Critical Challenges in Cardiovascular Disease

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

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

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

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

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

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

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

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

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

The U.S. Population is Becoming Increasingly Diverse
Changing Trends Hispanics are the fastest-growing segment of the population, and now account for 13% U.S., as do African Americans. The U.S. Asian population currently consists of 10.6 million people, and represents 4% U.S.,; however, this population group is expected to triple in size by 2050. This graph, showing data from the U.S. Census Bureau 2004, illustrates past and projected population statistics by race and Hispanic origin as a percentage of the U.S. population. Hispanics are the fastest growing segment of the population and accounted for 13% of the U.S. population, as did African Americans, in It is projected that by 2050, the African American, Hispanic (any race), and Asian populations will all increase as a percentage of the U.S. population. U.S. Census Bureau, U.S. Interim Projections by Age, Sex, Race, and Hispanic Origin. Table 1a. Accessed December 1, Adapted from U.S. Census Bureau, Table 1a. Accessed Dec. 1, 2006.

Southern U.S. Has the Highest Concentration of African-Americans
This map is taken from the U.S. Census Bureau from the Census It represents the percentage by population by state, that people indicated 1 race, either Black or African-American. The dark green states are those where the African-American population is between 25.0% and 60.0%. U.S. Census Bureau, Census 2000 Redistricting Data (PL ) Summary File. Mapping Census 2000: The Geography of U.S. Diversity. Percent of Population, One Race: Black or African American (p 39). 25.0 to 60.0 12.3 to 24.9 5.0 to 12.2 0.3 to 4.9 People indicating exactly one race, Black or African American, as a percent of total population by state Adapted from U.S. Census Bureau, 2002 Redistricting Data (PL ) Summary File

Hypertensive Adults (Rate, Percent ± SE)
Estimated Rates of US Adults With Hypertension by Sex, Race, and Ethnicity NHANES to 45 1.8% age adj. increase 40 7.2% age adj. increase Non-Hispanic Black F M 35 30 Hypertensive Adults (Rate, Percent ± SE) 25 20 The NHANES hypertension data were also analyzed by race/ethnicity. This comparison of data from 1988 to 1994 with those from 1999 to 2000 in the rate of hypertension increased significantly in the overall population. There were increases for all the subpopulations studied: non-Hispanic black men and women, non-Hispanic white men and women, and Mexican American men and women. The only group in which the increase was significant was non-Hispanic white women.6 15 10 5 M F M F All Non-Hispanic White Mexican American Fields et al. Hypertension. 2004;44: Hajjar and Kotchen. JAMA. 2003;290:199–206 6. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States : a rising tide. Hypertension. 2004;44:

Percentage increase from 1988 to 2000
Hypertension Treatment and Control Rates by Race/Ethnicity: NHANES 2000 70 63 60.1 Treatment 60 55.6 Control 50 44.6 44 40.3 40 % 30 Percentage increase from 1988 to 2000 7.2 0.9 6.2 8.2 3.7 20 Evidence indicates that even when African Americans are treated for their hypertension, therapy is far from adequate. More striking than the disparity between African Americans and whites in the prevalence of hypertension is the difference in rates of control when treated. NHANES data indicate that only 44.6% of all treated hypertensive non-Hispanic African Americans have their BP controlled to less than 140/90 mmHg, compared with 55.6% of all non-Hispanic Whites. In addition, control of hypertension in whites increased significantly from 1988 to 2000, by 8.2%. This benefit was not shared by non-Hispanic African Americans, in whom control improved by only 0.9% in this time.1 In ALLHAT, African Americans were treated less intensely than non-African Americans and had more factors (eg, obesity, target-organ injury) that were linked to hypertension treatment resistance.2 1. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, JAMA. 2003;290:199–206. 2. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich). 2002;4: 10 African Americans* Whites* Mexican Americans *Non-Hispanic. Hajjar and Kotchen. JAMA. 2003;290:199–206.

Mortality From High Blood Pressure Higher in African Americans
Overall Mortality Rates From Causes Related to Hypertension, 2003* 60 49.7 50 40.8 40 Mortality Rate, % 30 20 14.9 14.5 10 Male Female Male Female African American White The overall death rate from hypertension for African Americans is over three times that seen in white Americans. In 2003, the age-adjusted death rate from hypertension was 14.9% for white men and 14.5% for white women, compared with 49.7% for African American men and 40.8% for African American women.1 The increased risk of African Americans is not related to a lack of awareness or limited access to medical care: in fact, more African Americans than white Americans are aware of and are treated for their hypertension, although control rates are similar for both races.1 1. Thom T, Haase N, Rosamond W, et al. Heart Disease and Stroke Statistics–2006 Update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85–e151. In hypertensive African Americans, 30% and 20% of all deaths in men and women, respectively, may be due to high blood pressure. *High blood pressure listed as a primary or contributing cause of death. High blood pressure=systolic ≥140 mmHg or diastolic ≥90 mmHg, taking antihypertensive medicine, being told ≥2 times by a physician that you have high blood pressure. Adapted from Thom T et al. Circulation. 2006;113:e85–e151.

Patients Not at JNC VI BP Goals
% Not at Goal BP Systolic Diastolic Patient Type (mm Hg) BP BP NHANES ( ) Total hypertensives <140/90 57% 26% African American <140/90 60% 32% Mexican American/ Hispanic <140/90 63% 30% Older patients (60 years) <140/90 71% 9% Symptomatic CHD <140/90 47% 4% Patients with diabetes† <130/85 81% 24% The NHANES surveys have examined risk factor control in the US population. NHANES most recent survey documents characteristics of 9965 people from 1999 to The NHANES surveys have shown that only about one fourth of individuals with hypertension have met The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI) goals for BP. In the United States, an estimated 31.3% of people with high BP are unaware of their disease; 16.7% are aware of their hypertension but are taking no medication; 28.6% are on medication but remain uncontrolled; and 23.1% have achieved BP control with medication. As shown here, failure to reach JNC VI goals is the case for a wide range of patients—those with uncomplicated disease, blacks, the elderly, and those with diabetes—and most often reflects the failure to control systolic BP rather than diastolic BP. The percentage of patients not at systolic goal is particularly high for the elderly (>70%) and patients with diabetes (>80%). *Includes those 17 years of age with diagnosed and undiagnosed hypertension. National Center for Health Statistics. NHANES (CD-ROM); †NHANES III. National Center for Health Statistics. National Health and Nutrition Examination Survey NHANES; (CD-ROM). SLIDE 16

Risk-Factor Clustering by Race and Sex
10 20 30 40 50 60 70 1 ≥2 ≥3 White women African-American women White men African-American men Percentage African Americans are more likely to have multiple risk factors than are Caucasians. Stone et al JAMA. 1996;275:

Obesity and Diabetes Among US Adults: Growing prevalence
Obesity (BMI ≥30 kg/m2) Diagnosed diabetes +11.9% 30 +11.5% 8 6.5 6.6 6.6 6.4 25 24.3 6 5.9 23.9 23.7 Population (%) 23.0 21.8 A worldwide epidemic in obesity is occurring in parallel with a rising prevalence of diabetes. (Obesity is defined as body mass index [BMI] ≥30 kg/m2.) The prevalence of obesity among US adults ages ≥20 years increased from 21.8% to 24.3% between January 2000 and June 2004, an absolute increase of 2.5% and a relative increase of 11.5% in less than 5 years.1 There has been a parallel upward trend in diabetes among US adults. From January 2000 to June 2004, diabetes among US adults aged ≥18 years increased from 5.9 to 6.6%, a relative increase of 11.9% in less than 5 years.1 1. Centers for Disease Control National Health Interview Survey. Accessed February 2005. 20 4 15 2 2000 2001 2002 2003 2004* 2000 2001 2002 2003 2004* *Jan–June CDC NHIS;

Age-Adjusted Prevalence of Diabetes* by Race/Ethnicity in the US
American Indians/ Alaska Natives Non-Hispanic Blacks 19% Hispanic/Latino Americans 15% Non-Hispanic Whites 14% 7% Age-Adjusted Prevalence of Diabetes by Race/Ethnicity in the US In 2000, the age-adjusted prevalence of diabetes for people 20 years old was 18.8% among American Indians and Alaska Natives, 15.0% among non-Hispanic blacks, 13.6% among Hispanic/Latino Americans, and 7.4% among non-Hispanic whites. It is estimated that 11.4 million non-Hispanic whites, 3.0 million non-Hispanic blacks, 2.0 million Hispanic/Latino Americans, and 105,000 American Indians and Alaska Natives who receive care from the Indian Health Service had diabetes. Non-Hispanic blacks and Hispanic/Latino Americans were 2 times more likely, while American Indian and Alaska Natives were 2.6 times more likely, to have diabetes than non-Hispanic whites. Reference: The Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2002. *In people 20+ years old Percent Sources: National Health Interview Survey and National Health and Nutrition Examination Survey (NHANES) estimates projected to year outpatient database of the Indian Health Service CDC. National Diabetes Fact Sheet

Estimated Percentage of Americans Age 18 and Older Who Report No Leisure-Time Physical Activity by Race and Sex African American men and women are more likely to report no leisure time physical activity. Source: Physical Activity and Health: A Report of the Surgeon General, United States Department of HHS

The Rising Tide of ESRD Diabetes: The Number One Cause of ESRD Year
50.1% Hypertension 27% Glomerulonephritis 13% Other 10% 700 No of Patients Projection 600 500 400 No. of ESRD Patients (x 1000) 661,330 300 372,407 200 326,217 100 R2 = 99.8% 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 Year USRDS. Annual data report

Years of Potential Life Lost to Total Heart Disease Before Age 75 by Race and Gender
4000 3000 Years 2000 this impact is far greater in years of potential life lost to total heart disease. 1000 1980 1980 1985 1985 1990 1990 1995 1995 White women African-American women White men African-American men Clark et al Heart Dis. 2001;3:97-108; National Vital Statistics System, Health, United States, 1996–97.

Failure to Reach Treatment Goals Carries Costly Burden
N = 1000 managed-care patients with treated hypertension Greater medication costs More physician visits 600 12 9.7 Mean drug cost per patient per year* ($ US) 400 Mean visits per year 8 Costs of poor control can be substantial Paramore et al examined the relationship between BP control and utilization and cost of healthcare resources in a retrospective database study of 1000 hypertensive managed-care patients. Antihypertensive medication use and cost, number of physician visits, and interval between hypertension-related physician visits were assessed. Medication costs increased progressively across all BP categories and higher average systolic BP was significantly correlated with increased cost. The authors concluded that poor control of hypertension is associated with higher drug costs and more physician visits; intensive treatment could reverse the trend. 4.1 200 4 <130/85 ≥160/100 130/85 – 139/89 140/90 – 159/99 <120 mm Hg ≥180 mm Hg Maximum SBP Controlled Uncontrolled Severity of hypertension (mm Hg) *Based on 1999 average wholesale price Paramore LC et al. Am J Manag Care. 2001;7:

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

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

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

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

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

Deciphering The Etiology and Associations
The Association of Skin Color with Blood pressure in US blacks with Low Socioeconomic Status Klag, M J. Whelton, P K. Coresh, J. Grim, C E. Kuller, L H. JAMA 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.

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

Blood Pressure Response to Quinapril: The ATIME Study
20.0 Mean –15.3 SD 12.2 Lower Quartile –7.3 Upper Quartile –23.5 Interquartile Range 16.2 15.0 White, % 10.0 5.0 20.0 Mean –10.5 SD 13.4 Lower Quartile –2.2 Upper Quartile –20.0 Interquartile Range 17.8 15.0 African American, % 10.0 African Americans with hypertension have been reported to be less responsive to monotherapy with ACE inhibitorss, beta blockers, and ARBs than to diuretics and calcium channel blockers (CCBs).1 The Quinapril Titration Interval Management Evaluation (ATIME) examined the impact of race and other confounders on the BP response to monotherapy with quinapril, an ACE inhibitor, in 533 African Americans and 2,046 white patients. Despite somewhat greater BP lowering in Whites, most of then variation in BP response was within, not between, the racial groups. The interquartile range (middle 50% of the response distribution) in both racial groups is 4-fold larger than the between-race BP response difference to monotherapy wth quinapril, an ACE inhibitor. Also, both the SBP and DBP change distributions overlapped significantly. 1. Mokwe E, Ohmit SE, Nasser SA, et al. Determinants of blood pressure response to quinapril in black and white hypertensive patients: the Quinapril Titration Interval Management Evaluation trial. Hypertension. 2004;43:1202–1207. 5.0 39 27 15 3 –9 –21 –33 –45 –57 SBP (average change) SD = standard deviation. Mokwe E et al. Hypertension. 2004;43(6):1202–7.

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

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

Achieved Blood Pressure in AASK
ACE CCB BB LOW USUAL SBP 133.6 131.4 134.2 126.9 140.0 DBP 81.1 80.7 80.9 76.6 85.2 NEED FOR STEP 5 28% 24% 32% 35% 23%

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

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

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

Vascular Matrix Summit
Dr. Gary Gibbons Dr. Abraham Aviv Rick Kittles, MD Charles Rotimi, MD David Harrison, MD Willa Hsueh, MD Helmy Siragy, MD Douglas Vaughan, MD Dr. Brent Egan Ken Jamerson, MD

The Problem

Does Being African American Modify the Problem?

Models to Explain Health Disparities
Racial Genetic Model Cause of HD: Population differences in the distribution of genetic variants Health-behavior Model Cause of HD: Differences between R/E groups in the distribution of individual behaviors related to health such as diet, exercise, and tobacco use SES Model Cause of HD: Over-representation of some R/E groups within lower SES Psychosocial Stress Model Cause of HD: Stresses associated with minority group status, especially the experience of racism and discrimination 1. Review of lit on HD reveals five explanatory models that have been used to account for the differences; each model emphasizes different sets of variables examples used are low birth weight and HTN. bracket life span health problems that contribute most to HD associated therefore may be linked to bicultural processes that lead to HD Focusing on PSM and SCM b/c they seem to be most promising explicit in this model is the cultural construction of race itself

Critical Relationships
Race (Social) Disease Ancestry (Genetic)

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

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

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

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

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

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

ACCOMPLISH: Primary Endpoint
Time to first event of composite cardiovascular morbidity and mortality CV MORBIDITY Nonfatal MI Nonfatal stroke Hospitalization for unstable angina Resuscitated sudden cardiac death Coronary revascularization procedures CV MORTALITY Sudden cardiac death Fatal MI Fatal stroke Death due to coronary intervention, congestive heart failure, or other cardiovascular causes All endpoints in the ACCOMPLISH trial will be rigorously adjudicated by an Endpoints Committee of experienced trialists. The primary endpoint is the time to first event of composite cardiovascular morbidity and mortality. Cardiovascular morbidity is defined as nonfatal, clinically evident acute MI, nonfatal stroke, hospitalization for unstable angina, resuscitated sudden cardiac death, or coronary revascularization procedures. Cardiovascular mortality is defined as death due to sudden cardiac death, fatal MI, fatal stroke, death due to coronary intervention, or death due to congestive heart failure or other cardiovascular causes.1 (Jamerson et al. Am J Hypertens. 2004;17: Page 795-B) 1. Jamerson KA, Bakris GL, Wun CC, et al. Rationale and design of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens. 2004;17:793–801. Jamerson KA et al. Am J Hypertens. 2004;17:793–801.

ACCOMPLISH: Statistical Power
1,642 primary endpoints needed (~5 years) 90% power to detect a 15% risk reduction for the primary endpoint at a two-sided overall significance level of 5% Four (4) interim analyses and 1 final analysis Allow for lost-to-follow-up rate of less than 5% Sample size is calculated with 90% power to detect a 15% risk reduction for the primary efficacy endpoint for the benazepril/amlodipine group compared with the benazepril/HCTZ group at a two-sided overall significance level of 5%. Based on the data reported by major large-scale cardiovascular event trials, an annual first-event rate of 3.5% is assumed for patients in the benazepril/HCTZ group. Considerations for the performance of four equally spaced interim analyses and one final analysis using O’Brien-Fleming group-sequential methods are also made. To fulfill these assumptions, 1,642 patients with a primary endpoint are required for both treatment groups combined. A total of 12,600 randomized and completed patients are required to achieve this number of events and allow for a rate of less than 5% of patients lost to follow-up.1 (Jamerson et al. Am J Hypertens. 2004;17: Page 797-A) 1. Jamerson KA, Bakris GL, Wun CC, et al. Rationale and design of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens. 2004;17:793–801. Jamerson KA et al. Am J Hypertens. 2004;17:793–801.

ACCOMPLISH: Design Randomization
Free add-on antihypertensive agents* Titrated to achieve BP <140/90 mmHg; <130/80 mmHg in patients with diabetes or renal insufficiency Amlodipine/ benazepril 10/40 mg Amlodipine/ benazepril 5/40 mg Amlodipine/ benazepril 5/20 mg Screening (N=12,600) Randomization Benazepril 20 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 25 mg Forced titration Free add-on antihypertensive agents* 14 Days Day 1 Month 1 Month 2 Month 3 Year 5 *Beta blockers; alpha blockers; clonidine; loop diuretics. Patients were seen at 6 months after the start of study and thereafter at 6-month intervals until the end of the 5 year trial. Jamerson KA et al. Am J Hypertens. 2004;17:793–801.

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

ACCOMPLISH: Key Demographic Data
Race: Caucasian 83.9% Black 11.9% Oriental 0.4% Other 3.8% Ethnicity: Hispanic 5.4% Gender Male 60.7% Female 39.3% % of Population Baseline BP (mmHg) Control Rate at Baseline+ All Patients* 40% 145.4/80 37.5% Diabetic Sub-Population 60% 145.2/79.3 16.3% Mean Age, years % of Pts >70 68.4 40.9% +BP<140/90 for non-diabetics and <130/80 for diabetics * including 6.8% of CKD based on Serum Creatinine

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

ACCOMPLISH: Effect of Initial Combination Therapy on SBP Over Time
160 All Patients 155 150 Baseline N=11,400 145.4 (18.3) 145 SBP (mmHg) 140 Month 12 N=10,335 132.7 (16.0) 135 Month 6 N=10,736 132.5 (16.0) Month 18 N=9,898 131.8 (16.0) 130 125 120 (sd) Data on file. Novartis Pharmaceuticals Corporation.

ACCOMPLISH: Significant Reduction in SBP in All Patient Populations
African American All Nordic U.S. 155 152.6 Baseline Range (N=3,333) 136.8 150 145.4 145.1 145 (N=11,400) 131.8 142.4 (N=1,361) 133.6 140 (N=8,067) JNC-7 Goal: SBP 140 mmHg SBP (mmHg) 135 130 129.4 125 120 P<0.05 Neither age nor gender appeared to influence the effects on SBP. Data on file. Novartis Pharmaceuticals Corporation.

ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy
80.5 N=8,067 90 75.6 N=11,400 71.8 N=1,361 80 65.1 N=3,333 70 60 50 Control rate (%) 40 Baseline Control Rates 44.4 38.6 37.6 30 20 21.0 10 All Nordic U.S. African American Data on file. Novartis Pharmaceuticals Corporation.

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

Considering Combination Therapy
Hypertension – A Systemic Disease Requiring Systematic Approaches To Therapy Recent Clinical Practice Recommendations Focusing on Combination Therapy in Difficult-to-Treat Patient Populations with High Blood Pressure and Compelling Conditions It is always a pleasure to present to ISHIB. My charge is to discuss the implications of the AASK trial on the management of hypertension in Blacks. The first implication is that we are beginning to accumulate data on the best way to lessen the toll that this disease extracts from our community. Jackson T. Wright, Jr. MD, PhD Professor of Medicine Case Western Reserve University Program Director, General Clinical Research Center Director, Clinical Hypertension Program University Hospitals Case Medical Center and the Louis Stokes Cleveland VAMC

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

Hypertension in African Americans
(versus Whites) Epidemiology Treatment Higher prevalence & incidence (esp. women) Greater severity Earlier onset Higher hospitalization rates (~8 x  ) More target-organ injury Renin more often suppressed Less intensively treated More factors linked to HTN Tx resistance Diabetes Obesity Proteinuria Female sex  GFR Target-organ injury Living in SE USA Lesser BP response to ACEI than whites Less likely to receive RAS drugs

Combination Therapy is Needed to Achieve Target SBP Goals
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) Points of Emphasis / Key Messages This figure shows the number of antihypertensive medications required by patients in different clinical trials to achieve target SBP goals. On average, 3.2 different antihypertensive medications taken daily are required to achieve the recommended BP goal of <130/80 mm Hg in patients with type 2 diabetes and <130/85 mm Hg in patients with renal insufficiency. The achieved SBPs shown are for the low-pressure groups in these trials. This figure used data from ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), MDRD (Modification of Dietary Protein in Renal Disease Trial), INVEST (International Verapamil SR-Trandolapril Study), AASK (African-American Study of Kidney Disease and Hypertension), UKPDS (United Kingdom Prospective Diabetes Study), RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan), ABCD (Appropriate Blood Pressure Control in Diabetes), HOT (Hypertension Optimal Treatment), and IDNT (Irbesartan in Diabetic Nephropathy Trial). Reference Updated from Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36: Updated from Bakris GL et al. Am J Kidney Dis. 2000;36:

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

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

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

JNC-7 Algorithm for Treatment of Hypertension
Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices 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 Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Guidelines also consistent with those developed by the British (2006), Canadian (2005), European, and WHO-ISH HTN guideline committees Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.

Consensus Statement: Management of High BP in African Americans
Patient with elevated BP Uncomplicated hypertension Goal BP: <140/90 mm Hg Diabetes/nondiabetic renal disease with proteinuria >1 g/24 h* Goal BP: <130/80 mm Hg If BP <155/100 mm Hg, monotherapy† If BP 155/100 mmHg, combination therapy‡ If BP <145/90 mm Hg, monotherapy or combination therapy including a RAS blocker§ If BP 145/90 mm Hg, combination therapy including a RAS blocker§ Not at BP goal? Intensify lifestyle changes AND Not at BP goal? Intensify lifestyle changes AND Add a 2nd agent from a different class or increase dose Increase dose or add a 3rd agent from a different class Add a 2nd agent from a different class or increase dose Increase dose or add a 3rd agent from a different class Released before JNC-7; revised ISHIB guidelines under development Many similarities with JNC-7 No preference for initial Rx in Blacks Strategy consistent with previous (2003) and probable pending European guidelines 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:

Lisinopril versus Chlorthalidone
Black vs. Non-Black Lisinopril versus Chlorthalidone Relative Risk and 95% Confidence Intervals Black Non-Black Favors Lisinopril Chlorthalidone 0.50 1 2 1.13 ( ) 0.93 ( ) 1.00 ( ) 1.06 ( ) 1.01 ( ) 0.97 ( ) 0.94 ( ) Nonfatal MI + CHD Death All-Cause Mortality Combined CHD Combined CVD Stroke End Stage Renal Disease Heart Failure 0.50 1 2 1.30 ( ) 1.30 ( ) 1.40 ( ) 1.19 ( ) 1.15 ( ) 1.06 ( ) 1.10 ( ) Racial differences ACEI vs Diuretic. A 4 mmHg difference in BP in the ALLHAT was associated with substantial differences in CV outcome. Thus, ACEI (and ARBs) while effective in slowing progression of renal disease are not that effective in preventing CVD events, esp in Blacks ALLHAT Favors Lisinopril Favors Chlorthalidone Wright JT et al; JAMA 2005; 293:1593

Blood Pressure at 5 Years by Race
Chlorthalidone Amlodipine Lisinopril SBP – mean (sd) Black 135.0 (15.8) 136.1 (15.3) 139.1 (19.7) Non-black 133.3 (14.8) 133.8 (14.6) 134.2 (16.7) DBP – mean (sd) 77.4 (10.0) 76.3 (10.1) 78.0 (11.4) 74.4 (9.5) 73.6 (9.6) 74.1 (10.1) ∆ BP compared with chlorthalidone --- +1.1 / -1.1* +4.1* / +0.6 +0.5 / -0.8* +0.9 / -0.3 Randomized to ACEI resulted in significantly poorer BP control at 5yrs of followup ALLHAT * P < 0.005 05/15/03

Frequency Distribution: SBP in Response to Quinapril in Black and White Participants
20.0 Mean –15.3 SD 12.2 Lower Quartile –7.3 Upper Quartile –23.5 Interquartile Range 16.2 Whites n = 2046 15.0 White, % 10.0 5.0 20.0 Mean –10.5 SD 13.4 Lower Quartile –2.2 Upper Quartile –20.0 Interquartile Range 17.8 Blacks n = 533 15.0 African American, % 10.0 In addition, we know that ACEI are less effective in lowering BP. While substantial overlap, the mean and median difference in BP reduction in Black and White hypertensives is 5-6mmHg 5.0 39 27 15 3 –9 –21 –33 –45 –57 SBP (average change) E. Mokwe et. al., HTN 2004;43:1

Angioedema ALLHAT Total Blacks Non-blacks Chlorthalidone 8 / 15,255
0.1% 2 / 5,369 <0.1% 6 / 9,886 Lisinopril 38 / 9,054 0.4% 23 / 3,210 0.7% 15 / 5,844 0.3% p<.001 p=.002 Angioedema was four times as likely among participants assigned to lisinopril compared with participants assigned to lisinopril (p<.001). The difference was significant for both Blacks and non-Blacks, but the difference was most pronounced in Blacks (0.7% in the lisinopril group and <0.1% in the chlorthalidone group). There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to chlorthalidone not significant). ALLHAT

Results Of Primary Composite End Point in LIFE By Ethnic Group
Race N Hazard Ratio White Black Hispanic 100 Asian 25 20 15 10 5 Blacks Non-Blacks Atenolol (23.36) Losartan Time in Months Results of primary composite end point by ethnic group. The dots represent the hazard ratio; dot size is proportional to the number of patients for each ethnic group, as shown to the left. The line through each dot corresponds to the 95% confidence interval. Results of primary composite end point by ethnic group in the U.s.: blacks versus non-blacks. Julius et al. J Am Coll Cardiol 2004;43:

AASK Clinical Endpoint Analysis
ACEI vs. CCB ACEI vs. BB Outcome % Risk Reduction1 95 % Confidence Interval Reduction GFR event, ESRD or Death2 38% (+ 14 to + 55) p<0.005 22% (+ 1 to + 38) p< 0.042 GFR event or ESRD3 40% (+ 13 to + 59) p<0.007 (- 1 to + 41) p< 0.066 ESRD or Death4 48% (+ 26 to + 65) p<0.004 21% (- 5 to + 40) p< 0.11 ESRD alone5 59% (+ 34 to + 74) p< 0.001 23% (- 10 to + 45) p< 0.14 Every hypertensive with renal insufficiency should receive an ACEI or ARB We have made some progress as evidenced by the striking results of the AASK trial on reducing renal outcomes with an ACEI regimen. Main Results paper: Main Clinical Outcome 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; events, deaths censored. Wright et al 2002; JAMA, 288:2421

ASCOT All-Cause Mortality — Amlodipine versus Atenolol
10.0 % Atenolol (No. of events 820) 8.0 6.0 Amlodipine (No. of events 738) 4.0 2.0 HR = 0.89 (0.810.99) p = A regimen initiated with a DHP-CCB showed dramatically CVD protection against one initiated with a beta blocker in preventing CVD and even total mortality 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

Amlodipine versus Chlorthalidone
Black vs. Non-Black Amlodipine versus Chlorthalidone Relative Risk and 95% Confidence Intervals Black Non-Black Nonfatal MI + CHD Death All-Cause Mortality Combined CHD Combined CVD Stroke End Stage Renal Disease Heart Failure Favors Amlodipine 0.50 1 2 1.46 ( ) 1.15 ( ) 0.93 ( ) 1.06 ( ) 1.03 ( ) 0.97 ( ) 1.01 ( ) 0.97 ( ) 0.94 ( ) 0.99 ( ) 1.04 ( ) 0.93 ( ) CCB just as effective as diuretic in Black hypertensives for preventing CVD for all outcomes except HF 1.08 ( ) 1.32 ( ) 0.50 1 2 Favors Chlorthalidone Favors Amlodipine Favors Chlorthalidone ALLHAT Wright JT et al; JAMA 2005; 293:1593

VALUE Trial: Primary Composite Cardiac Endpoint
14 12 10 8 6 4 2 Valsartan-based regimen Amlodipine-based regimen Proportion of Patients With First Event (%) HR = 1.03; 95% CI = 0.94–1.14; P = 0.49 CCB equal to ARB in preventing CVD Time (months) Number at risk Valsartan 7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3765 1474 Amlodipine 7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474 Julius S et al. Lancet. June 2004;363

VALUE Trial — Hazard Ratios for Pre-specified Analyses
Valsartan/Amlodipine Primary cardiac composite endpoint cardiac mortality cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes 0.5 1 2 Favours valsartan Favours amlodipine Julius S et al. Lancet. June 2004;363

Staessen Meta-Regression Analysis: Robust Correlation Between Difference in SBP and Risk of CV Events All Trials Recent Trials 1.50 − 1.50 − P < VALUE? 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 1.25 − 1.25 − 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 • Odds Ratio (experimental/control) 1.00 − 1.00 − 0.75 − HOPE 0.75 − 0.50 − 0.50 − The X axis depicts the difference in SBP as determined by subtracting the SBP achieved by the control group from that achieved by the experimental group. When the SBP achieved by the control group is lower than that achieved by the experimental group, this number is negative. When the SBP achieved by the experimental group is lower than that of the control group, the number is positive. This indicates that the experimental drug lowered SBP more than the control treatment. The control treatment consisted of patients who received one of the following: no treatment, placebo, older drug classes, or a treatment strategy that lead to less BP control. The Y axis depicts the odds ratio for CV events (experimental divided by control) . This ratio was calculated from meta-regression models. At the intersection of the 2 dashed lines, there is no difference in lowering of SBP or in odds for CV events between the experimental and control treatments. One example that will assist in describing the graph is the HOPE study. In the HOPE study, a 3 mm Hg difference in SBP led to a 25% reduction in CV events. The authors looked at the difference between BP and CV events in all the clinical trials used in their first meta-analysis. They fit a meta-regression line for the data. Next they determined the 95% Cis for the meta-regression line and found that scatter around the line was fairly limited. The authors then applied their analysis strategy to new trials published between October 2001 and March 2003. Both graphs show that improved control of SBP was associated with reduced CV events. Note that In order to compare trials with differing endpoints, various events are grouped as “cardiovascular events.” Also note that trials are represented with black circles where the control treatment resulted in superior lowering of SBP compared with the experimental therapy. 0.25 − 0.25 − -5 5 10 15 20 25 -5 5 10 15 20 25 Difference in SBP (control minus experimental) mm Hg Difference in SBP (control minus experimental) mm Hg Adapted from Staessen JA, Wan JG, Thijs L. J Hypertens. 2003;21:

BP Reduction and Major Cardiovascular Outcomes
Relative risk of stroke Relative risk of CVD 0.25 0.50 0.75 1.00 1.25 1.50 Relative risk of heart failure -10 -8 -6 -4 -2 2 4 Relative risk of CHD Stroke CHD Heart Failure CVD Systolic blood pressure difference between randomised groups (mmHg) Blood Pressure Lowering Treatment Trialists’ Collaboration Lancet. 2003;362:

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

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

Drug Treatment Standards
WHO/ISH JNC 7 HAAWG ISHIB Initiate TX Uncomplicated HTN 140/90 (previously 160/90; currently 160/100 in UK) Initiate Combination TX- Uncomplicated 160/100 155/100 Initiate TX Complicated HTN & Goal 130/80 (140/90 for women & elderly and in UK) Initiate Combination TX- Complicated HTN 150/90 145/90 SD Nesbitt 2004

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 Complicated HTN Treat according to the compelling condition similarly according to all guidelines. SD Nesbitt 2004

NKF Guideline 3 – Management of Hypertension in Diabetes and CKD
Hypertensive people with diabetes and CKD Stage 1-4 should be treated with an ACE inhibitor or an ARB, usually in combination with a diuretic (A) Target blood pressure in diabetes and CKD should be <130/80 mmHg (B) The hypertension guideline included normotensive patients in the guideline statement. We moved those patients to a clinical practice recommendation, since the evidence for renoprotective efficacy in normotensive patients is sparse, largely due to the lack of such patients in most clinical trials and to the use of surrogate endpoints in trials that do involve these patients.

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

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

Combination Drug Therapy In Hypertension

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

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

ISHIB Consensus Statement: Management of Hypertension in African Americans
Patient with elevated BP 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 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 Large, randomized clinical trials have established that adults with uncomplicated hypertension will require two to four antihypertensive agents to achieve BP goals.1 Likewise, trials in diabetes or renal disease indicate that these high-risk patients will require an average of 3.2 different antihypertensive drugs to achieve the ISHIB recommendations of <130/80 mmHg.2 In the African American Study of Kidney Disease and Hypertension (AASK) study, African Americans with mild-to-moderate renal dysfunction required 2 to 3 drugs to reduce mean arterial BP to < mmHg.3 In hypertensive African Americans with diabetes, or with renal disease with significant proteinuria, the ISHIB Working Group recommends initial therapy with either monotherapy or combination therapy including a RAS blocker if BP <145/90 mmHg. Where BP is 145/90 mmHg, combination therapy including a RAS blocker is advised.1 1. Douglas JG, Bakris GL, Epstein M, et al. Management of high blood pressure in African Americans: consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003;163:525–541. 2. Bakris GL. Maximizing cardiorenal benefit in the management of hypertension: achieve blood pressure goals. J Clin Hypertens (Greenwich). 1999;1:141–147. 3. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;285:2719–2728. *Preferable BP goal for patients with renal disease with proteinuria >1 gm/24 h is <125/75 mmHg. †Initiate monotherapy at the recommended starting dose with an agent from any of the following classes: diuretics, b-blockers, CCBs, ACEIs, or ARBs. ‡To achieve BP goals more expeditiously, initiate low-dose combination therapy with any of the following combinations: b-blocker/diuretic, ACEI/diuretic, ACEI inhibitor/CCB, or ARB/diuretic. §Consider specific clinical indications when selecting agents. Douglas JG et al. Arch Intern Med. 2003;163:525–541

JNC 7 Algorithm for Treatment of Hypertension
Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease) Initial Drug Choices Without Compelling Indications With Compelling Indications As recommended by JNC 7, hypertension treatment should start with lifestyle modifications. If the patient is not at goal blood pressure of <140/90 mm Hg (<130/80 mm Hg for those with diabetes or chronic kidney disease), pharmacologic therapy should be initiated. Initial drug choices for patients without compelling indications should be a thiazide diuretic for most patients with stage 1 hypertension. Typically, combination therapy with 2 drugs is required for stage 2 hypertension. When use of a single drug fails to achieve the blood pressure goal, addition of a second drug from a different class should be initiated. A 2-drug combination usually consists of a thiazide-type diuretic plus an ACEI, an ARB, a -blocker, or a CCB.71 Specific antihypertensives are designated for compelling indications (eg, HF, post-MI, high coronary artery disease [CAD] risk, diabetes, etc).71 If a patient is still not at goal blood pressure following the treatment algorithm, optimize the patient’s dosages or add additional drugs until goal blood pressure is achieved. Also consider consulting with a hypertension specialist.71 Stage 1 Hypertension (SBP or DBP mm Hg) Thiazide-type diuretics for most May consider ACEI, ARB, BB, CCB, or combination Stage 2 Hypertension (SBP 160 or DBP 100 mm Hg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, ARB, BB, or CCB) Drug(s) for the Compelling Indications Other antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB) as needed Not at Goal Blood Pressure Optimize Dosages or Add Additional Drugs Until Goal Blood Pressure Is Achieved Consider consultation with hypertension specialist Chobanian et al. JAMA. 2003;289: 71. Chobanian AV, Bakris GL, Black HR, et al, and the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA. 2003;289:

Published Guidelines Have Set Lower Treatment Goals
JNC 7 / ADA / NKF / ISHIB Guidelines for Hypertension and Patients at High Risk <140/90 <130/80 mmHg Essential hypertension Diabetes mellitus Chronic renal disease High-risk* hypertension Condition Recent guidelines1,2,3,4 have been consistent in advocating aggressive therapy to lower levels of blood pressure in patients with hypertension and cardiovascular risk factors. Current JNC 7 guidelines as well as those of the American Diabetes Association (ADA), National Kidney Foundation (NKF), and International Society on Hypertension in Blacks (ISHIB) all urge clinicians to bring patients, particularly those at increased risk due to special clinical situations, to the new lower goals by aggressive titration of agents and use of combination therapy when appropriate. Aggressive therapy and aggressive follow-up will improve the poor cardiovascular outcomes now seen in this high-risk population. 1. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA. 2003;289:2560–2572. 2. Arauz-Pacheco C, Parrott MA, Raskin P; American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26(suppl):S80–S82. 3. Douglas JG, Bakris GL, Epstein M, et al. Management of high blood pressure in African Americans: consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003;163:525–541. 4. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. 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). Chobanian AV et al. JAMA. 2003;289:2560–2572. Arauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82. Douglas JG et al. Arch Intern Med. 2003;163:525–541. Bakris GL et al. Am J Kidney Dis. 2000;36:646–661

JNC-7 Compelling Indications
Diuretic BB ACEI ARB CCB AA CHF Post MI CAD risk DM Chronic kidney disease 2° stroke prevention         BB=beta blocker; ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; CCB=calcium channel blocker; AA=aldosterone antagonist; CHF=chronic heart failure; MI=myocardial infarction; CAD=coronary artery disease; DM=diabetes mellitus The JNC 7 Report. JAMA. 2003;289:2560

Mortality From High Blood Pressure Higher in African Americans
Overall Mortality Rates From Causes Related to Hypertension, 2003* 60 49.7 50 40.8 40 Mortality Rate, % 30 20 14.9 14.5 10 Male Female Male Female African American White The overall death rate from hypertension for African Americans is over three times that seen in white Americans. In 2003, the age-adjusted death rate from hypertension was 14.9% for white men and 14.5% for white women, compared with 49.7% for African American men and 40.8% for African American women.1 The increased risk of African Americans is not related to a lack of awareness or limited access to medical care: in fact, more African Americans than white Americans are aware of and are treated for their hypertension, although control rates are similar for both races.1 1. Thom T, Haase N, Rosamond W, et al. Heart Disease and Stroke Statistics–2006 Update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85–e151. In hypertensive African Americans, 30% and 20% of all deaths in men and women, respectively, may be due to high blood pressure. *High blood pressure listed as a primary or contributing cause of death. High blood pressure=systolic ≥140 mmHg or diastolic ≥90 mmHg, taking antihypertensive medicine, being told ≥2 times by a physician that you have high blood pressure. Adapted from Thom T et al. Circulation. 2006;113:e85–e151

RAS Blockade in African-American Patients
Drugs that block the renin-angiotensin system (RAS) provide less antihypertensive efficacy than in white patients* Physiologic basis for this proposition: Lower levels of plasma renin activity (PRA) Relative expansion of plasma volume Higher prevalence of salt dependency Higher Na+ and Ca+, may suppress PRA† Slide Summary Data now clearly support the use of RAS-blocking agents in African Americans with renal disease [1], and there is also a strong rationale for their use in patients with LVH or diabetes [2,3]. Background The final results of AASK [4] showed that ramipril reduced the decline in kidney function to a significantly greater extent than did metoprolol or amlodipine. Further, ramipril reduced clinical events by 46% compared with amlodipine. Differences in blood pressure level did not account for the protective effects on renal function. These data provide strong evidence for including an ACE inhibitor in the antihypertensive regimen for African-American patients with renal disease. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study followed 9193 patients with high blood pressure and LVH (6% were African American) who were randomized to receive either the ARB losartan or the CCB amlodipine for a mean of 4.8 years [2,3]. There was little difference between the 2 groups in the degree of blood pressure reduction; however, losartan reduced the incidence of stroke by 25% more than did atenolol, and 25% fewer losartan-treated patients were diagnosed with new-onset diabetes during the course of the study [2]. However, the benefit in the above studies may not extend to the very small groups of African Americans included in these trials. ACE inhibitors are preferred in African Americans with high blood pressure, until adequate clinical data regarding ARBs become available in this population. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;285: 2. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359: Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359: Douglas-Baltimore JG. Drug therapy in African-Americans with high blood pressure and renal insufficiency. Paper presented at: American Heart Association Scientific Sessions; November 11-14, 2001; Anaheim, Calif. * Weir MR et al. Hypertension. 1995;26: †Douglas JG. Unpublished data ‡Agodoa LY et al. JAMA. 2001;285:

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

Relative Risk Reduction With Ramipril vs Amlodipine Besylate: AASK
RRR=38% P=0.005 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 Ramipril Amlodipine besylate RRR=44% P=0.01 RRR=41% P=0.03 Events per person-yr Slide Summary In the African American Study of Kidney Disease and Hypertension (AASK), the relative risk reduction with ramipril was significantly greater than that with amlodipine for all endpoints related to glomerular filtration rate, end-stage renal disease, and all-cause death. Background The AASK study demonstrated that angiotensin-converting enzyme (ACE) inhibitors, usually underprescribed in African Americans, are important in providing necessary renal protection. Though not a conclusion of the AASK study, the addition of a calcium channel blocker to an ACE inhibitor can provide the needed blood pressure reduction in African Americans with renal disease. Agodoa LY, Appel L, Bakris GL, et al, for the AASK Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis. JAMA. 2001;285: GFR ESRD GFR, ESRD, or death GFR, glomerular filtration rate; ESRD, end-stage renal disease Agodoa LY et al. JAMA. 2001;285:

Favors Chlorthalidone
ALLHAT: Lisinopril vs Chlorthalidone Primary Endpoint (Nonfatal MI + CHD Death) Subgroups Relative Risk (95% CI) Total Age <65 Age 65 Men Women Black Nonblack Diabetic Nondiabetic Favors Lisinopril Favors Chlorthalidone 0.99 ( ) 0.95 ( ) 1.01 ( ) 0.94 ( ) 1.06 ( ) 1.10 ( ) 1.00 ( ) 0.99 ( ) The treatment effect of lisinopril versus chlorthalidone on the primary endpoint was consistent across all subgroups: age <65 and 65 years, men and women, blacks and nonblacks, diabetics and nondiabetics. ALLHAT Collaborative Research Group. JAMA. 2002;288: The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288: SLIDE 43

Relative Risk Reduction, %
ACEIs and ARBs Yield Reduction in Cardiovascular Morbidity and Mortality HOPE1 SOLVD3 CONSENSUS2 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<.001 27% P=.003 16% P=.003 LIFE5 Atenolol (n=4588) Losartan (n=4605) CHARM-Alternative4 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=.021 23% P=.0004 [1/Yusef/p 148/ Fig 1 and Table 3] [2/CONSENSUS/ p 1429/ Abstract/line 14-17] [3/SOLVD/p 293/ Abstract/line 14-17] [4/Granger/p 774/ Fig 2] [5/Dahlöf/p 999/ C 1/P 3/line 3-5] -10 Relative Risk Reduction, % -20 -30 -40 SLIDE SUMMARY: ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AND ANGIOTENSIN RECEPTOR BLOCKER THERAPIES ARE EFFECTIVE, BUT THERE IS ROOM FOR IMPROVEMENT Although clinical trial data indicate that angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapies do provide a significant benefit versus placebo (as measured by relative risk reduction for myocardial infarction, stroke, congestive heart failure, cardiovascular hospitalization, and cardiovascular-related mortality), the incidence of these events across all treatment groups remains substantial1-5 For example, while treatment with ramipril in the Heart Outcomes Prevention Evaluation (HOPE) trial did reduce the number of high-risk patients experiencing cardiovascular-related mortality, myocardial infarction, or stroke, compared with placebo, 14% of the patients in the treatment group nevertheless experienced a cardiovascular-related event, compared with 17.8% of placebo-treated patients1 In the SOLVD (Studies of Left Ventricular Dysfunction) trial, which compared enalapril versus placebo in heart-failure patients receiving conventional treatment, 35.2% (452) of the enalapril patients died, compared with 39.7% (510) of placebo patients. Although the treatment added benefit, a considerable number of treated patients did not survive3 In the CHARM-Alternative (Candesartan in Heart failure—Assessment of Reduction in Mortality and Morbidity) trial, heart-failure patients with ACEI intolerance were randomized to placebo or candesartan (target dose, 32 mg q24h). During the median follow-up of 33.7 months, hospitalization or cardiovascular-related death was reported in 33% (n=334) of candesartan patients versus 40% (n=406) of placebo patients. Once again, the treatment offered benefit compared with placebo, but a considerable number of patients did not survive or experienced an unfavorable outcome4 [1/Yusef/p 148/ Table 3] [2/CONSENSUS/ p 1429/ Abstract/ln 14-17] [3/SOLVD/p 295/ C 1/P 1/ln 1-2; P 2/line 2-6] [4/Granger/p 774; C 1/P 3/line 1; C 2/P 2/line 1-9] [5/Dahlöf/p 998/ Table 3] [4/Granger/p772/ C 1/P 3/line 3-9] ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HOPE, Heart Outcomes Prevention Evaluation; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; SOLVD, Studies of Left Ventricular Dysfunction; CHARM, Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity; LIFE, Losartan Intervention for Endpoint Reduction in Hypertension; MI, myocardial infarction; CV, cardiovascular; HF, heart failure; LVH, left ventricular hypertrophy. Yusuf S et al. N Engl J Med. 2000;342: The CONSENSUS Trial Study Group N Engl J Med. 1987;316: SOLVD Investigators. N Engl J Med. 1991;325: Granger CB et al. Lancet. 2003;362: Dahlöf B et al. Lancet. 2002;359: Yusuf S, Sleight P, Pogue J, Bosch J, et al, and the HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342: The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med. 1987;316: The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325: Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: CHARM-Alternative trial. Lancet. 2003;362: Dahlöf B, Devereux RB, Kjelden SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:

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

Diabetics Exposed to Telmisartan and Enalapril Study (DETAIL)
250 Type 2 diabetes, hypertension and nephropathy Forced titration of telmisartan (40-80 mg) and enalapril (10-20 mg) Primary outcome was a change in glomerular filtration rate (GFR) after 5 years Decrease in GFR Death Rate Several years ago, the NEJM published several articles showing the ARBs delayed the progression of diabetic nephropathy (type II patients). We did not have good data on ACE inhibitors in that group of patients (although we did have good data in type I diabetes). An editorial at that time lamented the lack of a study comparing ACE inhibitors and ARBs in these patients. This echoes my plea earlier this week for comparative drug studies. In a head-to-head comparison, the angiotensin-converting enzyme (ACE) inhibitor enalapril and the angiotensin-receptor blocker (ARB) telmisartan were equally effective in slowing kidney damage in people with type 2 diabetes, hypertension, and nephropathy, according to results from the Diabetics Exposed to Telmisartan and Enalapril (DETAILS) study reported here at the European Society of Cardiology Congress The primary outcome was change in glomerular filtration rate after five years. In the telmisartan group, the average decline in the glomerular filtration rate was 17.9 mL per minute, while in the enalapril group it was 14.9 mL per minute. The differences were not significant. In addition, a dramatic reduction in predicted mortality was seen with the use of either drug. Dr. Barnett said the death rate over the five-year trial was expected to be 35% to 50%, which was based on established five-year mortality rates in people with newly diagnosed diabetic nephropathy. But only six people in each group died - a 5% mortality rate. 14.9 17.9 p=ns 35-50% mL/min Percent 5% 5% enalapril telmisartan enalapril telmisartan expected rate over 5 years Barnett A et al N Engl J Med 2004

TRial Of Preventing HYpertension (TROPHY)
Kaplan-Meier Curves of Clinical Hypertension in the Two Groups 4 Years RR ↓15.8 AR ↓ 9.6 1.0 0.9 Candesartan Placebo 0.8 0.7 0.6 % Cumulative incidence 0.5 2 Years RR ↓66% AR ↓ 26% 0.4 0.3 0.2 0.1 1 2 3 4 Years in study Candesartan Placebo Numbers under the graph refer to hypertension-free individuals Julius S, Nesbitt SD et al NEJM 2006;354

Proportion Reaching Endpoint, %
Combination Therapy Delays but Does Not Prevent End-Stage Renal Disease COOPERATE Findings Proportion Reaching Endpoint, % 30 10 20 25 6 12 18 15 5 24 36 Combination (N=88) P=.02 Losartan (N=89) Trandolapril (N=86) [1/Nakao/ p 121/Fig 2] SLIDE SUMMARY: COMBINED ACEI AND ARB THERAPY IN PATIENTS WITH NONDIABETIC RENAL DISEASE YIELDED ADDITIONAL BENEFIT; BUT THERE IS STILL ROOM FOR IMPROVEMENT In the COOPERATE (combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in nondiabetic renal disease) trial, 336 patients with nondiabetic renal disease (>90% were also hypertensive) were randomized to treatment with an angiotensin II blocker (losartan, 100 mg daily), an angiotensin-converting enzyme inhibitor (trandolapril, 3 mg daily), or a combination of both drugs at equivalent doses. Drugs and regimens were compared based on the combined primary endpoint of time to doubling of serum creatinine concentrations and development of end-stage renal disease1 The trial was stopped after 3 years. At study end, 10 patients (11%) in the combination therapy group had reached combined study endpoint (1 patient had developed end-stage renal disease and required dialysis); 20 patients (23%) in both the losartan monotherapy and the trandolapril monotherapy groups reached the combined primary endpoint (3 losartan patients developed end-stage renal disease and required dialysis, compared with 7 trandolapril patients)1 Although combination therapy with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker was significantly superior to monotherapy with either agent (P=.02), some patients on combination treatment nevertheless reached the combined primary endpoint. These findings suggest the need for further treatment strategies or agents in order to prevent progressive nondiabetic renal disease1 Months After Randomization Number at risk Losartan Trandolapril Combination [1/Nakao/p 117/ Summary/ln 8-17; p 120/Table 1] [1/Nakao/p 121/C 1/ P 1/ln 5-7; P 2/ln 1-10] [1/Nakao/p 121/ Fig 2; p 123/C 2/ P 7/ln 1-8] COOPERATE, combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease Nakao N et al. Lancet. 2003;361: 1. Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet. 2003;361:

ASCOT: Blood Pressure Results
Amlodipine Besylate/Perindopril vs Atenolol/Bendroflumethiazide All CV events + revasc Fatal + nonfatal stroke New cases of diabetes mellitus 1°* endpoint All-cause mortality CV mortality ‒10 ‒10 NS Change(%) ‒15 P<0.005 ‒16 P<0.0001 ‒20 ‒23 P=0.0007 ‒26 P=0.0017 ‒30 ‒32 P<0.0001 N=19,257 *1° endpoint: nonfatal MI and fatal CHD CHD, coronary heart disease; MI, myocardial infarction; NS, nonsignificant ‒40 Presented March 8, 2005 at the American College of Cardiology Annual Scientific Session, Orlando, Florida

Renin System Suppression by ACE Inhibitors and ARBs
Summary Renin System suppression with ACEIs and ARBs has demonstrated significant clinical benefit Renin System suppression with ACEIs, ARBs, and even combinations of ACEI + ARB therapy may elevate key components and processes; such as PRA, Ang I, and Ang II with ARB usage and PRA and Ang I with ACEI usage Increased peptide levels have not been shown to overcome the blood pressure-lowering effect of these agents Consequently, benefits have not been demonstrated for all endpoints and in all patients Could even greater clinical benefits be expected from more complete Renin System suppression? SLIDE SUMMARY: CURRENT THERAPIES FOR RS INHIBITION OFFER SOME BENEFIT, BUT MORBIDITY AND MORTALITY ARE STILL HIGH The evidence from numerous large clinical trials indicates that renin system (RS) suppression is a valuable strategy in the treatment of hypertension and the prevention of end-organ disease that often accompanies hypertension However, even with high doses or the combination of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) (though at lower doses in clinical trials), the two currently available therapies targeting RS suppression, many patients will not achieve blood pressure control and will develop, or experience an exacerbation of, cardiovascular disease and kidney disease, along with unacceptably high rates of morbidity and mortality For these patients, RS suppression may be suboptimal ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker

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

Plasma Renin Activity (PRA)
PRA is a surrogate measure of renin activity Indicates the capacity of circulating renin to form Ang I (and ultimately Ang II) PRA is independently associated with the occurrence of cardiovascular disease among hypertensive patients1 A 25% increase in the risk of myocardial infarction for every 2 ng/mL/h increase in PRA1 Increased PRA activates the RAAS leading to increased generation of Ang II. Ang II is important in the generation of hypertension and both the short-term and long-term effects leading to organ damage2 Slide Grade: A Abbreviations PRA = plasma renin activity RAAS = renin-angiotensin-aldosterone system Ang = angiotensin References Alderman MH, Ooi WL, Cohen H, et al. Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients. Am J Hypertens 1997;10:1–8. Burnier M, Bunner HR. Angiotensin II receptor antagonists. Lancet 2000;355:637–645. 1. Alderman MH, et al Burnier M, et al. 2000

Crystal Structure of Renin
Renin Cleaves its Substrate, Angiotensinogen, to Form ANG I [1/Rahuel/p 232/ Fig 4] Angiotensinogen SLIDE SUMMARY: SCHEMATIC OF THE CRYSTALLIZED STRUCTURE OF THE RENIN MOLECULE The schematic shows the structure of renin, with the arrow pointing to the binding pocket where the peptide bond between Leu10 and Val11 in the angiotensinogen molecule is cleaved to form angiotensin I, an inactive decapeptide that is subsequently cleaved to form Angiotensin II1 [1/Rahuel/ p 227/C 2/ P 2/ln 3-9] Ang I Adapted from Rahuel J et al. J Struct Biol. 1991;107: 1. Rahuel J, Priestle JP, Grutter MG. The crystal structure of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor. J Struc Biol. 1991;107:

Only Direct Renin Inhibition Inhibits the Entire Renin System1-6
[1/Johnston/p 10/ C 1/P 3/ln 6-14, C 2/P 1/ln 1-3] [2/Widdop/p 516/ C 2/P 1/ln 1-3] [3/Fabiani/p 267/ P 2/ln 1-3] [4/Waybill/p963/ C 1/P 6/ln 1-3] [5/Reid/p S241/ C 2/P 6/ln 1-13; p S237/C 1/ P 3/ln 1-5/Fig 1] [6/Lin/p 1026/C 2/ P 3/ln 8-15] Class PRA Ang I Ang II Diuretic ACEI ARB Direct Renin Inhibitor (DRI) SLIDE SUMMARY: DIURETICS, ACEIs, AND ARBs ACTIVATE THE RS; RENIN INHIBITION DOES NOT Although angiotensin-converting enzyme inhibitor (ACE) inhibition reduces levels of angiotensin (Ang) II (by preventing the formation of Ang II from Ang I), angiotensin-converting enzyme inhibitor (ACEI) therapy is associated with a reactive rise in plasma renin activity and plasma Ang I levels, perhaps due to the negation of the short feedback loop wherein Ang II inhibits renin secretion by AT1 receptor stimulation. Such a process may overcome the effects of ACE inhibition1 Far from blocking the formation of circulating Ang II, angiotensin-receptor blocker (ARB) therapy is associated with elevated plasma Ang II concentrations, driven by a rise in plasma renin activity linked to inhibition of AT1-mediated negative feedback on renin release2,3 The major mechanism of action of diuretics, the reduction of extracellular volume, is an important physiological or pathophysiologic initiator of renin secretion. Renin secretion is the initial step in the renin system (RS) cascade, leading to increased levels of Ang I and Ang II4,5 Diuretic therapy in patients with hypertension has been associated with increases in both plasma renin activity (PRA) and aldosterone concentrations6 Direct renin inhibitors block the formation of Ang I, and thus Ang II becomes unavailable to maintain its vasopressor and volume-regulatory effects on the circulation. Thus renin inhibitors decrease PRA, in addition to systemic blood pressure and systemic vascular resistance7 [1/Johnston/p 10/ C 1/P 3/ln 6-14, C 2/P 1/ln 1-3] [2/Widdop/p 516/ C 2/P 1/ln 1-3] [3/Fabiani/p 267/ P 2/ln 1-3] [4/Waybill/p963/ C 1/P 6/ln 1-3] [5/Reid/p S241/ C 2/P 6/ln 1-13; p S237/C 1/ P 3/ln 1-5/Fig 1] [6/Fernandez/ p 515/Tables 2 and 3] [7/Lin/p 1026/C 2/ P 3/ln 8-15] Increased peptide levels have not been shown to overcome the blood pressure-lowering effect of these agents. PRA, plasma renin activity; Ang, angiotensin; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker. Johnston CI. Blood Pressure. 2000;9(suppl 1):9-13 Widdop RE et al. Hypertension. 2002;40: 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 Lin C et al. Am Heart J. 1996;131: Johnston CI. Angiotensin II type 1 receptor blockade: a novel therapeutic concept. Blood Pressure. 2000;9(suppl 1):9-13. Widdop RE, Matrougui K, Levy BI, et al. AT2 receptor-mediated relaxation is preserved after long-term AT1 receptor blockade. Hypertension. 2002;40: Fabiani ME, Johnston CI. AT1 receptor antagonists as antihypertensive agents. In: Epstein M, Brunner HR, eds. Angiotensin II Receptor Antagonists. Philadelphia, Pa: Hanley & Belfus, Inc; 2001: Waybill MM, Waybill PN. A practical approach to hypertension in the 21st Century. J Vasc Interv Radiol. 2003;14: Reid IA. The renin-angiotensin system: physiology, pathophysiology, and pharmacology. Adv Physiol Ed. 1998;20:S236-S245. Fernandez PG, Snedden W, Nath C, et al. Hemodynamic and neurohumoral factors in the response of hypertensives to hydrochlorothiazide therapy. Clin Invest Med. 1987;10: Lin C, Frishman WH. Renin inhibition: a novel therapy for cardiovascular disease. Am Heart J. 1996;131:

Renin System Suppression via Direct Renin Inhibition1-3
Targets the point of activation in the Renin System Binds to renin, neutralizing its ability to convert angiotensinogen to Ang I Reduces plasma renin activity PRA is a marker for Renin System activity/stimulation Elevated levels of prorenin have been shown with direct renin inhibition; potential physiological effects are being investigated in animal studies Decreases formation of Ang I and Ang II Ang I unavailable for ACE and non-ACE conversion to Ang II Ang II unavailable to stimulate AT receptors Ang II unavailable for conversion to Ang subtypes [eg, Ang (2-8), also called Ang III] [1/Stanton/p 7/ C 2/P 3/line 8-12] [2/Wood/p310/ Table 1] [3/Nussberger/p 3/ Discussion/ln 1-3/ p 6/C 1/ln 1-6] SLIDE SUMMARY: RENIN INHIBITION IS AN ATTRACTIVE OPTION COMPARED WITH OTHER THERAPIES FOR RENIN-ANGIOTENSIN SYSTEM SUPPRESSION Upstream renin system (RS) suppression via renin inhibition is therapeutically attractive: Renin inhibition blocks the first, rate-limiting step in the RS cascade, ie, the interaction of renin with angiotensinogen to form angiotensin I (Ang I).1,2 Because angiotensinogen is the only known substrate of renin, renin inhibition should therefore provide very specific blockade of the RS2 AT receptors are located on cell membranes in a variety of tissue sites. Blocking agents must therefore penetrate the interstitial fluid to reach the target receptor. In contrast, the main target of renin inhibitors appears to be circulating renin2 [1/Stanton/p 6/ C 2/P 2/line 1-2] [2/Wood/p 309/ C 2/P 2/line 7-13] [2/Wood/p 309/ C 2/P 2/ln 13-20; p 310/C 1/P 1/ln 1-2, P 2/line 1-5] [2/Wood/p 310/ Table 1] [1/Stanton/p 6/ Abstract/ln 1-10] Ang, angiotensin; ACE, angiotensin-converting enzyme; AT, angiotensin receptor Stanton A. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10 Wood JM et al. Cardiovasc Drugs Ther. 1996;10: Nussberger J et al. Hypertension. 2002;39:e1-e8 Stanton A. Potential of renin inhibition in cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10. Wood JM, Close P. Renin inhibitors: cardiovascular drugs of the future? Cardiovasc Drugs Ther. 1996;10:

An Efficient Strategy to Achieve Interruption of the Renin System Is Direct Renin Inhibition1-3
AT1 Receptor Feedback Loop Ang I Angiotensinogen Ang II Renin ARBs ACE ACEIs [1/Stanton/p 6/C 2/ P 1/ln 1-10] [2/Kelly/p 471/ C 1/P 2] [3/Fisher/p 593/ Fig 1] 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)* SLIDE SUMMARY: INHIBITING RENIN IS A PHARMACOLOGICALLY EFFICIENT WAY TO INHIBIT THE RENIN SYSTEM (RS) Pathophysiologically, inappropriate activation of the renin system (RS) contributes to the development of hypertension, primarily by means of the stimulation of the AT1 receptor by angiotensin (Ang) II1 An efficient way to inhibit a biochemical pathway is to effectively block the rate-limiting step in the pathway2 In the RS pathway, the action of renin on angiotensin is the rate-limiting reaction; to block this reaction, it is imperative either to block the production of renin or to inhibit renin activity2 “No pharmacologist would have chosen angiotensin-converting enzyme (ACE) inhibition”3 as a preferred means of interfering with RS. ACE inhibition became the first attempt (chronologically) at RS inhibition because, in essence, it was a byproduct of the search for an explanation for the drop in blood pressure induced by snake venom. Renin inhibition would have been the logical first choice for RS interruption, both because it is the initial, rate-limiting step, and because of the specificity of renin for its substrate, angiotensinogen. The latter point would argue for little in the way of additional interactions, thus greatly reducing the chance of side effects3 [1/Gibbons/p 177S/ C 1/P 1/ln 9-14; p 178S/C 1/ln 18-23/ C2/ln 1-12] [2/Stanton/p 6/ Abstract/ln 1-5/ C2/P 2/ln 1-5] [2/Stanton/p 6/ C2/P 2/ln 1-5] [3/Fisher/p 592/ C 1/P 2/ln 10-13/ C 2/P 1/ln 6-14/ C 2/P 2/ln 8-10] *Increased peptide levels have not been shown to overcome the blood pressure-lowering effect of these agents. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Ang, angiotensin. Adapted from: Stanton A. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10 Kelly DJ et al. Hypertension. 2005;46: Fisher NDL et al. J Am Soc Nephrol. 2005;16: Gibbons GH. The pathophysiology of hypertension: the importance of angiotensin II in cardiovascular remodeling. Am J Hypertens. 1998;11:177S-181S. Stanton A. Potential of renin inhibition in cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10. Fisher NDL, Hollenberg NK. Renin inhibition: what are the opportunities? J Am Soc Nephrol. 2005;16:

Aliskiren Exhibits Dose-dependent Reductions In PRA Compared With ACE Inhibitors In Healthy Volunteers PRA (ng/mL/h) 100 Placebo Enalapril 20 mg 10 Aliskiren 640 mg Aliskiren 160 mg Aliskiren 80 mg 1 Aliskiren 40 mg In this study investigating pharmacodynamic effects of aliskiren in healthy volunteers, aliskiren produced significant, dose-dependent decreases in plasma renin activity (PRA). This was in contrast to observations in subjects receiving the ACE inhibitor enalapril, which led to an increase in PRA. Healthy volunteers (n=18) participating in this double-blind, three-way crossover study received two doses of aliskiren (40 and 80 mg once daily or 160 and 640 once daily) and randomized placebo or enalapril 20 mg in three 8-day dosing periods, separated by 6-day washout periods. PRA was measured in blood samples taken on Days 1 and 8. Dose-dependent reductions in PRA compared with baseline were observed on both Days 1 and 8 of aliskiren dosing. Enalapril, in contrast, was associated with a >15-fold increase in PRA on Day 1, and an even greater increase on Day 8. These findings show that, while ACE inhibition activates a compensatory feedback mechanism leading to a rise in PRA, renin inhibition suppresses PRA. Abbreviations ACE = angiotensin converting enzyme PRA = plasma renin activity References Nussberger J, Wuerzner G, Jensen C, et al. Angiotensin II suppression in humans by the orally active renin inhibitor aliskiren (SPP100): comparison with enalapril. Hypertension. 2002;39:e1e8. 0.1 2 4 6 8 10 24 Time (hours) Treatment day 8 Nussberger J, et al. Hypertension. 2002;39:e1e8

Aliskiren Reduces PRA as Compared to an ARB
PRA (ng Ang I/mL/h) 8 * † Valsartan 160 mg Aliskiren 150 mg + valsartan 80 mg 6 Placebo * † Aliskiren 300 mg 4 * † * † ‡ 2 † ‡ † ‡ * Renin-angiotensin-aldosterone system (RAAS) blockade at some points in the cycle, including angiotensin II receptor blockade, activates feedback mechanisms leading to increases in plasma renin activity (PRA). This study demonstrated that renin inhibition by aliskiren has the opposite effect, suppressing PRA, and when co-administered with an angiotensin receptor blocker (ARB), aliskiren counteracts the rise in PRA seen with ARB alone. PRA was measured in 12 mildly sodium-depleted, normotensive adults (aged 18–35 years) in a double-dummy, double-blind, randomized, placebo-controlled, four-period crossover study. Subjects received single doses of aliskiren 300 mg alone, aliskiren 150 mg in combination with valsartan 80 mg, valsartan 160 mg alone and placebo, separated by 2-week washout periods. Aliskiren 300 mg and valsartan 160 mg had opposing effects on PRA, with aliskiren 300 mg completely inhibiting PRA within 1 hour of drug administration and maintaining PRA below baseline for 48 hours, while valsartan 160 mg induced a sharp and persistent rise in PRA. The combination of aliskiren 150 mg and valsartan 80 mg reduced PRA to below levels observed with placebo within 1 hour of drug administration, and maintained PRA at placebo levels for up to 48 hours, indicating that aliskiren effectively suppresses ARB-induced increases in PRA. Abbreviations Ang I = angiotensin I ARB = angiotensin receptor blocker PRA = plasma renin activity RAAS = renin-angiotensin-aldosterone system References Azizi M, Ménard J, Bissery A, et al. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol 2004;15:3126–3133. * * 1 2 4 6 12 18 24 30 48 Time (hours) *p<0.05 vs aliskiren 150 mg + valsartan 80 mg †p<0.05 vs aliskiren 300 mg; ‡p<0.05 vs valsartan 160 mg n=12 mildly sodium-depleted normotensive subjects Azizi M, et al. J Am Soc Nephrol 2004;15:3126–3133

Aliskiren Offers Dose-dependent Reductions In SeDBP
Aliskiren 150 mg Aliskiren 300 mg Aliskiren 600 mg Placebo n=165 n=172 n=169 n=166 −2 −4 −6 −4.9 −8 −10.3 −10 −11.1 −12.5 −12 * −14 In this double-blind, randomized, placebo-controlled trial aliskiren significantly lowered mean seated diastolic blood pressure (SeDBP; p< versus placebo for all aliskiren doses). The magnitude of effect on SeDBP was dose-related – aliskiren 150, 300 and 600 mg reduced DBP (least squares mean±SEM) by 10.3±0.63, 11.1±0.64 and 12.5±0.64 mmHg, respectively, compared with 4.9±0.64 mmHg for placebo. Abbreviations Δ SeDBP = change in seated diastolic blood pressure Reference Novartis, data on file 2005 (CSPP100A2308). * * −16 Mean  SeDBP (mmHg) * p< versus placebo § p<0.05 for aliskiren 600 mg compared to aliskiren 150 mg Hypertension Mitchell J, et al. J Clin Hypertens 2006; suppl A, 8(5): A93 Herron J, et al. J Clin Hypertens 2006; suppl A, 8(5): A86 Monotherapy

Aliskiren Offers Dose-dependent Reductions in SeSBP
Aliskiren 150 mg Aliskiren 300 mg Aliskiren 600 mg Placebo n=165 n=172 n=169 n=166 −2 −3.8 −4 −6 −8 −10 −12 −13.0 −14.7 −14 In this double-blind, randomized, placebo-controlled trial aliskiren significantly lowered mean seated systolic blood pressure (SeSBP; p< versus placebo for all aliskiren doses). The magnitude of effect on SeSBP was dose-related – aliskiren 150, 300 and 600 mg reduced SBP (least squares mean±SEM) by 13.0±1.0, 14.7±1.0 and 15.8±1.0 mmHg, respectively, compared with 3.8±1.0 mmHg for placebo. Abbreviations Δ SeSBP = change in seated systolic blood pressure Reference Novartis, data on file 2005 (CSPP100A2308). −15.8 * −16 Mean  SeSBP (mmHg) * * * p< versus placebo Hypertension Mitchell J, et al. J Clin Hypertens 2006; suppl A, 8(5): A93 Herron J, et al. J Clin Hypertens 2006; suppl A, 8(5): A86 Monotherapy

Clinical Trials: Aliskiren Combination
Change in SBP for Aliskiren, HCTZ, and Aliskiren + HCTZ 0 mg HCTZ 6.25 mg HCTZ 12.5 mg HCTZ 25 mg HCTZ Placebo Mean Reductions from Baseline in SBP (mm Hg) SLIDE SUMMARY: AT ALL DOSE COMBINATIONS, THE ADDITION OF HCTZ TO ALISKIREN RESULTS IN GREATER SYSTOLIC BP REDUCTIONS The graph demonstrates that each increase in dosage of hydrochlorothiazide and aliskiren used in combination results in incremental systolic BP reduction. Thus the highest dose of HCTZ (25 mg) plus the highest dose of aliskiren (300 mg) produced the largest reduction in systolic BP As you can see by the shading of the bars, we’re addressing the placebo mean change from baseline the same way that we did in the earlier charts

Clinical Trials: Aliskerin in Combination
Change in DBP for Aliskiren, HCTZ, and Aliskiren + HCTZ 0 mg HCTZ 6.25 mg HCTZ 12.5 mg HCTZ 25 mg HCTZ Placebo Mean Reductions from Baseline in DBP (mm Hg) SLIDE SUMMARY: AT ALL DOSE COMBINATIONS, THE ADDITION OF HCTZ TO ALISKIREN RESULTS IN GREATER DIASTOLIC BP REDUCTIONS The graph demonstrates that each increase in dosage of hydrochlorothiazide and aliskiren used in combination results in incremental diastolic BP reduction. Thus, as we saw with systolic BP, the highest dose of HCTZ (25 mg) plus the highest dose of aliskiren (300 mg) produced the largest reduction in diastolic BP As you can see by the shading of the bars, we’re addressing the placebo mean change from baseline the same way that we did in the earlier charts

Clinical Trials: Aliskiren in Combination
Change in SBP for Aliskiren, Valsartan, and Aliskiren + Valsartan Week 4 Week 8 Aliskiren 150 mg + Valsartan 160 mg Aliskiren 300 mg + Valsartan 320 mg Placebo Aliskiren 150 mg Valsartan 160 mg Placebo Aliskiren 300 mg Valsartan 320 mg Mean Reductions from Baseline in SBP (mm Hg) SLIDE SUMMARY: CHANGE IN SYSTOLIC BP GREATER WITH COMBINATION THERAPY At each dosage level, the combination of aliskiren and valsartan resulted in a greater reduction in systolic BP than either agent at any dose used as monotherapy If we look at the week 4 results on the left, the grey bar is the placebo mean change from baseline. The magenta bar represents aliskiren 150 mg by itself. The orange bar is valsartan 160 mg by itself. And the purple bar represents the combination of aliskiren plus valsartan. And you’ll see that the combination of the two agents has a greater effect on blood pressure than either agent as monotherapy After 4 weeks, patients were then titrated up to higher doses of aliskiren and valsartan. At 8 weeks, what we see on the right side of the chart with the first bar is the placebo mean change from baseline. In the green bar, we see the results of aliskiren 300 mg by itself. The orange bar represents the results of valsartan 320 mg by itself. And the purple bar is the combination of 300 mg of aliskiren plus 320 mg of valsartan. Once again, you’ll see that the combination results show a greater blood pressure reduction than either monotherapy

Clinical Trials: Aliskiren in Combination
Change in DBP for Aliskiren, Valsartan, and Aliskiren + Valsartan Week 4 Week 8 Aliskiren 150 mg + Valsartan 160 mg Aliskiren 300 mg + Valsartan 320 mg Placebo Aliskiren 150 mg Valsartan 160 mg Placebo Aliskiren 300 mg Valsartan 320 mg Mean Reductions from Baseline in DBP (mm Hg) SLIDE SUMMARY: CHANGE IN DIASTOLIC BP GREATER WITH COMBINATION THERAPY As you can see by the shading of the bars, we’re addressing the placebo mean change from baseline the same way that we did in the earlier charts At each dosage level, the combination of aliskiren and valsartan resulted in a greater reduction in diastolic BP than either agent at any dose used as monotherapy

Conclusions and Summary
Hypertension is prevalent, underdiagnosed, and inadequately treated. Many patients don’t get to BP goal Treating hypertension involves more than BP reduction; sustained 24-hour control and end-organ protection are important Inappropriate activation of the Renin System is a central component in the development of hypertension and cardiovascular and renal disease Some agents that suppress the Renin System have unique end-organ protection benefits beyond BP reduction Targeting the Renin System at the point of activation, by direct renin inhibition, provides inhibition of the entire Renin System Future clinical trials are needed to elucidate additional benefits of direct renin inhibition

Critical Challenges in Cardiovascular Disease

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Critical Challenges in Cardiovascular Disease

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