2 Critical Challenges in Cardiovascular Disease ISHIB 2007Innovating Vascular Health: Practical Applications to Clinical PracticeCritical Challenges inCardiovascular DiseaseProgram ChairwomanShawna D. Nesbitt, MD, MSAssociate ProfessorDepartment of Internal MedicineDivision of HypertensionUniversity of Southwestern TexasMedical SchoolDallas, TX
3 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
4 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.
5 Program Educational Objectives Recognize markers of target organ damage and learn which antihypertensive agents are useful for preventing end organ complications such as CV disease and diabetic renal disease.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
6 Program Faculty Program Chairwoman Shawna D. Nesbitt, MD, MS Associate ProfessorDepartment of Internal MedicineDivision of HypertensionUniversity of Southwestern TexasMedical SchoolDallas, TexasKen Jamerson, MDProfessor of MedicineCardiovascular MedicineUniversity of Michigan HealthSystemAnn Arbor, MichiganJackson T. Wright, Jr., MD, PhD, FACPProfessor of MedicineProgram Director, General ClinicalResearch CenterCase Western Reserve UniversityDirector, Clinical Hypertension ProgramUniversity Hospitals of ClevelandChief, Case Western ReserveUniversity Hypertension Section(Louis Stokes VAMC)Cleveland, Ohio
8 Program Agenda 7:15 – 7:30 PMIntroduction and OverviewThe Current Landscape of Cardiovascular Risk Management in African Americans—Where Co-morbidity Matters: The Evolving Relationship Between Risk Factors, Diabetes, Hypertension, and Vascular ComplicationsShawna D. Nesbitt, MD, MS7:30 – 8:00 PMAre 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 ThereKen Jamerson, MD8
9 Program Agenda8:00 – 8:25 PMHypertension—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 PMThe Evolving Landscape of Antihypertensive Therapy: Direct Renin Inhibition, Combination Therapy, and Implications for African American and Other Ethnic PopulationsShawna D. Nesbitt, MD, MS 8:55 PMQuestions and Interactions with the Faculty9
10 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 ComplicationsShawna D. Nesbitt MD, MSAssociate Professor of Internal MedicineUniversity of Texas SouthwesternDallas, Texas
11 The U.S. Population is Becoming Increasingly Diverse Changing TrendsHispanics 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, 2006Adapted from U.S. Census Bureau, Table 1a. Accessed Dec. 1, 2006.
12 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 60.012.3 to 24.95.0 to 12.20.3 to 4.9People indicating exactly one race, Black or African American, as a percent of total population by stateAdapted from U.S. Census Bureau, 2002 Redistricting Data (PL ) Summary File
13 Hypertensive Adults (Rate, Percent ± SE) Estimated Rates of US Adults With Hypertension by Sex, Race, and Ethnicity NHANES to451.8% age adj. increase407.2% age adj. increaseNon-Hispanic BlackFM3530Hypertensive Adults (Rate, Percent ± SE)2520The 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.615105MFMFAllNon-Hispanic WhiteMexican AmericanFields et al. Hypertension. 2004;44:Hajjar and Kotchen. JAMA. 2003;290:199–2066. 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:
14 Percentage increase from 1988 to 2000 Hypertension Treatment and Control Rates by Race/Ethnicity: NHANES 2000706360.1Treatment6055.6Control5044.64440.340%30Percentage increase from 1988 to 20007.20.96.28.23.720Evidence 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.1In 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.21. 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;4:10African Americans*Whites*Mexican Americans*Non-Hispanic.Hajjar and Kotchen. JAMA. 2003;290:199–206.
15 Mortality From High Blood Pressure Higher in African Americans Overall Mortality Rates From Causes Related to Hypertension, 2003*6049.75040.840Mortality Rate, %302014.914.510MaleFemaleMaleFemaleAfrican AmericanWhiteThe 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.1The 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.11. 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 inmen 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.
16 Patients Not at JNC VI BP Goals % Not at Goal BP Systolic Diastolic Patient Type (mm Hg) BP BPNHANES ( )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
17 Risk-Factor Clustering by Race and Sex 102030405060701≥2≥3White womenAfrican-American womenWhite menAfrican-American menPercentageAfrican Americans are more likely to have multiple risk factors than are Caucasians.Stone et al JAMA. 1996;275:
18 Obesity and Diabetes Among US Adults: Growing prevalence Obesity (BMI ≥30 kg/m2)Diagnosed diabetes+11.9%30+11.5%184.108.40.206.42524.365.923.923.7Population(%)23.021.8A 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.1There 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.11. Centers for Disease Control National Health Interview Survey. Accessed February 2005.20415220002001200220032004*20002001200220032004**Jan–JuneCDC NHIS;
19 Age-Adjusted Prevalence of Diabetes* by Race/Ethnicity in the US American Indians/ Alaska NativesNon-Hispanic Blacks19%Hispanic/Latino Americans15%Non-Hispanic Whites14%7%Age-Adjusted Prevalence of Diabetes by Race/Ethnicity in the USIn 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 oldPercentSources: National Health Interview Survey and National Health and Nutrition Examination Survey (NHANES) estimates projected to year outpatient database of the Indian Health ServiceCDC. National Diabetes Fact Sheet
20 Estimated Percentage of Americans Age 18 and Older Who Report No Leisure-Time Physical Activity by Race and SexAfrican 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
21 The Rising Tide of ESRD Diabetes: The Number One Cause of ESRD Year 50.1%Hypertension27%Glomerulonephritis13%Other10%700No of PatientsProjection600500400No. of ESRD Patients (x 1000)661,330300372,407200326,217100R2 = 99.8%19841986198819901992199419961998200020022004200620082010YearUSRDS. Annual data report
22 Years of Potential Life Lost to Total Heart Disease Before Age 75 by Race and Gender 40003000Years2000this impact is far greater in years of potential life lost to total heart disease.100019801980198519851990199019951995White womenAfrican-American womenWhite menAfrican-American menClark et al Heart Dis. 2001;3:97-108; National Vital Statistics System, Health, United States, 1996–97.
23 Failure to Reach Treatment Goals Carries Costly Burden N = 1000 managed-care patients with treated hypertensionGreater medication costsMore physician visits600129.7Mean drug cost per patient per year*($ US)400Mean visits per year8Costs of poor control can be substantialParamore 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.4.12004<130/85≥160/100130/85 – 139/89140/90 – 159/99<120 mm Hg≥180 mm HgMaximum SBPControlledUncontrolledSeverity of hypertension (mm Hg)*Based on 1999 average wholesale priceParamore LC et al. Am J Manag Care. 2001;7:
24 Are We in Control? The Importance of Early Risk Challenges and Solutions inMinority PopulationsAre We in Control?The Importance of Early RiskIdentification and TreatmentGetting To Goal and Staying There inEthnic Minority PopulationsKenneth A. Jamerson, M.D. Professor of Cardiovascular Medicine University of Michigan Medical Director, Program for Multi-cultural Health Ann Arbor, Michigan
25 The Tecumseh Blood Pressure Study A prospective epidemiological study of the antecedents of hypertension and cardiovascular disease in 1,100 young men and womenAnn ArborTecumseh
26 Tecumseh BP Study: Association of DBP and Other CHD Risk Factors HematocritCholesterolDBPTriglyceridesInsulinOverweightHeart RateP<0.001P<0.01P<0.05N=124 (aged years)Adapted from Julius et al. JAMA 1990;264:
27 Blood Pressure Trends in Tecumseh, Michigan *******HypertensiveNormotensive*P< .01S. Julius, et al: JAMA 264: , 1990P<.001**
28 Is There a Unique Etiology for Hypertension in African Americans? Causes and Causes for ConcernIs There a Unique Etiology for Hypertension in African Americans?
29 Deciphering The Etiology and Associations The Association of Skin Color with Blood pressure in US blacks with Low Socioeconomic StatusKlag, M J. Whelton, P K. Coresh, J. Grim, C E. Kuller, L H.JAMA Feb 6;265(5):639-40;AbstractTo 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.
30 A Critical Issue for Drug Selection and Care Response to TherapyA Critical Issue for Drug Selection and CareDo African Americans respond to antihypertensive therapy differently than other races or ethnic groups?
31 Blood Pressure Response to Quinapril: The ATIME Study 20.0Mean –15.3SD 12.2Lower Quartile –7.3Upper Quartile –23.5Interquartile Range 16.215.0White, %10.05.020.0Mean –10.5SD 13.4Lower Quartile –2.2Upper Quartile –20.0Interquartile Range 17.815.0African American, %10.0African 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;43:1202–1207.5.03927153–9–21–33–45–57SBP (average change)SD = standard deviation.Mokwe E et al. Hypertension. 2004;43(6):1202–7.
32 Is It Important To Block The RAS In African Americans? Landmark Trials That Give Us Data,Guidance, and PerspectiveHOPEPROGRESSSOLVDValHeftV-HeftLIFEOCTAVEALLHAT
33 African American Study of Kidney Disease and Hypertension Landmark and Longitudinal StudiesAfrican American Study of Kidney Disease and Hypertension
34 Achieved Blood Pressure in AASK ACECCBBBLOWUSUALSBP133.6131.4134.2126.9140.0DBP81.180.780.976.685.2NEED FOR STEP 528%24%32%35%23%
35 Cumulative Incidence of Confirmed Declining GFR Event, Dialysis or Death by Drug Group (Data as of 10/19/01)p-value A vs B C vs B* A vs C*adjustedCumulative Incidence.
36 Implications Of The AASK Study Aggressive control of blood pressure can eliminate ethnic differences in ESRDInadequate treatment of hypertension may cause excess risk of target organ diseaseCultural, rather than genetic differences, may underlay the excess risk of hypertensive ESRD
37 International Society of Hypertension in Blacks IMPACT CampaignScience Guidelines Behavioral Change
38 Vascular Matrix Summit Dr. Gary GibbonsDr. Abraham AvivRick Kittles, MDCharles Rotimi, MDDavid Harrison, MDWilla Hsueh, MDHelmy Siragy, MDDouglas Vaughan, MDDr. Brent EganKen Jamerson, MD
40 Does Being African American Modify the Problem?
41 Models to Explain Health Disparities Racial Genetic ModelCause of HD: Population differences in the distribution of genetic variantsHealth-behavior ModelCause of HD: Differences between R/E groups in the distribution of individual behaviors related to health such as diet, exercise, and tobacco useSES ModelCause of HD: Over-representation of some R/E groups within lower SESPsychosocial Stress ModelCause of HD: Stresses associated with minority group status, especially the experience of racism and discrimination1. Review of lit on HD reveals five explanatory models that have been used to account for the differences; each model emphasizes different sets of variablesexamples used are low birth weight and HTN.bracket life spanhealth problems that contribute most to HDassociated therefore may be linked to bicultural processes that lead to HDFocusing on PSM and SCM b/c they seem to be most promisingexplicit in this model is the cultural construction of race itself
43 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).
44 Ancestry Can Be Estimated Across Chromosomal Regions Seldin et al. Genome Res. 14: , 2004Smith et al. AJHG 74: , 2004
45 European Genetic Contribution in African-American Populations Living in Different Areas of the U.S. Parra et al. AJHG 1998; Parra et al. AJPA 2002; Kittles et al. unpublished
46 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”.
47 RESULTS BP Control at 18 Months Accomplishing SomethingRESULTS BP Control at 18 Months
48 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.
49 ACCOMPLISH: Primary Endpoint Time to first event of composite cardiovascular morbidity and mortalityCV MORBIDITYNonfatal MINonfatal strokeHospitalization for unstable anginaResuscitated sudden cardiac deathCoronary revascularization proceduresCV MORTALITYSudden cardiac deathFatal MIFatal strokeDeath due to coronary intervention, congestive heart failure, or other cardiovascular causesAll 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.
50 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 analysisAllow 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.
51 ACCOMPLISH: Design Randomization Free add-on antihypertensive agents*Titrated to achieve BP <140/90 mmHg; <130/80 mmHg in patients with diabetes or renal insufficiencyAmlodipine/ benazepril 10/40 mgAmlodipine/ benazepril 5/40 mgAmlodipine/ benazepril 5/20 mgScreening (N=12,600)RandomizationBenazepril 20 mg + HCTZ 12.5 mgBenazepril 40 mg + HCTZ 12.5 mgBenazepril 40 mg + HCTZ 25 mgForced titrationFree add-on antihypertensive agents*14 DaysDay 1Month 1Month 2Month 3Year 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.
52 Targeted Population for Recruitment into the ACCOMPLISH Trial Men or women of any racial background, age ≥55 yearsSBP ≥160 mmHg or currently on antihypertensive therapyEvidence of cardiovascular or renal disease or target organ damage
53 ACCOMPLISH: Key Demographic Data Race:Caucasian83.9%Black11.9%Oriental0.4%Other3.8%Ethnicity:Hispanic5.4%GenderMale60.7%Female39.3%% of PopulationBaseline BP (mmHg)Control Rate at Baseline+All Patients*40%145.4/8037.5%Diabetic Sub-Population60%145.2/79.316.3%Mean Age, years% of Pts >7068.440.9%+BP<140/90 for non-diabetics and <130/80 for diabetics* including 6.8% of CKD based on Serum Creatinine
54 Patient enrollment completed. Baseline Traits of ACCOMPLISH Cohort May Reflect New Secular Trends in Disease ManagementPatient enrollment completed.50% of patients are obese60% of patients have Diabetes Mellitus97% of patients were treated previously for hypertension.74% of patients were treated with > 2 Hypertensive AgentsOnly 37.5% of patients were controlled to <140/90 mmHgUpdate after Dr. Jamerson reviews
55 ACCOMPLISH: Effect of Initial Combination Therapy on SBP Over Time 160All Patients155150BaselineN=11,400145.4(18.3)145SBP (mmHg)140Month 12N=10,335132.7(16.0)135Month 6N=10,736132.5(16.0)Month 18N=9,898131.8(16.0)130125120(sd)Data on file. Novartis Pharmaceuticals Corporation.
56 ACCOMPLISH: Significant Reduction in SBP in All Patient Populations African AmericanAllNordicU.S.155152.6Baseline Range(N=3,333)136.8150145.4145.1145(N=11,400)131.8142.4(N=1,361)133.6140(N=8,067)JNC-7 Goal: SBP140 mmHgSBP (mmHg)135130129.4125120P<0.05Neither age nor gender appeared to influence the effects on SBP.Data on file. Novartis Pharmaceuticals Corporation.
57 ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy 80.5N=8,0679075.6N=11,40071.8N=1,3618065.1N=3,333706050Control rate (%)40Baseline Control Rates44.438.637.6302021.010AllNordicU.S.African AmericanData on file. Novartis Pharmaceuticals Corporation.
58 ConclusionsMillions 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.
59 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 ConditionsIt 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, PhDProfessor of MedicineCase Western Reserve UniversityProgram Director, General Clinical Research CenterDirector, Clinical Hypertension ProgramUniversity Hospitals Case Medical Center andthe Louis Stokes Cleveland VAMC
60 Goals of This Presentation Need for multi-drug therapy for BP controlGuideline recommendations for treatment and rationale for these recommendationsImportance of BP vs. drug selectionCombination drug regimens—options and strategies
61 Hypertension in African Americans (versus Whites)EpidemiologyTreatmentHigher prevalence & incidence (esp. women)Greater severityEarlier onsetHigher hospitalization rates (~8 x )More target-organ injuryRenin more often suppressedLess intensively treatedMore factors linked to HTN Tx resistanceDiabetesObesityProteinuriaFemale sex GFRTarget-organ injuryLiving in SE USALesser BP response to ACEI than whitesLess likely to receive RAS drugs
62 Combination Therapy is Needed to Achieve Target SBP Goals Number of BP medsTrial/SBP Achieved1234UKPDS (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 MessagesThis 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).ReferenceUpdated from Bakris GL, Williams M, Dworkin L et al. Preserving renal function inadults with hypertension and diabetes: a consensus approach. National Kidney FoundationHypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis.2000;36:Updated from Bakris GL et al. Am J Kidney Dis. 2000;36:
63 Number of Antihypertensive Drugs Used and BP Control (<140/90 mm Hg) ChlorthalidoneAmlodipineLisinoprilALLHAT
64 Percent Controlled (BP < 140/90) at Five Years by Number of Drugs Prescribed ChlorthalidoneAmlodipineLisinoprilALLHAT
65 Number of Drugs Needed to Control BP (<140/90 mm Hg) in ALLHAT After 5 Years 26% of participants were controlled on 1 drug (another 2% were untreated):Therefore, at least 72% received or needed ≥ 2 drugs49% 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 BP60% were controlled on 3 or fewer drugs:Therefore, at least 16% received or needed ≥ 4 drugs to control BPALLHAT
66 JNC-7 Algorithm for Treatment of Hypertension Lifestyle ModificationsNot at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)Initial Drug ChoicesStage 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 IndicationsDrug(s) for the compelling indicationsOther antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.With Compelling IndicationsGuidelines also consistent with those developed by the British (2006), Canadian (2005), European, and WHO-ISH HTN guideline committeesNot at Goal Blood PressureOptimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.
67 Consensus Statement: Management of High BP in African Americans Patient with elevated BPUncomplicated hypertension Goal BP: <140/90 mm HgDiabetes/nondiabetic renal disease with proteinuria >1 g/24 h* Goal BP: <130/80 mm HgIf 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 ANDNot at BP goal? Intensify lifestyle changesANDAdd a 2nd agent from a different class or increase doseIncrease dose or add a 3rd agent from a different classAdd a 2nd agent from a different class or increase doseIncrease dose or add a 3rd agent from a different classReleased before JNC-7; revised ISHIB guidelines under developmentMany similarities with JNC-7No preference for initial Rx in BlacksStrategy consistent with previous (2003) and probable pending European guidelinesRAS, 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 agentsDouglas J et al. Arch Intern Med. 2003;16:
68 Lisinopril versus Chlorthalidone Black vs. Non-BlackLisinopril versus ChlorthalidoneRelative Risk and 95% Confidence IntervalsBlackNon-BlackFavorsLisinoprilChlorthalidone0.50121.13 ( )0.93 ( )1.00 ( )1.06 ( )1.01 ( )0.97 ( )0.94 ( )Nonfatal MI + CHD DeathAll-Cause MortalityCombined CHDCombined CVDStrokeEnd Stage Renal DiseaseHeart Failure0.50121.30 ( )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 BlacksALLHATFavorsLisinoprilFavorsChlorthalidoneWright JT et al; JAMA 2005; 293:1593
69 Blood Pressure at 5 Years by Race ChlorthalidoneAmlodipineLisinoprilSBP – mean (sd)Black135.0 (15.8)136.1 (15.3)139.1 (19.7)Non-black133.3 (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 / -0.3Randomized to ACEI resulted in significantly poorer BP control at 5yrs of followupALLHAT* P < 0.00505/15/03
70 Frequency Distribution: SBP in Response to Quinapril in Black and White Participants 20.0Mean –15.3SD 12.2Lower Quartile –7.3Upper Quartile –23.5Interquartile Range 16.2Whites n = 204615.0White, %10.05.020.0Mean –10.5SD 13.4Lower Quartile –2.2Upper Quartile –20.0Interquartile Range 17.8Blacks n = 53315.0African American, %10.0In 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 5-6mmHg5.03927153–9–21–33–45–57SBP (average change)E. Mokwe et. al., HTN 2004;43:1
71 Angioedema ALLHAT Total Blacks Non-blacks Chlorthalidone 8 / 15,255 0.1%2 / 5,369<0.1%6 / 9,886Lisinopril38 / 9,0540.4%23 / 3,2100.7%15 / 5,8440.3%p<.001p=.002Angioedema 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
72 Results Of Primary Composite End Point in LIFE By Ethnic Group Race N Hazard RatioWhiteBlackHispanic 100Asian252015105BlacksNon-BlacksAtenolol(23.36)LosartanTime in MonthsResults 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:
73 AASK Clinical Endpoint Analysis ACEI vs. CCBACEI vs. BBOutcome% RiskReduction195 %Confidence IntervalReductionGFR event,ESRD or Death238%(+ 14 to + 55)p<0.00522%(+ 1 to + 38)p< 0.042GFR event or ESRD340%(+ 13 to + 59)p<0.007(- 1 to + 41)p< 0.066ESRD or Death448%(+ 26 to + 65)p<0.00421%(- 5 to + 40)p< 0.11ESRD alone559%(+ 34 to + 74)p< 0.00123%(- 10 to + 45)p< 0.14Every hypertensive with renal insufficiency should receive an ACEI or ARBWe 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 Outcome1. Adjusted for baseline proteinuria, MAP,gender, Hx CHF and age; 2) 179 declining GFR, 84 ESRD, 77 death; 3) 170 declining GFR, 84 ESRD; 4) 171 ESRD, 79 deaths; events, deaths censored.Wright et al 2002; JAMA, 288:2421
74 ASCOT All-Cause Mortality — Amlodipine versus Atenolol 10.0%Atenolol(No. of events 820)8.06.0Amlodipine(No. of events 738)4.02.0HR = 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 mortality0.00.01.02.03.04.05.0YearsNumber at riskAmlodipine perindoprilAtenolol thiazide
75 Amlodipine versus Chlorthalidone Black vs. Non-BlackAmlodipine versus ChlorthalidoneRelative Risk and 95% Confidence IntervalsBlackNon-BlackNonfatal MI + CHD DeathAll-Cause MortalityCombined CHDCombined CVDStrokeEnd Stage Renal DiseaseHeart FailureFavorsAmlodipine0.50121.46 ( )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 HF1.08 ( )1.32 ( )0.5012FavorsChlorthalidoneFavorsAmlodipineFavorsChlorthalidoneALLHATWright JT et al; JAMA 2005; 293:1593
76 VALUE Trial: Primary Composite Cardiac Endpoint 1412108642Valsartan-based regimenAmlodipine-based regimenProportion of Patients With First Event (%)HR = 1.03; 95% CI = 0.94–1.14; P = 0.49CCB equal to ARB in preventing CVDTime (months)Number at riskValsartan764974597407725070856906673265366349591137651474Amlodipine759674697424726771176955677265766391595937251474Julius S et al. Lancet. June 2004;363
77 VALUE Trial — Hazard Ratios for Pre-specified Analyses Valsartan/AmlodipinePrimary cardiac composite endpointcardiac mortalitycardiac morbidityAll myocardial infarctionAll congestive heart failureAll strokeAll-cause deathNew-onset diabetes0.512Favours valsartanFavours amlodipineJulius S et al. Lancet. June 2004;363
78 Staessen Meta-Regression Analysis: Robust Correlation Between Difference in SBP and Risk of CV EventsAll TrialsRecent Trials1.50 −1.50 −P <VALUE?UKPDS C vs AALLHATCAPPPNORDILMIDAS/NICS/VHASSTOP2/CCBsHOT M vs HINSIGHTHOT L vs HPROGRESS/PerSTOP2/ACEIsRENAALPATSSyst-ChinaATMHMRC1MRC2Syst-EurSHEPHEPEWPHEPART2/SCATUKPDS L vs HPROGRESS/ComSTOP1RCT70–80STONE1.25 −1.25 −ALLHAT/Lis BlacksALLHAT/Lis ≥ 65 yALLHAT/LisALLHAT/AmlCONVINCEANBP2DIABHYCARABCD/NT L vs HIDNT2SCOPELIFE/ALLELSALIFE/DMPREVENTNICOLEAASK L vs H•Odds Ratio (experimental/control)1.00 −1.00 −0.75 −HOPE0.75 −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 −-5510152025-5510152025Difference in SBP(control minus experimental) mm HgDifference in SBP(control minus experimental) mm HgAdapted from Staessen JA, Wan JG, Thijs L. J Hypertens. 2003;21:
79 BP Reduction and Major Cardiovascular Outcomes Relative risk of strokeRelative risk of CVD0.250.500.751.001.251.50Relative risk of heart failure-10-8-6-4-224Relative risk of CHDStrokeCHDHeart FailureCVDSystolic blood pressure difference between randomised groups (mmHg) Blood Pressure Lowering Treatment Trialists’ CollaborationLancet. 2003;362:
80 Percent Controlled (BP < 140/90) at Five Years by Number of Drugs Prescribed ChlorthalidoneAmlodipineLisinoprilALLHAT
81 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
82 Drug Treatment Standards WHO/ISHJNC 7HAAWG ISHIBInitiate TX Uncomplicated HTN140/90(previously 160/90; currently 160/100 in UK)Initiate Combination TX- Uncomplicated160/100155/100Initiate TX Complicated HTN & Goal130/80(140/90 for women & elderly and in UK)Initiate Combination TX- Complicated HTN150/90145/90SD Nesbitt 2004
83 Drug Choice Recommendations WHO/ISHJNC 7HAAWG ISHIBUncomplicated HTNThiazide as initial agentMay use ACE, ARB, Beta-B, CCBMay initiate diuretic, ACE, ARB, Beta-B, CCBCombination TX- UncomplicatedNot uniformly recommendedDiuretic + (ACE, Beta-B, ARB)or ACE/CCBComplicated HTNTreat according to the compelling condition similarly according to all guidelines.SD Nesbitt 2004
84 NKF Guideline 3 – Management of Hypertension in Diabetes and CKD Hypertensive people with diabetes and CKD Stage 1-4 should be treated with an ACE inhibitor or an ARB, usually in combination with a diuretic (A)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.
85 Combination Therapies b-adrenergic blockers and diureticsACE inhibitors and diureticsAngiotensin II receptor antagonists (ARBs) and diureticsCalcium antagonists and ACE inhibitorsCalcium antagonists and ARBsRenin inhibitors and diuretics
86 Combination Drug Therapy In HTN — Advantages Improved blood pressure controlUses different approachesBlocking counter-regulatory mechanismsEase of titration to BP goalReduce side effects (less dosage requirement)Improve protection of target organs
88 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 patientsClinical outcome data are available for CCBs, diuretics (thiazide-type), and RAS inhibitors (ACEIs and ARBs) as initial RxDifferences between guideline recommendations for treatment are minor and all focus on achieving BP goal and need for multi-drug regimensWith available agents, BP goals can be achieved
89 Emerging Therapies— Focus on RAS The Evolving Landscape of Antihypertensive Therapy Direct Renin Inhibition, Combination Therapy, and Implications for African American and other Ethnic PopulationsShawna D. Nesbitt MD, MSAssociate Professor of Internal MedicineDepartment of MedicineUniversity of Texas SouthwesternDallas, Texas
90 ISHIB Consensus Statement: Management of Hypertension in African Americans Patient with elevated BPAdd a 2nd agent from a different class or increase doseIf BP 155/100 mmHg, combination therapy‡If BP <155/100 mmHg, monotherapy†Increase dose or add a 3rd agent from a different classUncomplicated hypertension Goal BP: <140/90 mmHgNot at BP goal? Intensify lifestyle changes ANDIf 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 doseIncrease dose or add a 3rd agent from a different classDiabetes/nondiabetic renal disease with proteinuria >1 g/24 h* Goal BP: <130/80 mmHgNot at BP goal? Intensify lifestyle changes ANDLarge, 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.11. 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
91 JNC 7 Algorithm for Treatment of Hypertension Lifestyle ModificationsNot at Goal Blood Pressure (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease)Initial Drug ChoicesWithout Compelling IndicationsWith Compelling IndicationsAs 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.71Specific antihypertensives are designated for compelling indications (eg, HF, post-MI, high coronary artery disease [CAD] risk, diabetes, etc).71If 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.71Stage 1 Hypertension (SBP or DBP mm Hg) Thiazide-type diuretics for most May consider ACEI, ARB, BB, CCB, or combinationStage 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 IndicationsOther antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB) as neededNot at Goal Blood PressureOptimize Dosages or Add Additional Drugs Until Goal Blood Pressure Is Achieved Consider consultation with hypertension specialistChobanian 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:
92 Published Guidelines Have Set Lower Treatment Goals JNC 7 / ADA / NKF / ISHIB Guidelines for Hypertension and Patients at High Risk<140/90<130/80mmHgEssential hypertensionDiabetes mellitusChronic renal diseaseHigh-risk* hypertensionConditionRecent 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
94 Mortality From High Blood Pressure Higher in African Americans Overall Mortality Rates From Causes Related to Hypertension, 2003*6049.75040.840Mortality Rate, %302014.914.510MaleFemaleMaleFemaleAfrican AmericanWhiteThe 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.1The 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.11. 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 inmen 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
95 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 volumeHigher prevalence of salt dependencyHigher Na+ and Ca+, may suppress PRA†Slide SummaryData now clearly support the use of RAS-blocking agents in African Americans with renal disease , and there is also a strong rationale for their use in patients with LVH or diabetes [2,3].BackgroundThe final results of AASK  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 . 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:
96 Benefits of Renin System (RS) Suppression to Date Renin Angiotensin SystemBenefits of Renin System (RS) Suppression to DateClinical Trial Data
97 Relative Risk Reduction With Ramipril vs Amlodipine Besylate: AASK RRR=38% P=0.0050.010.020.030.040.050.060.070.08RamiprilAmlodipine besylateRRR=44% P=0.01RRR=41% P=0.03Events per person-yrSlide SummaryIn 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.BackgroundThe 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:GFRESRDGFR, ESRD, or deathGFR, glomerular filtration rate; ESRD, end-stage renal disease Agodoa LY et al. JAMA. 2001;285:
98 Favors Chlorthalidone ALLHAT: Lisinopril vs Chlorthalidone Primary Endpoint (Nonfatal MI + CHD Death) SubgroupsRelative Risk (95% CI)TotalAge <65Age 65MenWomenBlackNonblackDiabeticNondiabeticFavors LisinoprilFavors Chlorthalidone0.99 ( )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
99 Relative Risk Reduction, % ACEIs and ARBs Yield Reduction in Cardiovascular Morbidity and MortalityHOPE1SOLVD3CONSENSUS2Placebo (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 patientsMortality in chronic HFTotal mortality in severe HFACEIs22% P<.00127% P=.00316% P=.003LIFE5Atenolol (n=4588) Losartan (n=4605)CHARM-Alternative4Death, MI, or stroke in patients aged years with hypertension and LVHCV death or HF hospitalization in patients with chronic HF and intolerance of ACEIPlacebo (n=1015)Candesartan (n=1013)ARBs13% P=.02123% 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]-10Relative Risk Reduction, %-20-30-40SLIDE SUMMARY: ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AND ANGIOTENSIN RECEPTOR BLOCKER THERAPIES ARE EFFECTIVE, BUT THERE IS ROOM FOR IMPROVEMENTAlthough 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 substantial1-5For 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 patients1In 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 survive3In 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 GroupN 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:
100 Reduction of Progressive Nephropathy with ARB: IDNT Irbesartan vs ControlIrbesartan vs AmlodipineAmlodipine vs ControlDoubling Cr, ESRD, or Death (%)20*23**4nsDoubling of Cr, (%)3337***6ESRD (%)* p< .05** p< .01*** p<.001Lewis EJ NEJM 2001;345:851
101 Diabetics Exposed to Telmisartan and Enalapril Study (DETAIL) 250 Type 2 diabetes, hypertension and nephropathyForced titration of telmisartan (40-80 mg) and enalapril (10-20 mg)Primary outcome was a change in glomerular filtration rate (GFR) after 5 yearsDecrease in GFRDeath RateSeveral 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.14.917.9p=ns35-50%mL/minPercent5%5%enalapriltelmisartanenalapriltelmisartanexpectedrate over5 yearsBarnett A et al N Engl J Med 2004
102 TRial Of Preventing HYpertension (TROPHY) Kaplan-Meier Curves of Clinical Hypertension in the Two Groups4 YearsRR ↓15.8AR ↓ 9.61.00.9CandesartanPlacebo0.80.70.6% Cumulative incidence0.52 YearsRR ↓66%AR ↓ 26%0.40.30.20.11234Years in studyCandesartanPlaceboNumbers under the graph refer to hypertension-free individualsJulius S, Nesbitt SD et al NEJM 2006;354
103 Proportion Reaching Endpoint, % Combination Therapy Delays but Does Not Prevent End-Stage Renal DiseaseCOOPERATE FindingsProportion Reaching Endpoint, %30102025612181552436Combination (N=88)P=.02Losartan (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 IMPROVEMENTIn 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 disease1The 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)1Although 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 disease1Months After RandomizationNumber 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 diseaseNakao 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:
104 ASCOT: Blood Pressure Results Amlodipine Besylate/Perindopril vs Atenolol/BendroflumethiazideAll CV events + revascFatal + nonfatal strokeNew casesof diabetes mellitus1°* endpointAll-cause mortalityCV mortality‒10‒10 NSChange(%)‒15 P<0.005‒16 P<0.0001‒20‒23 P=0.0007‒26 P=0.0017‒30‒32 P<0.0001N=19,257 *1° endpoint: nonfatal MI and fatal CHD CHD, coronary heart disease; MI, myocardial infarction; NS, nonsignificant‒40Presented March 8, 2005 at the American College of Cardiology Annual Scientific Session, Orlando, Florida
105 Renin System Suppression by ACE Inhibitors and ARBs SummaryRenin System suppression with ACEIs and ARBs has demonstrated significant clinical benefitRenin 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 usageIncreased peptide levels have not been shown to overcome the blood pressure-lowering effect of these agentsConsequently, benefits have not been demonstrated for all endpoints and in all patientsCould 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 HIGHThe 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 hypertensionHowever, 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 mortalityFor these patients, RS suppression may be suboptimalACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker
106 Renin System (RS) Suppression via Direct Renin Inhibition Direct Renin Inhibition: What Do We Know?Renin System (RS) Suppression via Direct Renin InhibitionRenin SuppressionDevelopment of Direct Renin Inhibitors (DRIs)
107 Plasma Renin Activity (PRA) PRA is a surrogate measure of renin activityIndicates 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 patients1A 25% increase in the risk of myocardial infarction for every 2 ng/mL/h increase in PRA1Increased 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 damage2Slide Grade: AAbbreviationsPRA = plasma renin activityRAAS = renin-angiotensin-aldosterone systemAng = angiotensinReferencesAlderman 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
108 Crystal Structure of Renin Renin Cleaves its Substrate, Angiotensinogen, to Form ANG I[1/Rahuel/p 232/ Fig 4]AngiotensinogenSLIDE SUMMARY: SCHEMATIC OF THE CRYSTALLIZED STRUCTURE OF THE RENIN MOLECULEThe 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 IAdapted 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:
109 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]ClassPRAAng IAng IIDiureticACEIARBDirect Renin Inhibitor (DRI)SLIDE SUMMARY: DIURETICS, ACEIs, AND ARBs ACTIVATE THE RS; RENIN INHIBITION DOES NOTAlthough 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 inhibition1Far 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 release2,3The 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 II4,5Diuretic therapy in patients with hypertension has been associated with increases in both plasma renin activity (PRA) and aldosterone concentrations6Direct 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):9-13Widdop 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-S245Lin 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:
110 Renin System Suppression via Direct Renin Inhibition1-3 Targets the point of activation in the Renin SystemBinds to renin, neutralizing its ability to convert angiotensinogen to Ang IReduces plasma renin activityPRA is a marker for Renin System activity/stimulationElevated levels of prorenin have been shown with direct renin inhibition; potential physiological effects are being investigated in animal studiesDecreases formation of Ang I and Ang IIAng I unavailable for ACE and non-ACE conversion to Ang IIAng II unavailable to stimulate AT receptorsAng 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 SUPPRESSIONUpstream 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 RS2AT 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 receptorStanton A. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10Wood JM et al. Cardiovasc Drugs Ther. 1996;10:Nussberger J et al. Hypertension. 2002;39:e1-e8Stanton 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:
111 An Efficient Strategy to Achieve Interruption of the Renin System Is Direct Renin Inhibition1-3 AT1 ReceptorFeedback LoopAng IAngiotensinogenAng IIReninARBsACEACEIs[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 ActivationRenin initiates a chain of events within the systemCleaves angiotensinogen to form Ang IAng I is then converted to Ang IIFeedback LoopACEIs 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) II1An efficient way to inhibit a biochemical pathway is to effectively block the rate-limiting step in the pathway2In 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:
112 Aliskiren Exhibits Dose-dependent Reductions In PRA Compared With ACE Inhibitors In Healthy VolunteersPRA (ng/mL/h)100PlaceboEnalapril 20 mg10Aliskiren 640 mgAliskiren 160 mgAliskiren 80 mg1Aliskiren 40 mgIn 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.AbbreviationsACE = angiotensin converting enzymePRA = plasma renin activityReferencesNussberger 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:e1e8.0.124681024Time (hours)Treatment day 8Nussberger J, et al. Hypertension. 2002;39:e1e8
113 Aliskiren Reduces PRA as Compared to an ARB PRA (ng Ang I/mL/h)8* †Valsartan 160 mgAliskiren 150 mg + valsartan 80 mg6Placebo* †Aliskiren 300 mg4* †* † ‡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.AbbreviationsAng I = angiotensin IARB = angiotensin receptor blockerPRA = plasma renin activityRAAS = renin-angiotensin-aldosterone systemReferencesAzizi 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.**12461218243048Time (hours)*p<0.05 vs aliskiren 150 mg + valsartan 80 mg †p<0.05 vs aliskiren 300 mg; ‡p<0.05 vs valsartan 160 mgn=12 mildly sodium-depleted normotensive subjectsAzizi M, et al. J Am Soc Nephrol 2004;15:3126–3133
114 Aliskiren Offers Dose-dependent Reductions In SeDBP Aliskiren 150 mgAliskiren 300 mgAliskiren 600 mgPlacebon=165n=172n=169n=166−2−4−6−4.9−8−10.3−10−11.1−12.5−12*−14In 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.AbbreviationsΔ SeDBP = change in seated diastolic blood pressureReferenceNovartis, data on file 2005 (CSPP100A2308).**−16Mean SeDBP (mmHg)* p< versus placebo§ p<0.05 for aliskiren 600 mg compared to aliskiren 150 mgHypertensionMitchell J, et al. J Clin Hypertens 2006; suppl A, 8(5): A93Herron J, et al. J Clin Hypertens 2006; suppl A, 8(5): A86Monotherapy
115 Aliskiren Offers Dose-dependent Reductions in SeSBP Aliskiren 150 mgAliskiren 300 mgAliskiren 600 mgPlacebon=165n=172n=169n=166−2−3.8−4−6−8−10−12−13.0−14.7−14In 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.AbbreviationsΔ SeSBP = change in seated systolic blood pressureReferenceNovartis, data on file 2005 (CSPP100A2308).−15.8*−16Mean SeSBP (mmHg)*** p< versus placeboHypertensionMitchell J, et al. J Clin Hypertens 2006; suppl A, 8(5): A93Herron J, et al. J Clin Hypertens 2006; suppl A, 8(5): A86Monotherapy
116 Clinical Trials: Aliskiren Combination Change in SBP for Aliskiren, HCTZ, and Aliskiren + HCTZ0 mgHCTZ6.25 mgHCTZ12.5 mgHCTZ25 mgHCTZPlaceboMean Reductions from Baseline in SBP (mm Hg)SLIDE SUMMARY: AT ALL DOSE COMBINATIONS, THEADDITION OF HCTZ TO ALISKIREN RESULTS IN GREATERSYSTOLIC BP REDUCTIONSThe 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 BPAs 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
117 Clinical Trials: Aliskerin in Combination Change in DBP for Aliskiren, HCTZ, and Aliskiren + HCTZ0 mgHCTZ6.25 mgHCTZ12.5 mgHCTZ25 mgHCTZPlaceboMean Reductions from Baseline in DBP (mm Hg)SLIDE SUMMARY: AT ALL DOSE COMBINATIONS, THEADDITION OF HCTZ TO ALISKIREN RESULTS IN GREATERDIASTOLIC BP REDUCTIONSThe 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 BPAs 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
118 Clinical Trials: Aliskiren in Combination Change in SBP for Aliskiren, Valsartan, and Aliskiren + ValsartanWeek 4Week 8Aliskiren150 mg +Valsartan160 mgAliskiren300 mg +Valsartan320 mgPlaceboAliskiren150 mgValsartan160 mgPlaceboAliskiren300 mgValsartan320 mgMean Reductions from Baseline in SBP (mm Hg)SLIDE SUMMARY: CHANGE IN SYSTOLIC BP GREATER WITHCOMBINATION THERAPYAt 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 monotherapyIf 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 monotherapyAfter 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
119 Clinical Trials: Aliskiren in Combination Change in DBP for Aliskiren, Valsartan, and Aliskiren + ValsartanWeek 4Week 8Aliskiren150 mg +Valsartan160 mgAliskiren300 mg +Valsartan320 mgPlaceboAliskiren150 mgValsartan160 mgPlaceboAliskiren300 mgValsartan320 mgMean Reductions from Baseline in DBP (mm Hg)SLIDE SUMMARY: CHANGE IN DIASTOLIC BP GREATER WITHCOMBINATION THERAPYAs 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 chartsAt 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
120 Conclusions and Summary Hypertension is prevalent, underdiagnosed, and inadequately treated. Many patients don’t get to BP goalTreating hypertension involves more than BP reduction; sustained 24-hour control and end-organ protection are importantInappropriate activation of the Renin System is a central component in the development of hypertension and cardiovascular and renal diseaseSome agents that suppress the Renin System have unique end-organ protection benefits beyond BP reductionTargeting the Renin System at the point of activation, by direct renin inhibition, provides inhibition of the entire Renin SystemFuture clinical trials are needed to elucidate additional benefits of direct renin inhibition
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