N=12,600)

Amlodipine/Amlodipine/benazepril 5/20 mgbenazepril 5/20 mg

Ran

do

miz

atio

nR

and

om

izat

ion

Benazepril 40 mg + Benazepril 40 mg + HCTZ 12.5 mgHCTZ 12.5 mg

Benazepril 40 mg + Benazepril 40 mg + HCTZ 25 mgHCTZ 25 mg

Free add-on antihypertensive agents*

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

Month 3Month 3

Free add-on Free add-on antihypertensive antihypertensive agents*agents*



Benazepril 20 mg + Benazepril 20 mg + HCTZ 12.5 mgHCTZ 12.5 mg

Forced titrationForced titration

Targeted Population for Recruitment Targeted Population for Recruitment into the ACCOMPLISH Trialinto the ACCOMPLISH Trial

► Men or women of any racial background, age Men or women of any racial background, age ≥55 years≥55 years

► SBP ≥160 mmHg or currently on SBP ≥160 mmHg or currently on antihypertensive therapyantihypertensive therapy

► Evidence of cardiovascular or renal disease Evidence of cardiovascular or renal disease or target organ damageor target organ damage

ACCOMPLISH: Key Demographic DataACCOMPLISH: Key Demographic Data

Race:Race:

CaucasianCaucasian 83.9%83.9%

BlackBlack 11.9%11.9%

OrientalOriental 0.4%0.4%

OtherOther 3.8%3.8%

Ethnicity:Ethnicity:

HispanicHispanic 5.4%5.4%

GenderGender

MaleMale 60.7%60.7%

FemaleFemale 39.3%39.3%

Mean Age, Mean Age, yearsyears

% of Pts % of Pts >>70 70 68.468.4

40.9%40.9%

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

% of % of PopulationPopulation

Baseline Baseline BP BP

(mmHg)(mmHg)

Control Control Rate at Rate at

BaselineBaseline++

All All Patients*Patients* 40%40% 145.4/80145.4/80 37.5%37.5%

Diabetic Diabetic Sub-Sub-PopulationPopulation

60%60% 145.2/79.145.2/79.33

16.3%16.3%

Baseline Traits of ACCOMPLISH Cohort May Reflect Baseline Traits of ACCOMPLISH Cohort May Reflect New Secular Trends in Disease ManagementNew Secular Trends in Disease Management

► Patient enrollment completed.Patient enrollment completed. 50% of patients are obese50% of patients are obese 60% of patients have Diabetes Mellitus60% of patients have Diabetes Mellitus 97% of patients were treated previously for 97% of patients were treated previously for

hypertension.hypertension. 74% of patients were treated with 74% of patients were treated with >> 2 Hypertensive 2 Hypertensive

AgentsAgents

► Only 37.5% of patients were controlled to Only 37.5% of patients were controlled to <140/90 mmHg<140/90 mmHg

ACCOMPLISH: Effect of Initial ACCOMPLISH: Effect of Initial Combination Therapy on SBP Over TimeCombination Therapy on SBP Over Time

Data on file. Novartis Pharmaceuticals Corporation.

SB

P (

mm

Hg

)

160

120

130

140

150

125

135

145

155

BaselineN=11,400

145.4(18.3)

Month 6N=10,736

132.5(16.0)

Month 18N=9,898

131.8(16.0)

All Patients

Month 12N=10,335

132.7(16.0)

(sd)

Baseline Range

ACCOMPLISH: Significant Reduction ACCOMPLISH: Significant Reduction in SBP in All Patient Populationsin SBP in All Patient Populations

Data on file. Novartis Pharmaceuticals Corporation.

All

JNC-7 Goal:SBP140 mmHg

SB

P (

mm

Hg

)

120

130

140

150

125

135

145

155

(N=11,400)(N=11,400)

131.8

145.4145.4

(N=3,333)(N=3,333)

136.8

(N=8,067)(N=8,067)

129.4

(N=1,361)(N=1,361)

133.6

Nordic U.S.African

American

P<0.05

152.6152.6

142.4142.4145.1145.1

Neither age nor gender appeared to influence the effects on SBP.

ACCOMPLISH: Exceptional Control Rates ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapywith Initial Combination Therapy

Data on file. Novartis Pharmaceuticals Corporation.Data on file. Novartis Pharmaceuticals Corporation.

AllAll

Co

ntr

ol

rate

(%

)

NordicNordic U.S.U.S. African African AmericanAmerican

Baseline Control Rates

80.5

N=8,067

1010

20

30

40

50

60

70

80

90

37.637.6

21.021.0

44.444.4

75.6

N=11,400

65.1

N=3,333

71.8

N=1,361

38.638.6

ConclusionsConclusions

► Millions of Americans take anti-hypertension Millions of Americans take anti-hypertension medication, but do not achieve blood pressure medication, but do not achieve blood pressure control. Initial therapy with single-tablet, dual-control. Initial therapy with single-tablet, dual-mechanism drugs is highly effective (>80% mechanism drugs is highly effective (>80% control) and safe.control) and safe.

► We find substantial evidence to broaden the use We find substantial evidence to broaden the use of combination therapy as an initial strategy for of combination therapy as an initial strategy for the treatment of hypertension.the treatment of hypertension.

Hypertension – A Systemic Disease Hypertension – A Systemic Disease Requiring SystematicRequiring Systematic

Approaches To Therapy Approaches To Therapy

Recent Clinical Practice RecommendationsRecent Clinical Practice RecommendationsFocusing on Combination Therapy in Difficult-to-TreatFocusing on Combination Therapy in Difficult-to-Treat

Patient Populations with High Blood Pressure Patient Populations with High Blood Pressureand Compelling Conditionsand Compelling Conditions

Jackson T. Wright, Jr. MD, PhDJackson T. Wright, Jr. MD, PhDProfessor of MedicineProfessor of Medicine

Case Western Reserve UniversityCase Western Reserve UniversityProgram Director, General Clinical Research CenterProgram Director, General Clinical Research Center

Director, Clinical Hypertension ProgramDirector, Clinical Hypertension ProgramUniversity Hospitals Case Medical Center and University Hospitals Case Medical Center and

the Louis Stokes Cleveland VAMCthe Louis Stokes Cleveland VAMC

Considering Combination TherapyConsidering Combination TherapyConsidering Combination TherapyConsidering Combination Therapy

Goals of This PresentationGoals of This Presentation

► Need for multi-drug therapy for BP controlNeed for multi-drug therapy for BP control

► Guideline recommendations for treatment Guideline recommendations for treatment and rationale for these recommendationsand rationale for these recommendations

► Importance of BP vs. drug selectionImportance of BP vs. drug selection

► Combination drug regimens—options and Combination drug regimens—options and strategiesstrategies

Hypertension in African Hypertension in African AmericansAmericans

(versus(versus Whites Whites))

•Higher prevalence Higher prevalence & incidence (esp. & incidence (esp. women)women)

•Greater severityGreater severity

•Earlier onsetEarlier onset

•Higher Higher hospitalization hospitalization rates (~8 x rates (~8 x ) )

•More target-organ More target-organ injuryinjury

•Renin more often Renin more often suppressedsuppressed

•Less intensively treatedLess intensively treated•More factors linked to HTN More factors linked to HTN

Tx resistanceTx resistance− DiabetesDiabetes

− ObesityObesity− ProteinuProteinu

riaria− Female Female

sexsex

− GFRGFR− Target-organ Target-organ

injuryinjury− Living in SE Living in SE

USAUSA

•Lesser BP response to ACEILesser BP response to ACEIthan whitesthan whites

•Less likely to receive RAS Less likely to receive RAS drugsdrugs

TreatmentTreatmentEpidemiologyEpidemiology

Combination Therapy is Needed to Combination Therapy is Needed to Achieve Target SBP GoalsAchieve Target SBP Goals

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

Number of BP meds

Trial/SBP Achieved

1 2 3 4

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)

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

6867646158

53

28

6665635755

48

28

626359545146

27

1.9-2.11.8-2.0

1.7-1.81.5-1.7

1.4-1.51.3

0

20

40

60

80

100

0 6 12 24 36 48 60

Months of Follow-up

Per

cen

t

0

0.5

1

1.5

2

ALLHATALLHAT

ChlorthalidoneChlorthalidone

AmlodipineAmlodipine

LisinoprilLisinopril

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

68

3

11

2428

66

411

24 26

61

612

1824

0

10

20

30

40

50

60

70

80

1 2 3 4+ ALL

Number of Prescribed Drugs

Per

cen

t

ChlorthalidoneChlorthalidoneAmlodipineAmlodipine


ALLHATALLHAT

Number of Drugs Needed to Control BPNumber of Drugs Needed to Control BP(<140/90 mm Hg) in ALLHAT After 5 Years(<140/90 mm Hg) in ALLHAT After 5 Years

► 26% of participants were controlled on 1 drug 26% of participants were controlled on 1 drug (another 2% were untreated):(another 2% were untreated): Therefore, at least 72% received or Therefore, at least 72% received or

needed ≥ 2 drugsneeded ≥ 2 drugs

► 49% were controlled on 1 or 2 drugs (12% more 49% were controlled on 1 or 2 drugs (12% more were uncontrolled on 1 drug or untreated):were uncontrolled on 1 drug or untreated): Therefore, at least 39% received or would have Therefore, at least 39% received or would have

needed ≥ 3 drugs to control BPneeded ≥ 3 drugs to control BP

► 60% were controlled on 3 or fewer drugs:60% were controlled on 3 or fewer drugs: Therefore, at least 16% received or needed ≥ 4 Therefore, at least 16% received or needed ≥ 4

drugs to control BPdrugs to control BP

ALLHATALLHAT

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney

disease)

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney

disease)

Initial Drug ChoicesInitial Drug Choices

Drug(s) for the compelling indications Other antihypertensive drugs

(diuretics, ACEI, ARB, BB, CCB) as needed.

Drug(s) for the compelling indications Other antihypertensive drugs

(diuretics, ACEI, ARB, BB, CCB) as needed.

With Compelling Indications


Lifestyle ModificationsLifestyle Modifications

Not at Goal Blood Pressure


Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

Stage 2 Hypertension (SBP >160 or DBP >100

mmHg) 2-drug combination for most (usually thiazide-type diuretic

and ACEI, or ARB, or BB, or CCB)

Stage 2 Hypertension (SBP >160 or DBP >100

mmHg) 2-drug combination for most (usually thiazide-type diuretic

and ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99

mmHg) Thiazide-type diuretics for

most. May consider ACEI, ARB, BB,

CCB, or combination.

Stage 1 Hypertension(SBP 140–159 or DBP 90–99

mmHg) Thiazide-type diuretics for

most. May consider ACEI, ARB, BB,

CCB, or combination.

Without Compelling Indications


JNC-7 Algorithm for TreatmentJNC-7 Algorithm for Treatmentof Hypertensionof Hypertension

Consensus Statement: Consensus Statement: Management of High BP in Management of High BP in

African AmericansAfrican Americans

If BP <155/100 mm Hg, monotherapy†

If BP 155/100 mmHg, combination therapy‡

Increase doseor add a 3rd agent

from a different class

Uncomplicated hypertension

Goal BP: <140/90 mm Hg

Not at BP goal?Intensify lifestyle changes

AND

Add a 2nd agent from a different class or

increase dose

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

Not at BP goal?Intensify lifestyle changes

AND

Patient with elevated BP

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§


increase doseIncrease dose

or add a 3rd agentfrom a different

classRAS, 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

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

Black vs. Non-BlackBlack vs. Non-BlackLisinopril versus ChlorthalidoneLisinopril versus Chlorthalidone

Nonfatal MI + CHD DeathNonfatal MI + CHD Death

All-Cause MortalityAll-Cause Mortality

Combined CHDCombined CHD

Combined CVDCombined CVD

StrokeStroke

End Stage Renal DiseaseEnd Stage Renal Disease

Heart FailureHeart Failure

Black

Favors Favors LisinoprilLisinopril

Favors Favors ChlorthalidonChlorthalidon

ee

0.500.50 11 22

1.30 (1.10 - 1.54)1.30 (1.10 - 1.54)

1.30 (0.94 - 1.75)1.30 (0.94 - 1.75)

1.40 (1.17 - 1.68)1.40 (1.17 - 1.68)

1.19 (1.09 - 1.30)1.19 (1.09 - 1.30)

1.15 (1.02 - 1.30)1.15 (1.02 - 1.30)

1.06 (0.95 - 1.18)1.06 (0.95 - 1.18)

1.10 (0.94 - 1.28)1.10 (0.94 - 1.28)

Non-BlackNon-Black

Favors Favors LisinopriLisinopri

ll

Favors Favors ChlorthalidoneChlorthalidone

0.500.50 11 22

1.13 (1.00 - 1.28)1.13 (1.00 - 1.28)

0.93 (0.67 - 1.30)0.93 (0.67 - 1.30)

1.00 (0.85 - 1.17)1.00 (0.85 - 1.17)

1.06 (1.00 - 1.13)1.06 (1.00 - 1.13)

1.01 (0.93 - 1.09)1.01 (0.93 - 1.09)

0.97 (0.89 - 1.06)0.97 (0.89 - 1.06)

0.94 (0.85 - 1.05)0.94 (0.85 - 1.05)

Wright JT et al; JAMA 2005; 293:1593Wright JT et al; JAMA 2005; 293:1593Wright JT et al; JAMA 2005; 293:1593Wright JT et al; JAMA 2005; 293:1593

Relative Risk and 95% Confidence IntervalsRelative Risk and 95% Confidence Intervals

ALLHATALLHAT

ChlorthalidoneChlorthalidone AmlodipineAmlodipine LisinoprilLisinopril

SBP – mean (sd)SBP – mean (sd)BlackBlack 135.0 (15.8)135.0 (15.8) 136.1 (15.3)136.1 (15.3) 139.1 (19.7)139.1 (19.7)

Non-Non-blackblack 133.3 (14.8)133.3 (14.8) 133.8 (14.6)133.8 (14.6) 134.2 (16.7)134.2 (16.7)

DBP – mean (sd)DBP – mean (sd)BlackBlack 77.4 (10.0)77.4 (10.0) 76.3 (10.1)76.3 (10.1) 78.0 (11.4)78.0 (11.4)

Non-Non-blackblack 74.4 (9.5)74.4 (9.5) 73.6 (9.6)73.6 (9.6) 74.1 (10.1)74.1 (10.1)

∆ ∆ BP compared BP compared with with chlorthalidonechlorthalidone

BlackBlack ------ +1.1 / -1.1*+1.1 / -1.1* +4.1* / +0.6+4.1* / +0.6

Non-Non-blackblack ------ +0.5 / -0.8*+0.5 / -0.8* +0.9 / -0.3+0.9 / -0.3

* P < 0.00505/15/005/15/033

Blood Pressure at 5 Years by RaceBlood Pressure at 5 Years by Race

ALLHATALLHAT

Whites n = 2046Whites n = 2046

Blacks n = 533Blacks n = 533

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

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

Afr

ican

Am

eric

an,

%W

hit

e, %

SBP (average change)

20.0 Mean –10.5SD 13.4Lower Quartile –2.2Upper Quartile –20.0Interquartile Range 17.8

39 27 15 3 –9 –21 –33 –45 –57

15.0

10.0

5.0

0

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

20.0

15.0

10.0

5.0

0

AngioedemaAngioedema

TotalTotal BlacksBlacksNon-Non-

blacksblacks

ChlorthalidoneChlorthalidone 8 / 15,2558 / 15,255

0.1%0.1%

2 / 5,3692 / 5,369

<0.1%<0.1%

6 / 9,8866 / 9,886

0.1%0.1%

LisinoprilLisinopril 38 / 9,05438 / 9,054

0.4%0.4%

23 / 3,21023 / 3,210

0.7%0.7%

15 / 5,84415 / 5,844

0.3%0.3%

p<.001p<.001 p<.001p<.001 p=.002p=.002

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

ALLHATALLHAT

Results Of Primary Composite End Point Results Of Primary Composite End Point in LIFE By Ethnic Groupin LIFE By Ethnic Group

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

Race N Hazard Ratio

White 8503

Black 533

Hispanic 100

Asian 43

0.1 1 2 3 40.1 1 2 3 4

(23.36)(23.36)

2525

2020

1515

1010

55

000 12 24 36 48 600 12 24 36 48 60

BlacksBlacks Non-BlacksNon-Blacks

0 12 24 36 48 600 12 24 36 48 60

AtenololAtenololLosartanLosartan

Time in MonthsTime in Months

AASK Clinical Endpoint AnalysisAASK Clinical Endpoint Analysis

ACEI vs. CCBACEI vs. CCB ACEI vs. BBACEI vs. BB

OutcomeOutcome

% Risk% Risk

ReductionReduction11

95 % 95 %

Confidence Confidence IntervalInterval

% Risk% Risk

ReductionReduction

95 % 95 %

Confidence Confidence IntervalInterval

GFR event,GFR event,

ESRD or DeathESRD or Death22

38%38% (+ 14 to + 55)(+ 14 to + 55)

p<0.005p<0.005

22%22% (+ 1 to + 38)(+ 1 to + 38)

p< 0.042p< 0.042

GFR event or ESRDGFR event or ESRD33 40%40% (+ 13 to + 59)(+ 13 to + 59)

p<0.007p<0.007

22%22% (- 1 to + 41)(- 1 to + 41)

p< 0.066p< 0.066

ESRD or DeathESRD or Death44 48%48% (+ 26 to + 65)(+ 26 to + 65)

p<0.004p<0.004

21%21% (- 5 to + 40)(- 5 to + 40)

p< 0.11p< 0.11

ESRD aloneESRD alone55 59%59% (+ 34 to + 74)(+ 34 to + 74)

p< 0.001p< 0.001

23%23% (- 10 to + (- 10 to + 45)45)

p< 0.14p< 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, 288:2421Wright et al 2002; JAMA, 288:2421

ASCOT All-Cause Mortality —ASCOT All-Cause Mortality —Amlodipine versus Atenolol Amlodipine versus Atenolol

Number at riskNumber at riskAmlodipine Amlodipine perindopril perindopril 9639 9639 95449544 9441 9441 9332 9332 91679167 8078 8078Atenolol Atenolol thiazide thiazide 9618 9618 95329532 9415 9415 9261 9261 90859085 7975 7975

0.00.0 1.01.0 2.02.0 3.03.0 4.04.0 5.05.0

YearsYears

0.00.0

2.02.0

4.04.0

6.06.0

8.08.0

10.0

HR = 0.89 (0.81 0.99)HR = 0.89 (0.81 0.99)p = 0.0247p = 0.0247

%%

AmlodipineAmlodipine(No. of events 738)(No. of events 738)

AtenololAtenolol(No. of events 820(No. of events 820))

Black vs. Non-BlackAmlodipine versus Chlorthalidone

Nonfatal MI + CHD DeathNonfatal MI + CHD Death

All-Cause MortalityAll-Cause Mortality

Combined CHDCombined CHD

Combined CVDCombined CVD

StrokeStroke

End Stage Renal DiseaseEnd Stage Renal Disease

Heart FailureHeart Failure

BlackBlack

Favors Favors AmlodipinAmlodipin

ee

0.500.50 11 22

1.46 (1.24 - 1.73)1.46 (1.24 - 1.73)

1.15 (0.84 - 1.58)1.15 (0.84 - 1.58)

0.93 (0.76 - 1.14)0.93 (0.76 - 1.14)

1.06 (0.96 - 1.16)1.06 (0.96 - 1.16)

1.03 (0.91 - 1.17)1.03 (0.91 - 1.17)

0.97 (0.87 - 1.09)0.97 (0.87 - 1.09)

1.01 (0.86 - 1.18)1.01 (0.86 - 1.18)


ee

Non-BlackNon-Black

0.500.50 11 22

1.32 (1.17 - 1.49)1.32 (1.17 - 1.49)

1.08 (0.79 - 1.48)1.08 (0.79 - 1.48)

0.93 (0.79 - 1.10)0.93 (0.79 - 1.10)

1.04 (0.97 - 1.10)1.04 (0.97 - 1.10)

0.99 (0.92 - 1.07)0.99 (0.92 - 1.07)

0.94 (0.87 - 1.03)0.94 (0.87 - 1.03)

0.97 (0.87 - 1.08)0.97 (0.87 - 1.08)

Favors Favors AmlodipinAmlodipin

ee


ee

Relative Risk and 95% Confidence IntervalsRelative Risk and 95% Confidence Intervals

Wright JT et al; JAMA 2005; 293:1593Wright JT et al; JAMA 2005; 293:1593Wright JT et al; JAMA 2005; 293:1593Wright JT et al; JAMA 2005; 293:1593ALLHATALLHAT

VALUE Trial: Primary Composite VALUE Trial: Primary Composite Cardiac EndpointCardiac Endpoint

14

12

10

8

6

4

2

0

Time (months)

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

Pro

po

rtio

n o

f P

atie

nts

W

ith

Fir

st E

ven

t (%

)Valsartan-based regimen

Amlodipine-based regimen

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

Julius S et al. Julius S et al. LancetLancet. June 2004;363. June 2004;363

Number at risk

Valsartan

Amlodipine 7596

7649

7469

7459

7424

7407

7267

7250

7117

7085

6772

6732

6955

6906

6576

6536

5959

5911

3725

3765

1474

1474

6391

6349

Favours valsartanFavours valsartan Favours amlodipineFavours amlodipine

HazardHazard RatioRatioValsartan/AmlodipineValsartan/Amlodipine

Primary cardiac composite endpointPrimary cardiac composite endpoint

cardiac mortalitycardiac mortality

cardiac morbiditycardiac morbidity

All myocardial infarctionAll myocardial infarction

All congestive heart failureAll congestive heart failure

All strokeAll stroke

All-cause deathAll-cause death

New-onset diabetesNew-onset diabetes

0.50.5 11 22

VALUE Trial — Hazard Ratios VALUE Trial — Hazard Ratios for Pre-specified Analysesfor Pre-specified Analyses

Julius S et al. Julius S et al. LancetLancet. June 2004;363. June 2004;363

Od

ds

Rat

io

(exp

erim

enta

l/co

ntr

ol)

Difference in SBP (control minus experimental) mm Hg

1.50 −

1.25 −

1.00 −

0.75 −

0.50 −

0.25 −

HOPE

P < 0 .0001

-5 0 5 10 15 20 25

UKPDS C vs A

ALLHAT

CAPPPNORDILMIDAS/NICS/VHASSTOP2/CCBs HOT M vs H

INSIGHTHOT L vs HPROGRESS/Per

STOP2/ACEIs RENAAL

PATSSyst-China

ATMHMRC1MRC2

Syst-EurSHEP HEP

EWPHEPART2/SCAT

UKPDS L vs H PROGRESS/ComSTOP1

RCT70–80

STONE

All Trials

ALLHAT/Lis BlacksALLHAT/Lis ≥ 65 y

ALLHAT/LisALLHAT/Aml

CONVINCE

ANBP2DIABHYCAR

ABCD/NT L vs H

IDNT2SCOPELIFE/ALL

ELSALIFE/DM

PREVENTNICOLE

AASK L vs H

••

1.50 −

1.25 −

1.00 −

0.75 −

0.50 −

0.25 −

Difference in SBP (control minus experimental) mm Hg

-5 0 5 10 15 20 25

Recent Trials

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

Adapted from Staessen JA, Wan JG, Thijs L. Adapted from Staessen JA, Wan JG, Thijs L. J HypertensJ Hypertens. 2003;21:1055-1076. 2003;21:1055-1076

VALUE?

PPSI

Need assistance with build. Order should go: (1) both graphs (with text), (2) VALUE dotted line and label, (3) Red box

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

BP Reduction and Major BP Reduction and Major Cardiovascular OutcomesCardiovascular Outcomes

Re l

ati

ve

risk

of

stro

k e

Re l

ati

ve

risk

of

CV

D

0.25

0.50

0.75

1.00

1.25

1.50

Re l

ati

ve

risk

of

he a

rt

fai l

ure

0.25

0.50

0.75

1.00

1.25

1.50

-10 -8 -6 -4 -2 0 2 4 -10 -8 -6 -4 -2 0 2 4

Re l

ati

ve

risk

of

CH

D

StrokeStroke

CHDCHDHeart FailureHeart Failure

CVDCVD

Lancet.Lancet. 2003;362:1527-1535 2003;362:1527-1535

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

68

3

11

2428

66

411

24 26

61

612

1824

0

10

20

30

40

50

60

70

80

1 2 3 4+ ALL

Number of Prescribed Drugs

Per

cen

t

ChlorthalidoneChlorthalidone

AmlodipineAmlodipine


ALLHATALLHAT

If most hypertensive patientsIf most hypertensive patients(especially Black hypertensives)(especially Black hypertensives)require 2-3 medications for BP require 2-3 medications for BP

control, which agents should we control, which agents should we include in this mix?include in this mix?

CCB, DIURETICS, RAASICCB, DIURETICS, RAASI

Multi-Drug Therapy: Rule or Exception?Multi-Drug Therapy: Rule or Exception?

Drug Treatment StandardsDrug Treatment Standards

WHO/ISHWHO/ISH JNC 7JNC 7HAAWG HAAWG ISHIBISHIB

Initiate TX Initiate TX Uncomplicated HTN Uncomplicated HTN

140/90140/90

(previously 160/90; (previously 160/90; currently 160/100 in UK)currently 160/100 in UK)

140/90140/90 140/90140/90

Initiate Combination Initiate Combination TX- UncomplicatedTX- Uncomplicated

160/100160/100 155/100155/100

Initiate TX Initiate TX Complicated HTN & Complicated HTN & GoalGoal

130/80130/80

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

130/80130/80 130/80130/80

Initiate Combination Initiate Combination TX- Complicated HTNTX- Complicated HTN

150/90150/90 145/90145/90

SD Nesbitt 2004SD Nesbitt 2004

Drug Choice RecommendationsDrug Choice Recommendations

WHO/ISHWHO/ISH JNC 7JNC 7 HAAWG ISHIBHAAWG ISHIB

Uncomplicated Uncomplicated HTNHTN

Thiazide Thiazide as as initial agentinitial agent

Thiazide Thiazide as initial as initial agentagent

May use ACE, May use ACE, ARB, ARB, BetaBeta-B, CCB-B, CCB

May initiate May initiate diuretic, ACE, diuretic, ACE, ARB, ARB, BetaBeta-B, -B, CCBCCB

Combination TX- Combination TX- UncomplicatedUncomplicated

Not uniformly Not uniformly recommendedrecommended

Diuretic + (ACE, Diuretic + (ACE, BetaBeta-B, ARB)-B, ARB)

or or ACE/CCBACE/CCB

Diuretic + (ACE, Diuretic + (ACE, BetaBeta-B, ARB)-B, ARB)

or ACE/CCBor ACE/CCB

Complicated HTNComplicated HTN Treat according to the compelling condition similarly Treat according to the compelling condition similarly according to all guidelines.according to all guidelines.

SD Nesbitt 2004SD Nesbitt 2004

NKF Guideline 3 – Management of NKF Guideline 3 – Management of Hypertension in Diabetes and CKDHypertension in Diabetes and CKD

► Hypertensive people with diabetes and Hypertensive people with diabetes and CKD Stage 1-4 should be treated with CKD Stage 1-4 should be treated with an ACE inhibitor or an ARB, usually in an ACE inhibitor or an ARB, usually in combination with a diuretic (A)combination with a diuretic (A)

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

Combination TherapiesCombination Therapies

► -adrenergic blockers and diuretics-adrenergic blockers and diuretics

► ACE inhibitors and diureticsACE inhibitors and diuretics

► Angiotensin II receptor antagonists Angiotensin II receptor antagonists (ARBs)(ARBs)and diureticsand diuretics

► Calcium antagonists and ACE Calcium antagonists and ACE inhibitorsinhibitors

► Calcium antagonists and ARBsCalcium antagonists and ARBs

► Renin inhibitors and diureticsRenin inhibitors and diuretics

Combination Drug Therapy InCombination Drug Therapy InHTN — AdvantagesHTN — Advantages

► Improved blood pressure controlImproved blood pressure control Uses different approachesUses different approaches Blocking counter-regulatory Blocking counter-regulatory

mechanismsmechanisms Ease of titration to BP goalEase of titration to BP goal

► Reduce side effectsReduce side effects(less dosage requirement)(less dosage requirement)

► Improve protection of target organsImprove protection of target organs

Combination Drug TherapyCombination Drug TherapyIn HypertensionIn Hypertension

CONCLUSIONSCONCLUSIONS

► BP lowering reduces BP-related outcomesBP lowering reduces BP-related outcomes

► To achieve BP goals will require at least 2, and To achieve BP goals will require at least 2, and usually more, BPusually more, BP drugs, especially in Black drugs, especially in Black hypertensive patientshypertensive patients

► Clinical outcome data are available for CCBs, Clinical outcome data are available for CCBs, diuretics (thiazide-type), and RAS inhibitors (ACEIs diuretics (thiazide-type), and RAS inhibitors (ACEIs and ARBs) as initial Rxand ARBs) as initial Rx

► Differences between guideline recommendations for Differences between guideline recommendations for treatment are minor and all focus on achieving BP treatment are minor and all focus on achieving BP goal and need for multi-drug regimensgoal and need for multi-drug regimens

► With available agents, BP goals can be achievedWith available agents, BP goals can be achieved

The Evolving Landscape ofThe Evolving Landscape ofAntihypertensive TherapyAntihypertensive Therapy

Direct Renin Inhibition, Combination Therapy, and Direct Renin Inhibition, Combination Therapy, and Implications for African American and otherImplications for African American and other

Ethnic PopulationsEthnic Populations

Shawna D. Nesbitt MD, MSShawna D. Nesbitt MD, MSAssociate Professor of Internal MedicineAssociate Professor of Internal Medicine

Department of MedicineDepartment of MedicineUniversity of Texas SouthwesternUniversity of Texas Southwestern

Dallas, TexasDallas, Texas

Emerging Therapies— Focus on RASEmerging Therapies— Focus on RAS

*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, -blockers, CCBs, ACEIs, or ARBs. ‡To achieve BP goals more expeditiously, initiate low-dose combination therapy with any of the following combinations: -blocker/diuretic, ACEI/diuretic, ACEI inhibitor/CCB, or ARB/diuretic. §Consider specific clinical indications when selecting agents.

Patient with elevated BP

If BP <145/90 mmHg, monotherapy or

combination therapy including a RAS blocker§

If BP 145/90 mmHg, combination therapy

including a RAS blocker§


increase dose



Diabetes/nondiabetic renal disease with proteinuria >1 g/24 h*

Goal BP: <130/80 mmHg

Not at BP goal?Intensify lifestyle changes AND


increase dose

If BP 155/100 mmHg, combination therapy‡

If BP <155/100 mmHg, monotherapy†



Uncomplicated hypertensionGoal BP: <140/90 mmHg

Not at BP goal?Intensify lifestyle changes AND

ISHIB Consensus Statement: Management ISHIB Consensus Statement: Management of Hypertension in African Americansof Hypertension in African Americans

Douglas JG et al. Arch Intern Med. 2003;163:525–541

Not at Goal Blood Pressure (<140/90 mm Hg) Not at Goal Blood Pressure (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease)(<130/80 mm Hg for those with diabetes or chronic kidney disease)

Not at Goal Blood Pressure (<140/90 mm Hg) Not at Goal Blood Pressure (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease)(<130/80 mm Hg for those with diabetes or chronic kidney disease)

Initial Drug ChoicesInitial Drug Choices

Drug(s) for the Compelling Drug(s) for the Compelling Indications Indications

Other antihypertensive drugs Other antihypertensive drugs ((diuretic, diuretic, ACEI, ARB,, BB, CCB BB, CCB) )

as neededas needed

Drug(s) for the Compelling Drug(s) for the Compelling Indications Indications

Other antihypertensive drugs Other antihypertensive drugs ((diuretic, diuretic, ACEI, ARB,, BB, CCB BB, CCB) )

as neededas needed


Lifestyle ModificationsLifestyle Modifications



Optimize Dosages or Add Additional Drugs Optimize Dosages or Add Additional Drugs Until Goal Blood Pressure Is AchievedUntil Goal Blood Pressure Is Achieved

Consider consultation with hypertension specialistConsider consultation with hypertension specialist

Optimize Dosages or Add Additional Drugs Optimize Dosages or Add Additional Drugs Until Goal Blood Pressure Is AchievedUntil Goal Blood Pressure Is Achieved

Consider consultation with hypertension specialistConsider consultation with hypertension specialist

Stage 2 HypertensionStage 2 Hypertension (SBP (SBP 160 or DBP 160 or DBP 100 mm Hg) 100 mm Hg)

2-drug combination2-drug combination for most for most (usually thiazide-type diuretic and (usually thiazide-type diuretic and

ACEI, ARB, BB, or CCB) BB, or CCB)

Stage 2 HypertensionStage 2 Hypertension (SBP (SBP 160 or DBP 160 or DBP 100 mm Hg) 100 mm Hg)

2-drug combination2-drug combination for most for most (usually thiazide-type diuretic and (usually thiazide-type diuretic and

ACEI, ARB, BB, or CCB) BB, or CCB)

Stage 1 HypertensionStage 1 Hypertension(SBP 140-159 or DBP 90-99 mm (SBP 140-159 or DBP 90-99 mm

Hg)Hg) Thiazide-type diureticsThiazide-type diuretics for most for most

May consider May consider ACEI, ARB, BB, , BB, CCB, CCB,

or combinationor combination

Stage 1 HypertensionStage 1 Hypertension(SBP 140-159 or DBP 90-99 mm (SBP 140-159 or DBP 90-99 mm

Hg)Hg) Thiazide-type diureticsThiazide-type diuretics for most for most

May consider May consider ACEI, ARB, BB, , BB, CCB, CCB,

or combinationor combination


JNC 7 Algorithm for TreatmentJNC 7 Algorithm for Treatmentof Hypertensionof Hypertension

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

Published Guidelines Have SetPublished Guidelines Have SetLower Treatment GoalsLower Treatment Goals

Chobanian AV et al. Chobanian AV et al. JAMAJAMA. 2003;289:2560–2572. . 2003;289:2560–2572. Arauz-Pacheco C et al. Arauz-Pacheco C et al. Diabetes CareDiabetes Care. . 2003;26(suppl):S80–S82.2003;26(suppl):S80–S82. Douglas JG et al. Douglas JG et al. Arch Intern Med.Arch Intern Med. 2003;163:525–541. Bakris GL et al. 2003;163:525–541. Bakris GL et al. Am J Am J Kidney Dis.Kidney Dis. 2000;36:646–661 2000;36:646–661

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).

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).

<140/90

<130/80

<130/80

<130/80

mmHg

Essential hypertension

Diabetes mellitus

Chronic renal disease

High-risk* hypertension

Condition

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

JNC-7 Compelling IndicationsJNC-7 Compelling Indications

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

CHF

Post MI

CAD risk

DM

Chronic kidneydisease

2° strokeprevention

BB

ACEI

ARB

CCB

AADiuretic

The JNC 7 Report. The JNC 7 Report. JAMA.JAMA. 2003;289:2560 2003;289:2560

Mortality From High Blood Pressure Mortality From High Blood Pressure Higher in African AmericansHigher in African Americans

Overall Mortality Rates From Causes Related to Hypertension, 2003Overall Mortality Rates From Causes Related to Hypertension, 2003**

*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.

Mo

rtal

ity

Rat

e, %

Mo

rtal

ity

Rat

e, %

African AmericanAfrican AmericanFemaleFemale MaleMale FemaleFemale

2020

1010

3030

40405050

49.749.7

14.914.9

40.840.8

14.514.5

00

6060

MaleMaleWhiteWhite

In hypertensive African Americans, In hypertensive African Americans, 30% and 30% and 20% of all deaths in20% of all deaths inmen and women, respectively, may be due to high blood pressure.men and women, respectively, may be due to high blood pressure.

Adapted from Thom T et al. Adapted from Thom T et al. Circulation. Circulation. 2006;113:e85–e1512006;113:e85–e151

RAS Blockade inRAS Blockade inAfrican-American PatientsAfrican-American Patients

► Drugs that block the renin-angiotensin system Drugs that block the renin-angiotensin system (RAS) provide less antihypertensive efficacy (RAS) provide less antihypertensive efficacy than in white patients*than in white patients*

► Physiologic basis for this proposition:Physiologic basis for this proposition: Lower levels of plasma renin activity (PRA)Lower levels of plasma renin activity (PRA) Relative expansion of plasma volumeRelative expansion of plasma volume Higher prevalence of salt dependencyHigher prevalence of salt dependency Higher Na+ and Ca+, may suppress PRA†Higher Na+ and Ca+, may suppress PRA†

* Weir MR et al. * Weir MR et al. Hypertension. Hypertension. 1995;26:124-1301995;26:124-130††Douglas JG. Unpublished dataDouglas JG. Unpublished data‡‡Agodoa LY et al. Agodoa LY et al. JAMAJAMA. 2001;285:2719-2728. 2001;285:2719-2728

Benefits of Renin System (RS)Benefits of Renin System (RS)Suppression to DateSuppression to Date

Clinical Trial DataClinical Trial Data

Renin Angiotensin SystemRenin Angiotensin System

Relative Risk ReductionRelative Risk Reduction With With Ramipril vs Amlodipine Besylate: AASKRamipril vs Amlodipine Besylate: AASK

RamiprilRamiprilAmlodipine besylateAmlodipine besylate

EventsEventsperper

person-person-yryr

GFRGFR00

0.010.01

0.020.02

0.030.03

0.040.04

0.050.05

0.060.06

0.070.07

0.080.08

ESRDESRD GFR, ESRD,GFR, ESRD,or deathor death

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

RRR=41%RRR=41%PP=0.03=0.03

RRR=44%RRR=44%PP=0.01=0.01

RRR=38%RRR=38%PP=0.005=0.005

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

Relative Risk (95% CI)Relative Risk (95% CI)

0.5 1 1.5

Total Total

Age <65Age <65

Age Age 6565

MenMen

WomenWomen

BlackBlack

Nonblack Nonblack

Diabetic Diabetic

NondiabeticNondiabetic

Favors Favors LisinoprilLisinopril

Favors Favors ChlorthalidoneChlorthalidone

0.99 (0.91-1.08)0.99 (0.91-1.08)

0.95 (0.81-1.12)0.95 (0.81-1.12)

1.01 (0.91-1.12)1.01 (0.91-1.12)

0.94 (0.85-1.05)0.94 (0.85-1.05)

1.06 (0.92-1.23)1.06 (0.92-1.23)

1.10 (0.94-1.28)1.10 (0.94-1.28)

0.94 (0.85-1.05)0.94 (0.85-1.05)

1.00 (0.87-1.14)1.00 (0.87-1.14)

0.99 (0.88-1.11)0.99 (0.88-1.11)

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

1.1. Yusuf S et al. Yusuf S et al. N Engl J MedN Engl J Med. 2000;342:145-153 . 2000;342:145-153 2.2. The CONSENSUS Trial Study GroupThe CONSENSUS Trial Study Group3.3. N Engl J MedN Engl J Med. 1987;316:1429-1435. 1987;316:1429-1435

Re

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ve

Ris

k R

ed

uc

tio

n,

%

-40

-30

-20

-10

0

ACEIs and ARBs Yield Reduction in ACEIs and ARBs Yield Reduction in Cardiovascular Morbidity and MortalityCardiovascular Morbidity and Mortality

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.

3.3. SOLVD Investigators. SOLVD Investigators. N Engl J Med. N Engl J Med. 1991;325:293-302 1991;325:293-302 4.4. Granger CB et al. Granger CB et al. LancetLancet. 2003;362:772-776 . 2003;362:772-776 5.5. Dahlöf B et al.Dahlöf B et al. Lancet. Lancet. 2002;359:995-1003 2002;359:995-1003

HOPE1 SOLVD3CONSENSUS2

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

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

Placebo (n=1284)Enalapril (n=1285)

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

Mortality in chronic HF

Total mortalityin severe HF

ACEIs

22% P<.001 27%

P=.003

16%P=.003

LIFE5

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

CHARM-Alternative4

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

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

Placebo (n=1015)Candesartan (n=1013)

ARBs

13% P=.021

23% P=.0004

Reduction of Progressive Reduction of Progressive Nephropathy with ARB: IDNTNephropathy with ARB: IDNT

Irbesartan Irbesartan vs Controlvs Control

Irbesartan vs Irbesartan vs AmlodipineAmlodipine

Amlodipine Amlodipine vs Controlvs Control

Doubling Cr, ESRD, or Death (%)

2020**

2323****

44nsns

Doubling of Cr, (%)

3333****

3737******

66nsns

ESRD (%) 2323nsns

2323nsns

00nsns

Lewis EJ Lewis EJ NEJM NEJM 2001;345:851 2001;345:851

* p< .05** p< .01*** p<.001

DDiabetics iabetics EExposed to xposed to TTelmisartan elmisartan aand nd EnalaprEnalaprilil Study (DETAIL) Study (DETAIL)

► 250 Type 2 diabetes, hypertension and 250 Type 2 diabetes, hypertension and nephropathynephropathy

► Forced titration of telmisartan (40-80 mg) and Forced titration of telmisartan (40-80 mg) and enalapril (10-20 mg) enalapril (10-20 mg)

► Primary outcome was a change in glomerular Primary outcome was a change in glomerular filtration rate (GFR) after 5 yearsfiltration rate (GFR) after 5 years

Barnett A et al Barnett A et al N Engl J MedN Engl J Med 2004 2004

14.914.917.917.9

Decrease in GFR

p=ns

enalapril telmisartan

mL

/min

Death Rate

enalapril telmisartan

Pe

rce

nt 35-50%35-50%

expectedrate over 5 years

5%5% 5%5%

TRial Of Preventing HYpertension TRial Of Preventing HYpertension (TROPHY)(TROPHY)

0 1 2 3 4Years in study

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

% C

um

ula

tive

in

cid

ence Candesartan

Placebo

Candesartan 391 356 309 191 128

Placebo 381 269 184 118 85

Numbers under the graph refer to hypertension-free individuals

2 YearsRR ↓66%AR ↓ 26%

4 YearsRR ↓15.8AR ↓ 9.6

Julius S, Nesbitt SD et al Julius S, Nesbitt SD et al NEJMNEJM 2006;354 2006;354

Kaplan-Meier Curves of Clinical Hypertension in the Two GroupsKaplan-Meier Curves of Clinical Hypertension in the Two GroupsKaplan-Meier Curves of Clinical Hypertension in the Two GroupsKaplan-Meier Curves of Clinical Hypertension in the Two Groups

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

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

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

Pro

po

rtio

n R

each

ing

En

dp

oin

t, %

30

10

20

0

25

0 6 12 18

15

5

24 30 36

Combination (N=88)

P=.02

Losartan (N=89)

Trandolapril (N=86)

COOPERATE Findings

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

1°*endpoint

‒10NS

ASCOT: Blood Pressure ResultsASCOT: Blood Pressure Results

‒40

‒30

‒20

‒10

0

Change(%)

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

All-causemortality

‒15P<0.005

‒26P=0.0017

CVmortality

‒16P<0.0001

All CVevents +revasc

‒23P=0.0007

Fatal +nonfatalstroke

New casesof diabetes

mellitus

‒32P<0.0001

Amlodipine Besylate/Perindopril vs Atenolol/BendroflumethiazideAmlodipine Besylate/Perindopril vs Atenolol/BendroflumethiazideAmlodipine Besylate/Perindopril vs Atenolol/BendroflumethiazideAmlodipine Besylate/Perindopril vs Atenolol/Bendroflumethiazide

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

Renin System Suppression by ACE Renin System Suppression by ACE Inhibitors and ARBsInhibitors and ARBs

► Renin System suppression with ACEIs and ARBs has Renin System suppression with ACEIs and ARBs has demonstrated significant clinical benefitdemonstrated significant clinical benefit

► Renin System suppression with ACEIs, ARBs, and even Renin System suppression with ACEIs, ARBs, and even combinations of ACEI + ARB therapy may elevate key combinations of ACEI + ARB therapy may elevate key components and processes; such as PRA, Ang I, and Ang II components and processes; such as PRA, Ang I, and Ang II with ARB usage and PRA and Ang I with ACEI usagewith ARB usage and PRA and Ang I with ACEI usage Increased peptide levels have not been shown to overcome the Increased peptide levels have not been shown to overcome the

blood pressure-lowering effect of these agentsblood pressure-lowering effect of these agents

► Consequently, benefits have not been demonstrated for all Consequently, benefits have not been demonstrated for all endpoints and in all patientsendpoints and in all patients

► Could even greater clinical benefits be expected from more Could even greater clinical benefits be expected from more complete Renin System suppression? complete Renin System suppression?

Summary

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockerACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker

Renin System (RS) Suppression Renin System (RS) Suppression via via

Direct Renin InhibitionDirect Renin Inhibition

Renin SuppressionRenin SuppressionDevelopment of Direct Renin Inhibitors Development of Direct Renin Inhibitors

(DRIs)(DRIs)

Direct Renin Inhibition: What Do We Know?Direct Renin Inhibition: What Do We Know?

Plasma Renin Activity (PRA)Plasma Renin Activity (PRA)

► PRA is a surrogate measure of renin activityPRA is a surrogate measure of renin activity Indicates the capacity of circulating renin to form Ang I (and Indicates the capacity of circulating renin to form Ang I (and

ultimately Ang II)ultimately Ang II)

► PRA is independently associated with the occurrence PRA is independently associated with the occurrence of cardiovascular disease among hypertensive of cardiovascular disease among hypertensive patientspatients11

A 25% increase in the risk of myocardial infarction for every 2 A 25% increase in the risk of myocardial infarction for every 2 ng/mL/h increase in PRAng/mL/h increase in PRA11

► Increased PRA activates the RAAS leading to Increased PRA activates the RAAS leading to increased generation of Ang II. Ang II is important in increased generation of Ang II. Ang II is important in the generation of hypertension and both the short-the generation of hypertension and both the short-term and long-term effects leading to organ damageterm and long-term effects leading to organ damage22

1.1. Alderman MH, Alderman MH, et alet al. 1997. 19972. Burnier M, 2. Burnier M, et alet al. 2000. 2000

Ang I

AngiotensinogenAngiotensinogen

Crystal Structure of ReninCrystal Structure of Renin

Renin Cleaves its Substrate, Angiotensinogen, to Form ANG IRenin Cleaves its Substrate, Angiotensinogen, to Form ANG I

Adapted from Rahuel J et al. Adapted from Rahuel J et al. J Struct BiolJ Struct Biol. 1991;107:227-236. 1991;107:227-236

Only Direct Renin Inhibition Inhibits Only Direct Renin Inhibition Inhibits

the Entire Renin Systemthe Entire Renin System1-61-6

Class

DiureticDiuretic

ACEIACEI

ARBARB

Direct Renin Inhibitor (DRI)Direct Renin Inhibitor (DRI)

PRA Ang I Ang II

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.

1. Johnston CI. Blood Pressure. 2000;9(suppl 1):9-132. Widdop RE et al. Hypertension. 2002;40:516-5203. Fabiani ME et al. In: Angiotensin II Receptor Antagonists

2001:263-278

4. Waybill MM et al. J Vasc Interv Radiol. 2003;14:961-9755. Reid IA. Adv Physiol Ed. 1998;20:S236-S2456. Lin C et al. Am Heart J. 1996;131:1024-1034

Renin System Suppression via DirectRenin System Suppression via DirectRenin InhibitionRenin Inhibition1-31-3

► Targets the point of activation in the Renin SystemTargets the point of activation in the Renin System

► Binds to renin, neutralizing its ability to convert angiotensinogen Binds to renin, neutralizing its ability to convert angiotensinogen to Ang Ito Ang I

► Reduces plasma renin activityReduces plasma renin activity PRA is a marker for Renin System activity/stimulationPRA is a marker for Renin System activity/stimulation Elevated levels of prorenin have been shown with direct renin Elevated levels of prorenin have been shown with direct renin

inhibition; potential physiological effects are being investigated in inhibition; potential physiological effects are being investigated in animal studiesanimal studies

► Decreases formation of Ang I and Ang IIDecreases formation of Ang I and Ang II Ang I unavailable for ACE and non-ACE conversion to Ang IIAng I unavailable for ACE and non-ACE conversion to Ang II Ang II unavailable to stimulate AT receptorsAng II unavailable to stimulate AT receptors Ang II unavailable for conversion to Ang subtypes Ang II unavailable for conversion to Ang subtypes

[eg, Ang (2-8), also called Ang III][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 An Efficient Strategy to Achieve Interruption of the Renin System Is Direct Renin InhibitionRenin System Is Direct Renin Inhibition1-31-3

*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.

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)*

AT1 Receptor

Feedback Loop

Ang I

Angiotensinogen

Ang II

Renin

ARBsACE

ACEIs

Adapted from:Stanton A. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10Kelly DJ et al. Hypertension. 2005;46:471-472 Fisher NDL et al. J Am Soc Nephrol. 2005;16:592-599

100

0.1

10

1

Treatment day 8

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

PRA (ng/mL/h)

0Time (hours)

Aliskiren 40 mg

Aliskiren 80 mg

Aliskiren 160 mg

248 102 64

Aliskiren 640 mg

Enalapril 20 mg

Placebo

Nussberger J, et al. Hypertension. 2002;39:e1e8

0

8

4

2

6

Aliskiren Reduces PRA asAliskiren Reduces PRA asCompared to an ARBCompared to an ARB

*p<0.05 vs aliskiren 150 mg + valsartan 80 mg†p<0.05 vs aliskiren 300 mg; ‡p<0.05 vs valsartan 160 mgn=12 mildly sodium-depleted normotensive subjects

PRA (ng Ang I/mL/h)

0Time (hours)

48242 64 12 18

Aliskiren 150 mg + valsartan 80 mg

Aliskiren 300 mg

Placebo

Valsartan 160 mg

30

* † ‡

*

* †

* †

* *

* †

† ‡ † ‡

1

Azizi M, et al. J Am Soc Nephrol 2004;15:3126–3133

0

−10

−6

−2

−12

−4

−8

−14

−16

Aliskiren Offers Dose-dependent Aliskiren Offers Dose-dependent Reductions In SeDBPReductions In SeDBP

Mean SeDBP (mmHg)

n=166n=166n=169n=169n=172n=172n=165n=165

PlaceboAliskiren150 mg

Aliskiren300 mg

Aliskiren600 mg

**

−−4.94.9

−−10.310.3−−11.111.1

−−12.512.5

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

**** §§

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

0

−10

−6

−2

−12

−4

−8

−14

−16

Aliskiren Offers Dose-dependent Aliskiren Offers Dose-dependent Reductions in SeSBPReductions in SeSBP

Mean SeSBP (mmHg)

n=166n=166n=169n=169n=172n=172n=165n=165

PlaceboAliskiren150 mg

Aliskiren300 mg

Aliskiren600 mg

**

−−3.83.8

−−14.714.7 −−15.815.8

* 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

−−13.013.0

Clinical Trials: Clinical Trials: AliskAliskiren Combinationiren Combination

-25

-20

-15

-10

-5

0

Placebo Aliskiren 0 mg Aliskiren 75 mg

Aliskiren 150 mg Aliskiren 300 mg

PlaceboPlacebo0 mg0 mgHCTZHCTZ

6.25 mg6.25 mgHCTZHCTZ


25 mg25 mgHCTZHCTZ

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

Mea

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Bas

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SB

P (

mm

Hg

)B

asel

ine

in S

BP

(m

m H

g)

Clinical Trials: Clinical Trials: Aliskerin Aliskerin in Combinationin Combination

-25

-20

-15

-10

-5

0

Placebo Aliskiren 0 mg Aliskiren 75 mg

Aliskiren 150 mg Aliskiren 300 mg

PlaceboPlacebo0 mg0 mgHCTZHCTZ



25 mg25 mgHCTZHCTZ

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

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DB

P (

mm

Hg

)B

asel

ine

in D

BP

(m

m H

g)

Clinical Trials: Clinical Trials: AliskireAliskiren n in Combinationin Combination

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

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

Week 4Week 4Week 4Week 4 Week 8Week 8Week 8Week 8

PlaceboPlaceboPlaceboPlacebo PlaceboPlaceboPlaceboPlaceboAliskirenAliskiren150 mg150 mg

AliskirenAliskiren150 mg150 mg



ValsartanValsartan160 mg160 mg




AliskirenAliskiren150 mg + 150 mg + ValsartanValsartan160 mg160 mg




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P (

mm

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)B

asel

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BP

(m

m H

g)

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Bas

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SB

P (

mm

Hg

)B

asel

ine

in S

BP

(m

m H

g)

Clinical Trials: Clinical Trials: Aliskiren Aliskiren in Combinationin Combination

-14

-12

-10

-8

-6

-4

-2

0

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

Week 4Week 4Week 4Week 4 Week 8Week 8Week 8Week 8

PlaceboPlaceboPlaceboPlacebo PlaceboPlaceboPlaceboPlaceboAliskirenAliskiren150 mg150 mg












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P (

mm

Hg

)B

asel

ine

in D

BP

(m

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g)

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BP

(m

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g)

Conclusions and SummaryConclusions and Summary

► Hypertension is prevalent, underdiagnosed, and Hypertension is prevalent, underdiagnosed, and inadequately treated. Many patients don’t get to BP goalinadequately treated. Many patients don’t get to BP goal

► Treating hypertension involves more than BP reduction; Treating hypertension involves more than BP reduction; sustained 24-hour control and end-organ protection are sustained 24-hour control and end-organ protection are importantimportant

► Inappropriate activation of the Renin System is a central Inappropriate activation of the Renin System is a central component in the development of hypertension and component in the development of hypertension and cardiovascular and renal diseasecardiovascular and renal disease

► Some agents that suppress the Renin System have unique Some agents that suppress the Renin System have unique end-organ protection benefits beyond BP reductionend-organ protection benefits beyond BP reduction

► Targeting the Renin System at the point of activation, by direct Targeting the Renin System at the point of activation, by direct renin inhibition, provides inhibition of the entire Renin Systemrenin inhibition, provides inhibition of the entire Renin System

► Future clinical trials are needed to elucidate additional benefits Future clinical trials are needed to elucidate additional benefits of direct renin inhibitionof direct renin inhibition

ishib 2007 innovating vascular health: practical applications to clinical practice critical...

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