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ISHIB 2007 Innovating Vascular Health: Practical Applications to Clinical Practice Critical Challenges in Cardiovascular Disease Program Chairwoman Shawna.

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Presentation on theme: "ISHIB 2007 Innovating Vascular Health: Practical Applications to Clinical Practice Critical Challenges in Cardiovascular Disease Program Chairwoman Shawna."— Presentation transcript:

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2 ISHIB 2007 Innovating Vascular Health: Practical Applications to Clinical Practice Critical Challenges in Cardiovascular Disease Program Chairwoman Shawna D. Nesbitt, MD, MS Associate Professor Department of Internal Medicine Division of Hypertension University of Southwestern Texas Medical School Medical School Dallas, TX

3 CME-accredited symposium jointly sponsored by the American Society of Hypertension and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Novartis Pharmaceuticals Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview

4 Program 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 pressure, and the importance of treating both systolic and diastolic blood pressure abnormalities. Identify the importance of early treatment of patients with high blood pressure, and the importance of treating both systolic and diastolic blood pressure abnormalities. Implement clinical strategies that help patients achieve blood pressure goals as quickly as possible, using combination therapy, when indicated. Implement clinical strategies that help patients achieve blood pressure goals as quickly as possible, using combination therapy, when indicated. Identify prescribing strategies that reduce side effects and increase the likelihood of adherence to an antihypertensive drug regimen. Identify prescribing strategies that reduce side effects and increase the likelihood of adherence to an antihypertensive drug regimen. Characterize and distinguish among safety profiles of and efficacy characteristics of antihypertensive agents used in the African American population. Characterize and distinguish among safety profiles of and efficacy characteristics of antihypertensive agents used in the African 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 pressure, and the importance of treating both systolic and diastolic blood pressure abnormalities. Identify the importance of early treatment of patients with high blood pressure, and the importance of treating both systolic and diastolic blood pressure abnormalities. Implement clinical strategies that help patients achieve blood pressure goals as quickly as possible, using combination therapy, when indicated. Implement clinical strategies that help patients achieve blood pressure goals as quickly as possible, using combination therapy, when indicated. Identify prescribing strategies that reduce side effects and increase the likelihood of adherence to an antihypertensive drug regimen. Identify prescribing strategies that reduce side effects and increase the likelihood of adherence to an antihypertensive drug regimen. Characterize and distinguish among safety profiles of and efficacy characteristics of antihypertensive agents used in the African American population. Characterize and distinguish among safety profiles of and efficacy characteristics of antihypertensive agents used in the African American population.

5 Program Educational Objectives Recognize markers of target organ damage and learn which antihypertensive agents are useful for preventing end organ complications such as CV disease and diabetic renal disease. Recognize markers of target organ damage and learn which antihypertensive agents are useful for preventing end organ complications such as CV disease and diabetic renal disease. Manage hypertension as a systematic disease, with multiple manifestations, and associations, including metabolic syndrome and associated risk factors. Manage hypertension as a systematic disease, with multiple manifestations, and associations, including metabolic syndrome and associated risk factors. Address complications linked to healthcare disparities observed in specific patient populations, and the importance of providing access, treatment, and monitoring of patients with multiple risk CV risk factors. Address complications linked to healthcare disparities observed in specific patient populations, and the importance of providing access, treatment, and monitoring of patients with multiple risk CV risk factors. Manage African American patients with features of the metabolic syndrome, and its implications for multiple risk factor management Manage African American patients with features of the metabolic syndrome, and its implications for multiple risk factor management Recognize markers of target organ damage and learn which antihypertensive agents are useful for preventing end organ complications such as CV disease and diabetic renal disease. Recognize markers of target organ damage and learn which antihypertensive agents are useful for preventing end organ complications such as CV disease and diabetic renal disease. Manage hypertension as a systematic disease, with multiple manifestations, and associations, including metabolic syndrome and associated risk factors. Manage hypertension as a systematic disease, with multiple manifestations, and associations, including metabolic syndrome and associated risk factors. Address complications linked to healthcare disparities observed in specific patient populations, and the importance of providing access, treatment, and monitoring of patients with multiple risk CV risk factors. Address complications linked to healthcare disparities observed in specific patient populations, and the importance of providing access, treatment, and monitoring of patients with multiple risk CV risk factors. Manage African American patients with features of the metabolic syndrome, and its implications for multiple risk factor management Manage African American patients with features of the metabolic syndrome, and its implications for multiple risk factor management

6 Program Faculty Program Chairwoman Shawna D. Nesbitt, MD, MS Associate Professor Department of Internal Medicine Division of Hypertension University of Southwestern Texas Medical School Medical School Dallas, Texas Ken Jamerson, MD Professor of Medicine Cardiovascular Medicine University of Michigan Health System System Ann Arbor, Michigan Program Chairwoman Shawna D. Nesbitt, MD, MS Associate Professor Department of Internal Medicine Division of Hypertension University of Southwestern Texas Medical School Medical School Dallas, Texas Ken Jamerson, MD Professor of Medicine Cardiovascular Medicine University of Michigan Health System System Ann Arbor, Michigan Jackson T. Wright, Jr., MD, PhD, FACP Professor of Medicine Program Director, General Clinical Research Center Research Center Case Western Reserve University Director, Clinical Hypertension Program University Hospitals of Cleveland Chief, Case Western Reserve University Hypertension Section University Hypertension Section (Louis Stokes VAMC) (Louis Stokes VAMC) Cleveland, Ohio Jackson T. Wright, Jr., MD, PhD, FACP Professor of Medicine Program Director, General Clinical Research Center Research Center Case Western Reserve University Director, Clinical Hypertension Program University Hospitals of Cleveland Chief, Case Western Reserve University Hypertension Section University Hypertension Section (Louis Stokes VAMC) (Louis Stokes VAMC) Cleveland, Ohio

7 Faculty Disclosures Shawna D. Nesbitt, MD, MS Grant/Research Support: Pfizer Consultant: Novartis, BMS Speakers Bureau: Boerhinger Ingelheim, Novartis, AstraZeneca Ken Jamerson, MD Research Support: NIH, NHLBI, NIH, NIDDK, Novartis, King Pharmaceuticals Consultant: MSD, Pfizer, Novartis, Speedel Jackson T. Wright, Jr., MD, PhD, FACP Research Support: Glaxo Smith Kline, Novartis Consultant: Novartis, MSD, Sanofi, BMS, Pfizer, NIH Honoraria: Novartis, Biovail, Sanofi, Pfizer Shawna D. Nesbitt, MD, MS Grant/Research Support: Pfizer Consultant: Novartis, BMS Speakers Bureau: Boerhinger Ingelheim, Novartis, AstraZeneca Ken Jamerson, MD Research Support: NIH, NHLBI, NIH, NIDDK, Novartis, King Pharmaceuticals Consultant: MSD, Pfizer, Novartis, Speedel Jackson T. Wright, Jr., MD, PhD, FACP Research Support: Glaxo Smith Kline, Novartis Consultant: Novartis, MSD, Sanofi, BMS, Pfizer, NIH Honoraria: Novartis, Biovail, Sanofi, Pfizer

8 Program Agenda 7:15 – 7:30 PM 7:15 – 7:30 PM Introduction and Overview The Current Landscape of Cardiovascular Risk Management in African Americans Where Co-morbidity Matters: The Evolving Relationship Between Risk Factors, Diabetes, Hypertension, and Vascular Complications Shawna D. Nesbitt, MD, MS 7:30 – 8:00 PM Are We in Control? An Epidemiological Examination of How Well We Are Managing Hypertension in Ethnic Minority Populations: The Importance of Early Risk Identification and InterventionGetting to Goal and Staying There Ken Jamerson, MD

9 Program Agenda 8:00 – 8:25 PM HypertensionA Systemic Disease Requiring Systematic Approaches to Therapy: Recent Clinical Practice Recommendations Focusing on Combination Therapy in Difficult- to-Treat Patient Populations with High Blood Pressure and Compelling Conditions Jackson T. Wright, Jr., MD, PhD, FACP Jackson T. Wright, Jr., MD, PhD, FACP 8:25 – 8:55 PM The Evolving Landscape of Antihypertensive Therapy: Direct Renin Inhibition, Combination Therapy, and Implications for African American and Other Ethnic Populations Shawna D. Nesbitt, MD, MS 8:55 PM 8:55 PM Questions and Interactions with the Faculty

10 The Current Landscape of Cardiovascular Risk Management in African Americans Where Co-morbidity Matters The Evolving Relationship Between Risk Factors, Diabetes, Hypertension, And Vascular Complications Shawna D. Nesbitt MD, MS Associate Professor of Internal Medicine University of Texas Southwestern Dallas, Texas Introduction and Overview

11 Changing Trends Hispanics are the fastest- growing segment of the population, and now account for 13% U.S., as do African Americans. The U.S. Asian population currently consists of 10.6 million people, and represents 4% U.S.,; however, this population group is expected to triple in size by The U.S. Population is Becoming Increasingly Diverse Adapted from U.S. Census Bureau, Table 1a. Accessed Dec. 1, 2006.

12 Southern U.S. Has the Highest Concentration of African-Americans 25.0 to to to to 4.9 People indicating exactly one race, Black or African American, as a percent of total population by state Adapted from U.S. Census Bureau, 2002 Redistricting Data (PL ) Summary File

13 Non-Hispanic Black FM Estimated Rates of US Adults With Hypertension by Sex, Race, and Ethnicity NHANES to Fields et al. Hypertension. 2004;44: Hajjar and Kotchen. JAMA. 2003;290:199–206 All Mexican American Non-Hispanic White Hypertensive Adults (Rate, Percent ± SE) FMFM % age adj. increase7.2% age adj. increase

14 Hypertension Treatment and Control Rates by Race/Ethnicity: NHANES 2000 Hajjar and Kotchen. JAMA. 2003;290:199–206. % Treatment Control African Americans* Whites*Mexican Americans Percentage increase from 1988 to *Non-Hispanic.

15 Mortality From High Blood Pressure Higher in African Americans Overall 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. Mortality Rate, % African American FemaleMaleFemale Male White In hypertensive African Americans, 30% and 20% of all deaths in men and women, respectively, may be due to high blood pressure. Adapted from Thom T et al. Circulation. 2006;113:e85–e151.

16 *Includes those 17 years of age with diagnosed and undiagnosed hypertension. National Center for Health Statistics. NHANES (CD-ROM); NHANES III. % Not at Goal BP SystolicDiastolic Patient Type (mm Hg) BP BP % Not at Goal BP SystolicDiastolic Patient Type (mm Hg) BP BP Total hypertensives<140/9057%26% African American<140/9060%32% Mexican American/ Hispanic <140/9063%30% Older patients ( 60 years)<140/9071%9% Symptomatic CHD <140/9047%4% Patients with diabetes <130/8581%24% NHANES ( ) Patients Not at JNC VI BP Goals

17 Risk-Factor Clustering by Race and Sex Stone et al JAMA. 1996;275: White womenAfrican-American womenWhite menAfrican-American men Percentage

18 Obesity (BMI 30 kg/m 2 ) Population (%) *Jan–June * * Diagnosed diabetes CDC NHIS; Obesity and Diabetes Among US Adults: Growing prevalence +11.9% +11.5%

19 American Indians/ Alaska Natives Age-Adjusted Prevalence of Diabetes* by Race/Ethnicity in the US Percent Hispanic/Latino Americans Non-Hispanic Blacks Non-Hispanic Whites *In people 20+ years old CDC. National Diabetes Fact Sheet Sources: National Health Interview Survey and National Health and Nutrition Examination Survey (NHANES) estimates projected to year outpatient database of the Indian Health Service 19% 15% 14% 7%

20 Estimated Percentage of Americans Age 18 and Older Who Report No Leisure-Time Physical Activity by Race and Sex Source: Physical Activity and Health: A Report of the Surgeon General, United States Department of HHS

21 The Rising Tide of ESRD Diabetes: The Number One Cause of ESRD Diabetes 50.1% Hypertension 27% Glomerulonephritis 13% Other 10% USRDS. Annual data report No of Patients Projection R 2 = 99.8% 326, , ,330 No. of ESRD Patients (x 1000) Year

22 Years of Potential Life Lost to Total Heart Disease Before Age 75 by Race and Gender Clark et al Heart Dis. 2001;3:97-108; National Vital Statistics System, Health, United States, 1996– Years White womenAfrican-American womenWhite menAfrican-American men

23 Failure to Reach Treatment Goals Carries Costly Burden Paramore LC et al. Am J Manag Care. 2001;7: N = 1000 managed-care patients with treated hypertension Greater medication costs More physician visits <120 mm Hg 180 mm Hg180 mm Hg Meanvisits per year Severity of hypertension (mm Hg) <130/85 140/90 – 159/99 160/ /85 – 139/89 Mean drug cost per patient per year* Mean drug cost per patient per year* ($ US) ControlledUncontrolled *Based on 1999 average wholesale price Maximum SBP

24 Kenneth A. Jamerson, M.D. Professor of Cardiovascular Medicine University of Michigan Medical Director, Program for Multi-cultural Health Ann Arbor, Michigan Are We in Control? Are We in Control? The Importance of Early Risk The Importance of Early Risk Identification and Treatment Getting To Goal and Staying There in Ethnic Minority Populations Challenges and Solutions in Minority Populations

25 The Tecumseh Blood Pressure Study A prospective epidemiological study of the antecedents of hypertension and cardiovascular disease in 1,100 young men and women Ann Arbor Tecumseh

26 Hematocrit Cholesterol Overweight Heart Rate Insulin Triglycerides DBP N=124 (aged years) Adapted from Julius et al. JAMA 1990;264: P<0.001P<0.01P<0.05 Tecumseh BP Study: Association of DBP and Other CHD Risk Factors

27 S. Julius, et al: JAMA 264: , 1990 Blood Pressure Trends in Tecumseh, Michigan HypertensiveNormotensive * * * * ** * P<.01 ** P<.001 *

28 Is There a Unique Etiology for Hypertension in African Americans? Causes and Causes for Concern

29 The Association of Skin Color with Blood pressure in US blacks with Low Socioeconomic Status Klag, M J. Whelton, P K. Coresh, J. Grim, C E. Kuller, L H. JAMA Feb 6;265(5):639-40; JAMA Feb 6;265(5):639-40;Abstract To determine the association of skin color, measured by a reflectometer, with blood pressure in US blacks, we studied a community sample of 457 blacks from three US cities. Persons taking antihypertensive medications were excluded. Both systolic and diastolic blood pressure were higher in darker persons and increased by 2 mm Hg for every 1-SD increase in skin darkness. However, the association was dependent on socioeconomic status, whether measured by education or an index consisting of education, occupation, and ethnicity, being present only in person with lower levels of either indicator. Using multiple linear regression, both systolic and diastolic blood pressure remained significantly associated with darker skin color in the lower levels of socioeconomic status, independent of age, body mass index, and concentrations of blood glucose, serum urea nitrogen, serum uric acid, and urinary sodium and potassium. The association of skin color with blood pressure only in low socioeconomic strata may be due to the lesser ability of such groups to deal with the psychosocial stress associated with darker skin color. However, these findings also are consistent with an interaction between an environmental factor associated with low socioeconomic status and a susceptible gene that has a higher prevalence in persons with darker skin color. To determine the association of skin color, measured by a reflectometer, with blood pressure in US blacks, we studied a community sample of 457 blacks from three US cities. Persons taking antihypertensive medications were excluded. Both systolic and diastolic blood pressure were higher in darker persons and increased by 2 mm Hg for every 1-SD increase in skin darkness. However, the association was dependent on socioeconomic status, whether measured by education or an index consisting of education, occupation, and ethnicity, being present only in person with lower levels of either indicator. Using multiple linear regression, both systolic and diastolic blood pressure remained significantly associated with darker skin color in the lower levels of socioeconomic status, independent of age, body mass index, and concentrations of blood glucose, serum urea nitrogen, serum uric acid, and urinary sodium and potassium. The association of skin color with blood pressure only in low socioeconomic strata may be due to the lesser ability of such groups to deal with the psychosocial stress associated with darker skin color. However, these findings also are consistent with an interaction between an environmental factor associated with low socioeconomic status and a susceptible gene that has a higher prevalence in persons with darker skin color. Deciphering The Etiology and Associations

30 Do African Americans respond to antihypertensive therapy differently than other races or ethnic groups? Response to Therapy A Critical Issue for Drug Selection and Care

31 African American, % White, % Blood Pressure Response to Quinapril: The ATIME Study Mokwe E et al. Hypertension. 2004;43(6):1202–7. SBP (average change) 20.0 Mean–10.5 SD13.4 Lower Quartile–2.2 Upper Quartile–20.0 Interquartile Range –9–9–21–33–45– Mean–15.3 SD12.2 Lower Quartile–7.3 Upper Quartile–23.5 Interquartile Range SD = standard deviation.

32 Is It Important To Block The RAS In African Americans? HOPE HOPE PROGRESS PROGRESS SOLVD SOLVD ValHeft ValHeft V-Heft V-Heft LIFE LIFE OCTAVE OCTAVE ALLHAT ALLHAT Landmark Trials That Give Us Data, Guidance, and Perspective

33 African American Study of Kidney Disease and Hypertension Landmark and Longitudinal Studies

34 Achieved Blood Pressure in AASK ACECCBBBLOWUSUAL SBP DBP NEED FOR STEP 5 28%24%32%35%23%

35 Cumulative Incidence of Confirmed Declining GFR Event, Dialysis or Death by Drug Group (Data as of 10/19/01) p-valueA vs BC vs B*A vs C* adjusted Cumulative Incidence.

36 Implications Of The AASK Study Aggressive control of blood pressure can eliminate ethnic differences in ESRD Aggressive control of blood pressure can eliminate ethnic differences in ESRD Inadequate treatment of hypertension may cause excess risk of target organ disease Inadequate treatment of hypertension may cause excess risk of target organ disease Cultural, rather than genetic differences, may underlay the excess risk of hypertensive ESRD Cultural, rather than genetic differences, may underlay the excess risk of hypertensive ESRD

37 International Society of Hypertension in Blacks IMPACT Campaign Science Guidelines Behavioral Change

38 Vascular 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, MD David Harrison, MD Willa Hsueh, MD Willa Hsueh, MD Helmy Siragy, MD Helmy Siragy, MD Douglas Vaughan, MD Douglas Vaughan, MD Dr. Brent Egan Dr. Brent Egan Ken Jamerson, MD Ken Jamerson, MD

39 The Problem

40 Does Being African American Modify the Problem?

41 Models to Explain Health Disparities Racial Genetic Model Racial Genetic Model Cause of HD: Population differences in the distribution of genetic variants Health-behavior Model Health-behavior Model Cause of HD: Differences between R/E groups in the distribution of individual behaviors related to health such as diet, exercise, and tobacco use SES Model SES Model Cause of HD: Over-representation of some R/E groups within lower SES Psychosocial Stress Model Psychosocial Stress Model Cause of HD: Stresses associated with minority group status, especially the experience of racism and discrimination

42 Race Race(Social) Ancestry(Genetic) Disease Disease Critical Relationships

43 Although much genetic variation (85- 90%) is shared among all human populations, about 5% of SNPs have high levels of allele frequency differential (d>50%). We call these markers Ancestry Informative Markers (AIMs). Ancestry Informative Markers (AIMs)

44 Ancestry Can Be Estimated Across Chromosomal Regions Seldin et al. Genome Res. 14: , 2004 Smith et al. AJHG 74: , 2004

45 European Genetic Contribution in African-American Populations Living in Different Areas of the U.S. Parra et al. AJHG 1998; Parra et al. AJPA 2002; Kittles et al. unpublished

46 1.Group definition and membership. 2.Can we accurately assess genomic ancestry? 3.How does genomic ancestry relate to skin color and possibly SES? 4.How useful is genomic ancestry for informing us about disease risk? 5.Health Disparities: are they due to biological differences? 6.How do we prevent repeating the negative past abuses of race. Era of Genomic Ancestry and Challenges Related to Health

47 RESULTS BP Control at 18 Months RESULTS BP Control at 18 Months Accomplishing Something

48 ACCOMPLISH: Hypothesis ACCOMPLISH will test a new strategy for the treatment of hypertension: Dual therapy provided in a single tablet. ACCOMPLISH will test a new strategy for the treatment of hypertension: Dual therapy provided in a single tablet. The combination of benazepril and amlodipine will reduce cardiovascular morbidity and mortality in patients with high- risk hypertension by 15% when compared to the combination of benazepril and HCTZ. The combination of benazepril and amlodipine will reduce cardiovascular morbidity and mortality in patients with high- risk hypertension by 15% when compared to the combination of benazepril and HCTZ. Jamerson KA et al. Am J Hypertens. 2004;17:793–801.

49 ACCOMPLISH: Primary Endpoint CV MORBIDITY Nonfatal MI Nonfatal MI Nonfatal stroke Nonfatal stroke Hospitalization for unstable angina Hospitalization for unstable angina Resuscitated sudden cardiac death Resuscitated sudden cardiac death Coronary revascularization procedures Coronary revascularization procedures CV MORTALITY Sudden cardiac death Sudden cardiac death Fatal MI Fatal MI Fatal stroke Fatal stroke Death due to coronary intervention, congestive heart failure, or other cardiovascular causes Death due to coronary intervention, congestive heart failure, or other cardiovascular causes Jamerson KA et al. Am J Hypertens. 2004;17:793–801. Time to first event of composite cardiovascular morbidity and mortality

50 ACCOMPLISH: 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 the primary endpoint at a two-sided overall significance level of 5% 90% power to detect a 15% risk reduction for the primary endpoint at a two-sided overall significance level of 5% Four (4) interim analyses and 1 final analysis 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% Jamerson KA et al. Am J Hypertens. 2004;17:793–801.

51 ACCOMPLISH: Design Jamerson KA et al. Am J Hypertens. 2004;17:793–801. *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. 14 Days Day 1 Month 1 Month 2 Year 5 Screening (N=12,600) Amlodipine/ benazepril 5/20 mg Randomization Benazepril 40 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 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 3 Free add-on antihypertensive agents* Amlodipine/ benazepril 5/40 mg Amlodipine/ benazepril 10/40 mg Benazepril 20 mg + HCTZ 12.5 mg Forced titration

52 Targeted Population for Recruitment into the ACCOMPLISH Trial Men or women of any racial background, age 55 years Men or women of any racial background, age 55 years SBP 160 mmHg or currently on antihypertensive therapy SBP 160 mmHg or currently on antihypertensive therapy Evidence of cardiovascular or renal disease or target organ damage Evidence of cardiovascular or renal disease or target organ damage

53 ACCOMPLISH: Key Demographic Data Race:Caucasian83.9% Black11.9% Oriental0.4% Other3.8% Ethnicity:Hispanic5.4% GenderMale60.7% Female39.3% Mean Age, years % of Pts > % +BP<140/90 for non-diabetics and <130/80 for diabetics * including 6.8% of CKD based on Serum Creatinine % of Population Baseline BP (mmHg) Control Rate at Baseline + All Patients* 40%145.4/8037.5% Diabetic Sub- Population 60% 145.2/ %

54 Baseline Traits of ACCOMPLISH Cohort May Reflect New Secular Trends in Disease Management Patient enrollment completed. Patient enrollment completed. l 50% of patients are obese l 60% of patients have Diabetes Mellitus l 97% of patients were treated previously for hypertension. l 74% of patients were treated with > 2 Hypertensive Agents Only 37.5% of patients were controlled to <140/90 mmHg Only 37.5% of patients were controlled to <140/90 mmHg

55 ACCOMPLISH: Effect of Initial Combination Therapy on SBP Over Time Data on file. Novartis Pharmaceuticals Corporation. SBP (mmHg) Baseline N=11, (18.3) Month 6 N=10, (16.0) Month 18 N=9, (16.0) All Patients Month 12 N=10, ( 16.0) (sd)

56 Baseline Range ACCOMPLISH: Significant Reduction in SBP in All Patient Populations Data on file. Novartis Pharmaceuticals Corporation. All JNC-7 Goal: SBP 140 mmHg SBP ( mmHg ) (N=11,400) (N=3,333) (N=8,067) (N=1,361) NordicU.S. African American P< Neither age nor gender appeared to influence the effects on SBP.

57 ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy Data on file. Novartis Pharmaceuticals Corporation. All Control rate (%) Nordic U.S. African American Baseline Control Rates 80.5 N=8, N=11, N=3, N=1,

58 Conclusions Millions of Americans take anti-hypertension medication, but do not achieve blood pressure control. Initial therapy with single-tablet, dual- mechanism drugs is highly effective (>80% control) and safe. Millions of Americans take anti-hypertension medication, but do not achieve blood pressure control. Initial therapy with single-tablet, dual- mechanism drugs is highly effective (>80% control) and safe. We find substantial evidence to broaden the use of combination therapy as an initial strategy for the treatment of hypertension. We find substantial evidence to broaden the use of combination therapy as an initial strategy for the treatment of hypertension.

59 Hypertension – A Systemic Disease Requiring Systematic Approaches To Therapy Recent Clinical Practice Recommendations Focusing on Combination Therapy in Difficult-to-Treat Patient Populations with High Blood Pressure and Compelling Conditions Jackson T. Wright, Jr. MD, PhD Professor of Medicine Case Western Reserve University Program Director, General Clinical Research Center Director, Clinical Hypertension Program University Hospitals Case Medical Center and the Louis Stokes Cleveland VAMC Considering Combination Therapy

60 Goals of This Presentation Need for multi-drug therapy for BP control Need for multi-drug therapy for BP control Guideline recommendations for treatment and rationale for these recommendations Guideline recommendations for treatment and rationale for these recommendations Importance of BP vs. drug selection Importance of BP vs. drug selection Combination drug regimensoptions and strategies Combination drug regimensoptions and strategies

61 Hypertension in African Americans (versus Whites) Higher prevalence & incidence (esp. women)Higher prevalence & incidence (esp. women) Greater severityGreater severity Earlier onsetEarlier onset Higher hospitalization rates (~8 x )Higher hospitalization rates (~8 x ) More target-organ injuryMore target-organ injury Renin more often suppressedRenin more often suppressed Less intensively treatedLess intensively treated More factors linked to HTN Tx resistanceMore factors linked to HTN Tx resistance DiabetesDiabetes ObesityObesity ProteinuriaProteinuria Female sexFemale sex GFR GFR Target-organ injuryTarget-organ injury Living in SE USALiving in SE USA Lesser BP response to ACEI than whitesLesser BP response to ACEI than whites Less likely to receive RAS drugsLess likely to receive RAS drugs TreatmentEpidemiology

62 Combination Therapy is Needed to Achieve Target SBP Goals Updated from Bakris GL et al. Am J Kidney Dis. 2000;36: Number of BP meds Trial/SBP Achieved 1234 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)

63 Number of Antihypertensive Drugs Used and BP Control (<140/90 mm Hg) ALLHAT Chlorthalidone Amlodipine Lisinopril

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

65 Number of Drugs Needed to Control BP (<140/90 mm Hg) in ALLHAT After 5 Years 26% of participants were controlled on 1 drug (another 2% were untreated): 26% of participants were controlled on 1 drug (another 2% were untreated): l Therefore, at least 72% received or needed 2 drugs 49% were controlled on 1 or 2 drugs (12% more were uncontrolled on 1 drug or untreated): 49% were controlled on 1 or 2 drugs (12% more were uncontrolled on 1 drug or untreated): l Therefore, at least 39% received or would have needed 3 drugs to control BP 60% were controlled on 3 or fewer drugs: 60% were controlled on 3 or fewer drugs: l Therefore, at least 16% received or needed 4 drugs to control BP ALLHAT

66 Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Lifestyle Modifications Not at Goal Blood Pressure 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 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 Treatment of Hypertension

67 Consensus Statement: Management of High BP in African Americans If BP <155/100 mm Hg, monotherapy If BP 155/100 mmHg, combination therapy Increase dose or add a 3 rd agent from a different class Uncomplicated hypertension Goal BP: <140/90 mm Hg Not at BP goal? Intensify lifestyle changes AND Add a 2 nd 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 § Add a 2 nd agent from a different class or increase dose Increase dose or add a 3 rd agent from a different class RAS, renin-angiotensin system *Preferable BP goal for patients with renal disease with proteinuria >1 g/24 h is <125/75 mm Hg Initiate monotherapy at the recommended starting dose with an agent from any of the following classes: diuretics, beta blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARBs) To achieve BP goals more expeditiously, initiate low-dose combination therapy with any of the following combinations: beta blocker/diuretic, ACE inhibitor/diuretic, ACE inhibitor/CCB, or ARB/diuretic § Consider specific clinical indications when selecting agents Douglas J et al. Arch Intern Med. 2003;16:

68 Black vs. Non-Black Lisinopril versus Chlorthalidone Nonfatal MI + CHD Death All-Cause Mortality Combined CHD Combined CVD Stroke End Stage Renal Disease Heart Failure Black FavorsLisinopril FavorsChlorthalidoneNon-BlackFavorsLisinopril FavorsChlorthalidone ( ) 0.93 ( ) 1.00 ( ) 1.06 ( ) 1.01 ( ) 0.97 ( ) 0.94 ( ) Wright JT et al; JAMA 2005; 293:1593 Relative Risk and 95% Confidence Intervals ALLHAT

69 ChlorthalidoneAmlodipineLisinopril SBP – mean (sd) Black (15.8) (15.3) (19.7) Non- black (14.8) (14.6) (16.7) DBP – mean (sd) Black 77.4 (10.0) 76.3 (10.1) 78.0 (11.4) Non- black 74.4 (9.5) 73.6 (9.6) 74.1 (10.1) BP compared with chlorthalidone BP compared with chlorthalidone Black / -1.1* +4.1* / +0.6 Non- black / -0.8* +0.9 / -0.3 * P < /15/03 Blood Pressure at 5 Years by Race ALLHAT

70 Whites n = 2046 Blacks n = 533 Frequency Distribution: SBP in Response to Quinapril in Black and White Participants E. Mokwe et. al., HTN 2004;43:1 African American, % White, % SBP (average change) 20.0 Mean–10.5 SD13.4 Lower Quartile–2.2 Upper Quartile–20.0 Interquartile Range –9–9–21–33–45– Mean–15.3 SD12.2 Lower Quartile–7.3 Upper Quartile–23.5 Interquartile Range

71 Angioedema TotalBlacks Non- blacks Chlorthalidone 8 / 15, % 2 / 5,369 <0.1% 6 / 9, % Lisinopril 38 / 9, % 23 / 3, % 15 / 5, % p<.001p<.001p=.002 There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to chlorthalidone not significant). ALLHAT

72 Results Of Primary Composite End Point in 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. J Am Coll Cardiol 2004;43: Race N Hazard Ratio White 8503 Black 533 Hispanic 100 Asian (23.36) BlacksNon-Blacks Atenolol Losartan Time in Months

73 AASK Clinical Endpoint Analysis ACEI vs. CCB ACEI vs. BB Outcome % Risk Reduction 1 95 % 95 % Confidence Interval % Risk Reduction 95 % 95 % Confidence Interval GFR event, ESRD or Death 2 38% (+ 14 to + 55) p< % (+ 1 to + 38) p< GFR event or ESRD 3 40% (+ 13 to + 59) p< % (- 1 to + 41) p< ESRD or Death 4 48% (+ 26 to + 65) p< % (- 5 to + 40) p< 0.11 ESRD alone 5 59% (+ 34 to + 74) p< % (- 10 to + 45) p< 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; events, deaths censored. Wright et al 2002; JAMA, 288:2421

74 ASCOT All-Cause Mortality Amlodipine versus Atenolol Number at risk Amlodipine perindopril Atenolol thiazide Years HR = 0.89 (0.81­0.99) p = % Amlodipine (No. of events 738) Atenolol (No. of events 820 )

75 Black vs. Non-Black Amlodipine versus Chlorthalidone Nonfatal MI + CHD Death All-Cause Mortality Combined CHD Combined CVD Stroke End Stage Renal Disease Heart Failure Black FavorsChlorthalidone Non-Black ( ) 1.08 ( ) 0.93 ( ) 1.04 ( ) 0.99 ( ) 0.94 ( ) 0.97 ( ) FavorsAmlodipine Favors Chlorthalidon e Relative Risk and 95% Confidence Intervals Wright JT et al; JAMA 2005; 293:1593 ALLHAT

76 VALUE Trial: Primary Composite Cardiac Endpoint Time (months) Proportion of Patients With First Event (%) Valsartan-based regimen Amlodipine-based regimen HR = 1.03; 95% CI = 0.94–1.14; P = 0.49 Julius S et al. Lancet. June 2004;363 Number at risk Valsartan Amlodipine

77 Favours valsartan Favours amlodipine Hazard Ratio Valsartan/Amlodipine Primary cardiac composite endpoint cardiac mortality cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes VALUE Trial Hazard Ratios for Pre-specified Analyses Julius S et al. Lancet. June 2004;363

78 Odds Ratio (experimental/control) Difference in SBP (control minus experimental) mm Hg HOPE P < UKPDS C vs A ALLHAT CAPPP NORDIL MIDAS/NICS/VHAS STOP2/CCBs HOT M vs H INSIGHT HOT L vs H PROGRESS/Per STOP2/ACEIs RENAAL PATS Syst-China ATMH MRC1 MRC2 Syst-Eur SHEP HEP EWPHE PART2/SCAT UKPDS L vs H PROGRESS/Com STOP1 RCT70–80 STONE All Trials ALLHAT/Lis Blacks ALLHAT/Lis 65 y ALLHAT/Lis ALLHAT/Aml CONVINCE ANBP2 DIABHYCAR ABCD/NT L vs H IDNT2 SCOPE LIFE/ALL ELSA LIFE/DM PREVENT NICOLE AASK L vs H Difference in SBP (control minus experimental) mm Hg Recent Trials Staessen Meta-Regression Analysis: Robust Correlation Between Difference in SBP and Risk of CV Events Adapted from Staessen JA, Wan JG, Thijs L. J Hypertens. 2003;21: VALUE?

79 Systolic blood pressure difference between randomised groups (mmHg) Blood Pressure Lowering Treatment Trialists Collaboration BP Reduction and Major Cardiovascular Outcomes Lancet. 2003;362:

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

81 If most hypertensive patients (especially Black hypertensives) require 2-3 medications for BP control, which agents should we include in this mix? CCB, DIURETICS, RAASI Multi-Drug Therapy: Rule or Exception?

82 Drug Treatment Standards Drug Treatment Standards WHO/ISH JNC 7 HAAWG ISHIB Initiate TX Uncomplicated HTN 140/90 (previously 160/90; currently 160/100 in UK) 140/90140/90 Initiate Combination TX- Uncomplicated 160/100155/100 Initiate TX Complicated HTN & Goal 130/80 (140/90 for women & elderly and in UK) 130/80130/80 Initiate Combination TX- Complicated HTN 150/90145/90 SD Nesbitt 2004

83 Drug Choice Recommendations Drug Choice Recommendations WHO/ISH JNC 7 HAAWG ISHIB Uncomplicated HTN Thiazide as initial agent May use ACE, ARB, Beta-B, CCB May initiate diuretic, ACE, ARB, Beta-B, CCB Combination TX- Uncomplicated Not uniformly recommended Diuretic + (ACE, Beta-B, ARB) or ACE/CCB Diuretic + (ACE, Beta-B, ARB) or ACE/CCB Complicated HTN Treat according to the compelling condition similarly according to all guidelines. SD Nesbitt 2004

84 NKF Guideline 3 – Management of Hypertension in Diabetes and CKD Hypertensive people with diabetes and CKD Stage 1-4 should be treated with an ACE inhibitor or an ARB, usually in combination with a diuretic (A) Hypertensive people with diabetes and CKD Stage 1-4 should be treated with an ACE inhibitor or an ARB, usually in combination with a diuretic (A) Target blood pressure in diabetes and CKD should be <130/80 mmHg (B) Target blood pressure in diabetes and CKD should be <130/80 mmHg (B)

85 Combination Therapies -adrenergic blockers and diuretics -adrenergic blockers and diuretics ACE inhibitors and diuretics ACE inhibitors and diuretics Angiotensin II receptor antagonists (ARBs) and diuretics Angiotensin II receptor antagonists (ARBs) and diuretics Calcium antagonists and ACE inhibitors Calcium antagonists and ACE inhibitors Calcium antagonists and ARBs Calcium antagonists and ARBs Renin inhibitors and diuretics Renin inhibitors and diuretics

86 Combination Drug Therapy In HTN Advantages Improved blood pressure control Improved blood pressure control l Uses different approaches l Blocking counter-regulatory mechanisms l Ease of titration to BP goal Reduce side effects (less dosage requirement) Reduce side effects (less dosage requirement) Improve protection of target organs Improve protection of target organs

87 Combination Drug Therapy In Hypertension

88 CONCLUSIONS BP lowering reduces BP-related outcomes BP lowering reduces BP-related outcomes To achieve BP goals will require at least 2, and usually more, BP drugs, especially in Black hypertensive patients To achieve BP goals will require at least 2, and usually more, BP drugs, especially in Black hypertensive patients Clinical outcome data are available for CCBs, diuretics (thiazide-type), and RAS inhibitors (ACEIs and ARBs) as initial Rx Clinical outcome data are available for CCBs, diuretics (thiazide-type), and RAS inhibitors (ACEIs and ARBs) as initial Rx Differences between guideline recommendations for treatment are minor and all focus on achieving BP goal and need for multi-drug regimens Differences between guideline recommendations for treatment are minor and all focus on achieving BP goal and need for multi-drug regimens With available agents, BP goals can be achieved With available agents, BP goals can be achieved

89 The Evolving Landscape of Antihypertensive Therapy Direct Renin Inhibition, Combination Therapy, and Implications for African American and other Ethnic Populations The Evolving Landscape of Antihypertensive Therapy Direct Renin Inhibition, Combination Therapy, and Implications for African American and other Ethnic Populations Shawna D. Nesbitt MD, MS Associate Professor of Internal Medicine Department of Medicine University of Texas Southwestern Dallas, Texas Emerging Therapies Focus on RAS

90 *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 § Add a 2nd agent from a different class or increase dose Increase dose or add a 3rd agent from a different class Diabetes/nondiabetic renal disease with proteinuria >1 g/24 h* Goal BP: <130/80 mmHg Not at BP goal? Intensify lifestyle changes AND Add a 2nd agent from a different class or increase dose If BP 155/100 mmHg, combination therapy If BP <155/100 mmHg, monotherapy Increase dose or add a 3rd agent from a different class Uncomplicated hypertension Goal BP: <140/90 mmHg Not at BP goal? Intensify lifestyle changes AND ISHIB Consensus Statement: Management of Hypertension in African Americans Douglas JG et al. Arch Intern Med. 2003;163:525–541

91 Not at Goal Blood Pressure (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease) Initial Drug Choices Drug(s) for the Compelling Indications Other antihypertensive drugs (diuretic,, BB, CCB) as needed Other antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB) as needed With Compelling Indications Lifestyle Modifications Not at Goal Blood Pressure 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 mm Hg) 2-drug combination for most (usually thiazide-type diuretic and BB, or CCB) Stage 2 Hypertension (SBP 160 or DBP 100 mm Hg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, ARB, BB, or CCB) Stage 1 Hypertension (SBP or DBP mm Hg) Thiazide-type diuretics for most May consider, BB, CCB, or combination Stage 1 Hypertension (SBP or DBP mm Hg) Thiazide-type diuretics for most May consider ACEI, ARB, BB, CCB, or combination Without Compelling Indications JNC 7 Algorithm for Treatment of Hypertension Chobanian et al. JAMA. 2003;289:

92 Published Guidelines Have Set Lower Treatment Goals Chobanian AV et al. JAMA. 2003;289:2560–2572. Arauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82. Douglas JG et al. Arch Intern Med. 2003;163:525–541. Bakris GL et al. Am J Kidney Dis. 2000;36:646–661 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 mmHg Essential hypertension Diabetes mellitus Chronic renal disease High-risk * hypertension Condition JNC 7 / ADA / NKF / ISHIB Guidelines for Hypertension and Patients at High Risk

93 JNC-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 kidney disease 2° stroke prevention BB ACEI ARB CCB AA Diuretic The JNC 7 Report. JAMA. 2003;289:2560

94 Mortality From High Blood Pressure Higher in African Americans Overall 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. Mortality Rate, % African American FemaleMaleFemale Male White In hypertensive African Americans, 30% and 20% of all deaths in men and women, respectively, may be due to high blood pressure. Adapted from Thom T et al. Circulation. 2006;113:e85–e151

95 RAS Blockade in African-American Patients Drugs that block the renin-angiotensin system (RAS) provide less antihypertensive efficacy than in white patients* Drugs that block the renin-angiotensin system (RAS) provide less antihypertensive efficacy than in white patients* Physiologic basis for this proposition: Physiologic basis for this proposition: l Lower levels of plasma renin activity (PRA) l Relative expansion of plasma volume l Higher prevalence of salt dependency l Higher Na+ and Ca+, may suppress PRA * Weir MR et al. Hypertension. 1995;26: Douglas JG. Unpublished data Douglas JG. Unpublished data Agodoa LY et al. JAMA. 2001;285: Agodoa LY et al. JAMA. 2001;285:

96 Benefits of Renin System (RS) Suppression to Date Clinical Trial Data Renin Angiotensin System

97 Relative Risk Reduction With Ramipril vs Amlodipine Besylate: AASK Ramipril Amlodipine besylate Events per person- yr GFR ESRD GFR, ESRD, or death GFR, glomerular filtration rate; ESRD, end-stage renal disease Agodoa LY et al. JAMA. 2001;285: RRR=41% P=0.03 RRR=44% P=0.01 RRR=38% P=0.005

98 ALLHAT: Lisinopril vs Chlorthalidone Primary Endpoint (Nonfatal MI + CHD Death) Subgroups Relative Risk (95% CI) Total Age <65 Age 65 MenWomenBlackNonblackDiabeticNondiabetic Favors Lisinopril Favors Chlorthalidone 0.99 ( ) 0.95 ( ) 1.01 ( ) 0.94 ( ) 1.06 ( ) 1.10 ( ) 0.94 ( ) 1.00 ( ) 0.99 ( ) ALLHAT Collaborative Research Group. JAMA. 2002;288:

99 1.Yusuf S et al. N Engl J Med. 2000;342: The CONSENSUS Trial Study Group 3.N Engl J Med. 1987;316: Relative Risk Reduction, % ACEIs and ARBs Yield Reduction in Cardiovascular 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 FailureAssessment 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.SOLVD Investigators. N Engl J Med. 1991;325: Granger CB et al. Lancet. 2003;362: Dahlöf B et al. Lancet. 2002;359: HOPE 1 SOLVD 3 CONSENSUS 2 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 mortality in severe HF ACEIs 22% P< % P= % P=.003 LIFE 5 Atenolol (n=4588) Losartan (n=4605) CHARM-Alternative 4 Death, MI, or stroke in patients aged 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= % P=.0004

100 Reduction of Progressive Nephropathy with ARB: IDNT Irbesartan vs Control Irbesartan vs Amlodipine Amlodipine vs Control Doubling Cr, ESRD, or Death (%)20*23**4ns Doubling of Cr, (%)33**37***6ns ESRD (%)23ns23ns0ns Lewis EJ NEJM 2001;345:851 *p<.05 **p<.01 ***p<.001

101 Diabetics Exposed to Telmisartan and Enalapril Study (DETAIL) 250 Type 2 diabetes, hypertension and nephropathy 250 Type 2 diabetes, hypertension and nephropathy Forced titration of telmisartan (40-80 mg) and enalapril (10-20 mg) Forced titration of telmisartan (40-80 mg) and enalapril (10-20 mg) Primary outcome was a change in glomerular filtration rate (GFR) after 5 years Primary outcome was a change in glomerular filtration rate (GFR) after 5 years Barnett A et al N Engl J Med Decrease in GFR p=ns enalapriltelmisartan mL/min Death Rate enalapriltelmisartan Percent 35-50% expected rate over 5 years 5% 5%

102 TRial Of Preventing HYpertension (TROPHY) Years in study % Cumulative incidence Candesartan Placebo Candesartan Placebo Numbers under the graph refer to hypertension-free individuals 2 Years RR 66% AR 26% 4 Years RR 15.8 AR 9.6 Julius S, Nesbitt SD et al NEJM 2006;354 Kaplan-Meier Curves of Clinical Hypertension in the Two Groups

103 Combination Therapy Delays but Does Not 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 Randomization Number at risk Losartan Trandolapril Combination Proportion Reaching Endpoint, % Combination (N=88) P=.02 Losartan (N=89) Trandolapril (N=86) COOPERATE Findings Nakao N et al. Lancet. 2003;361:

104 1°* endpoint 10 NS ASCOT: Blood Pressure Results Change (%) N=19,257 *1° endpoint: nonfatal MI and fatal CHD CHD, coronary heart disease; MI, myocardial infarction; NS, nonsignificant All-cause mortality 15 P< P= CV mortality 16 P< All CV events + revasc 23 P= Fatal + nonfatal stroke New cases of diabetes mellitus 32 P< Amlodipine Besylate/Perindopril vs Atenolol/Bendroflumethiazide Presented March 8, 2005 at the American College of Cardiology Annual Scientific Session, Orlando, Florida

105 Renin System Suppression by ACE Inhibitors and ARBs Renin System suppression with ACEIs and ARBs has demonstrated significant clinical benefit Renin System suppression with ACEIs and ARBs has demonstrated significant clinical benefit Renin System suppression with ACEIs, ARBs, and even combinations of ACEI + ARB therapy may elevate key components and processes; such as PRA, Ang I, and Ang II with ARB usage and PRA and Ang I with ACEI usage Renin System suppression with ACEIs, ARBs, and even combinations of ACEI + ARB therapy may elevate key components and processes; such as PRA, Ang I, and Ang II with ARB usage and PRA and Ang I with ACEI usage l Increased peptide levels have not been shown to overcome the blood pressure-lowering effect of these agents Consequently, benefits have not been demonstrated for all endpoints and in all patients Consequently, benefits have not been demonstrated for all endpoints and in all patients Could even greater clinical benefits be expected from more complete Renin System suppression? Could even greater clinical benefits be expected from more complete Renin System suppression? Summary ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker

106 Renin System (RS) Suppression via Direct Renin Inhibition Renin Suppression Development of Direct Renin Inhibitors (DRIs) Direct Renin Inhibition: What Do We Know?

107 Plasma Renin Activity (PRA) PRA is a surrogate measure of renin activity PRA is a surrogate measure of renin activity l Indicates the capacity of circulating renin to form Ang I (and ultimately Ang II) PRA is independently associated with the occurrence of cardiovascular disease among hypertensive patients 1 PRA is independently associated with the occurrence of cardiovascular disease among hypertensive patients 1 l A 25% increase in the risk of myocardial infarction for every 2 ng/mL/h increase in PRA 1 Increased PRA activates the RAAS leading to increased generation of Ang II. Ang II is important in the generation of hypertension and both the short- term and long-term effects leading to organ damage 2 Increased PRA activates the RAAS leading to increased generation of Ang II. Ang II is important in the generation of hypertension and both the short- term and long-term effects leading to organ damage 2 1. Alderman MH, et al Burnier M, et al. 2000

108 Ang I Angiotensinogen Crystal Structure of Renin Renin Cleaves its Substrate, Angiotensinogen, to Form ANG I Adapted from Rahuel J et al. J Struct Biol. 1991;107:

109 Only Direct Renin Inhibition Inhibits the Entire Renin System 1-6 Class Diuretic ACEI ARB Direct Renin Inhibitor (DRI) PRAAng IAng 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): Widdop RE et al. Hypertension. 2002;40: Fabiani ME et al. In: Angiotensin II Receptor Antagonists 2001: Waybill MM et al. J Vasc Interv Radiol. 2003;14: Reid IA. Adv Physiol Ed. 1998;20:S236-S245 6.Lin C et al. Am Heart J. 1996;131:

110 Renin System Suppression via Direct Renin Inhibition 1-3 Targets the point of activation in the Renin System Targets the point of activation in the Renin System Binds to renin, neutralizing its ability to convert angiotensinogen to Ang I Binds to renin, neutralizing its ability to convert angiotensinogen to Ang I Reduces plasma renin activity Reduces plasma renin activity l PRA is a marker for Renin System activity/stimulation l Elevated levels of prorenin have been shown with direct renin inhibition; potential physiological effects are being investigated in animal studies Decreases formation of Ang I and Ang II Decreases formation of Ang I and Ang II l Ang I unavailable for ACE and non-ACE conversion to Ang II l Ang II unavailable to stimulate AT receptors l Ang II unavailable for conversion to Ang subtypes [eg, Ang (2-8), also called Ang III] Ang, angiotensin; ACE, angiotensin-converting enzyme; AT, angiotensin receptor 1.Stanton A. J Renin Angiotensin Aldosterone Syst. 2003;4: Wood JM et al. Cardiovasc Drugs Ther. 1996;10: Nussberger J et al. Hypertension. 2002;39:e1-e8

111 An Efficient Strategy to Achieve Interruption of the Renin System Is Direct Renin Inhibition 1-3 *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)* AT 1 Receptor Feedback Loop Ang I Angiotensinogen Ang II Renin ARBs ACE ACEIs Adapted from: Stanton A. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10 Kelly DJ et al. Hypertension. 2005;46: Fisher NDL et al. J Am Soc Nephrol. 2005;16:

112 Treatment day 8 Aliskiren Exhibits Dose-dependent Reductions In PRA Compared With ACE Inhibitors In Healthy Volunteers PRA (ng/mL/h) 0 Time (hours) Aliskiren 40 mg Aliskiren 80 mg Aliskiren 160 mg Aliskiren 640 mg Enalapril 20 mg Placebo Nussberger J, et al. Hypertension. 2002;39:e1 e8

113 Aliskiren Reduces PRA as Compared 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 mg n=12 mildly sodium-depleted normotensive subjects PRA (ng Ang I/mL/h) 0 Time (hours) 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

114 Aliskiren Offers Dose-dependent Reductions In SeDBP Mean SeDBP (mmHg) n=166 n=169 n=172 n=165 Placebo Aliskiren 150 mg Aliskiren 300 mg Aliskiren 600 mg * * p< versus placebo § p<0.05 for aliskiren 600 mg compared 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

115 Aliskiren Offers Dose-dependent Reductions in SeSBP Mean SeSBP (mmHg) n=166 n=169 n=172 n=165 Placebo Aliskiren 150 mg Aliskiren 300 mg Aliskiren 600 mg * * p< 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 13.0

116 Clinical Trials: Alisk iren Combination Placebo 0 mg HCTZ 6.25 mg HCTZ 12.5 mg HCTZ 25 mg HCTZ Change in SBP for Aliskiren, HCTZ, and Aliskiren + HCTZ Mean Reductions from Baseline in SBP (mm Hg)

117 Clinical Trials: Aliskerin in Combination Placebo 0 mg HCTZ 6.25 mg HCTZ 12.5 mg HCTZ 25 mg HCTZ Change in DBP for Aliskiren, HCTZ, and Aliskiren + HCTZ Mean Reductions from Baseline in DBP (mm Hg)

118 Clinical Trials: Aliskiren in Combination Change in SBP for Aliskiren, Valsartan, and Aliskiren + Valsartan Week 4 Week 8 Placebo PlaceboAliskiren 150 mg Aliskiren 300 mg Valsartan 160 mg Valsartan 320 mg Aliskiren 150 mg + Valsartan 160 mg Aliskiren 300 mg + Valsartan 320 mg Mean Reductions from Baseline in SBP (mm Hg)

119 Clinical Trials: Aliskiren in Combination Change in DBP for Aliskiren, Valsartan, and Aliskiren + Valsartan Week 4 Week 8 Placebo PlaceboAliskiren 150 mg Aliskiren 300 mg Valsartan 160 mg Valsartan 320 mg Aliskiren 150 mg + Valsartan 160 mg Aliskiren 300 mg + Valsartan 320 mg Mean Reductions from Baseline in DBP (mm Hg)

120 Conclusions and Summary Hypertension is prevalent, underdiagnosed, and inadequately treated. Many patients dont get to BP goal Hypertension is prevalent, underdiagnosed, and inadequately treated. Many patients dont get to BP goal Treating hypertension involves more than BP reduction; sustained 24-hour control and end-organ protection are important Treating hypertension involves more than BP reduction; sustained 24-hour control and end-organ protection are important Inappropriate activation of the Renin System is a central component in the development of hypertension and cardiovascular and renal disease Inappropriate activation of the Renin System is a central component in the development of hypertension and cardiovascular and renal disease Some agents that suppress the Renin System have unique end-organ protection benefits beyond BP reduction Some agents that suppress the Renin System have unique end-organ protection benefits beyond BP reduction Targeting the Renin System at the point of activation, by direct renin inhibition, provides inhibition of the entire Renin System Targeting the Renin System at the point of activation, by direct renin inhibition, provides inhibition of the entire Renin System Future clinical trials are needed to elucidate additional benefits of direct renin inhibition Future clinical trials are needed to elucidate additional benefits of direct renin inhibition


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