John M. Flack, MD, MPH Chair, Department of MedicineWayne State University (WSU)

Hypertension Academy

FACULTY DISCLOSURE

Has received grant support from Astra Merck Human Health,AstraZeneca, CardioDynamics, Centers for Disease Control (CDC), Daiichi Sankyo, GlaxoSmithKline, Merck, Mannheim,National Institutes for Health (NIH), Novartis Pharmaceuticals,Pfizer

Serves as a consultant for Bristol-Myers Squibb Co.,CardioDynamics, Centers for Disease Control (CDC), CVRx,GlaxoSmithKline, Merck, Myogen, Novartis Pharmaceuticals, and National Institutes for Health (NIH).

Serves on the speaker bureau for Daiichi Sankyo, NovartisPharmaceuticals, and Pfizer

SESSION OBJECTIVES

Upon completion of this activity, participants should be able to:

• Gain familiarity with solutions to commonly encountered clinical problems that undermine blood pressure control and target-organ protection when treating hypertensive African Americans

• Explain specific, in-depth knowledge of optimal diuretic use in hypertension treatment

• Apply knowledge of hypertension evaluation, risk stratification, and therapeutics to case scenarios

OVERVIEW

Overview - John M. Flack, MD, MPH

Basic Principles of Effective Hypertension Therapeutics –John M. Flack, MD, MPH

Hypertension Case Management –Angela L. Brown, MD

Hypertension Case Management –Jackson T. Wright, Jr., MD, PhD

Effective BP Lowering and Target Organ Protection in Patients with Compromised Kidney Function – Errol D. Crook, MD

Break

New Antihypertensive Agents –George L. Bakris, MD

Optimal Utilization Diuretics in Antihypertensive Regimens –Domenic A. Sica, MD

Conclusion – John M. Flack, MD, MPH

Basic Principles of Effective Hypertension Therapeutics

John M. Flack, M.D., M.P.H., F.A.H.A., F.A.C.PProfessor of Medicine and Physiology

Chairman and Chief, Division of Translational Research and Clinical EpidemiologyDept. of Medicine

Wayne State UniversitySpecialist in Clinical Hypertension

Specialist in Chief for Internal Medicine, Detroit Medical Center

Aims

• Explain the basic approaches to hypertension diagnosis, risk stratification, and selection of antihypertensive drug therapies; and

• Utilize effective approaches to patients with resistant hypertension and limited financial resources

Suggested Dietary/Lifestyle Interventions During Hypertension Treatment

• Reduce dietary sodium intake (~ < 2 grams)• Raise potassium intake (~ > 60 – 80 mmol/d if kidney function not

depressed)• Increase (elemental) dietary calcium intake to ~ 1000 – 1300 mg/d,

depending on age• Limit total caloric intake, especially from saturated fat, to a level that

maintains ideal body weight• Increase aerobic physical activity – as appropriate for an individuals CVD

status and co-morbidities• Avoid heavy weight lifting• Stop smoking • Maintain normal vitamin D status (>~ 80 nmol/L)?

Important Historical Information

• Family history of premature HTN onset (<40 years) as well as premature stroke onset (esp. hemorrhagic)

• Known duration of BP elevations/HT, typical range of BP, Highest known BP, and treatment history (e.g., number and types of drugs)

• Compliance with antihypertensive regimen – historical and current and timing of most recent medication changes

• Alcohol consumption

• Medications, including OTC drugs (e.g., NSAID’s, diet supplements)

• Recreational durgs (e.g., cocaine, amphetamines)

• Medical and psychiatric history – COPD, erectile dysfunction, depression

Risk Stratification

Key Diagnostic Testing

• EKG–LVH, biphasic or inverted P wave in V1, PR interval, ischemia

• Lytes, BUN, crea, glucose, estimated glomerular filtration rate

• Fasting lipid profile

• Urinalysis and dipstick

• Framingham 10-year risk score

• Random spot urine albumin:crea or protein:crea ratio

Potentially Useful Diagnostic Testing

• CXR (special situations)–Smoker–Chest-related symptoms (e.g., cough)

• Echocardiogram–Unexplained SOB–History, exam, or clinical suspicion of LV systolic dsyfunction–Low threshold for ordering in older patients, especially if rate-limiting

CA’s are being utilized–Consider when documenting LVH would lead to lower BP target

• Ambulatory blood pressure monitoring–when knowing BP level outside of the office is deemed important–Usefule when symptoms suggest hypotension but cuff BP does not

confirm

Essential Physical Exam

• Height and weight (calculate BMI)

• Waist circumference

• Cardiovascular and pulmonary examination

• Palpation of peripheral pulses and auscultation to detect bruits

• Fundoscopy

Minimum Therapeutic BP Goals: JNC 7 Criteria

• Diabetes and/or renal insufficiency

• All other hypertensives

<130/80

<140/90

JNC 7 Definition of CKD

EGFR < 60 ml/min/1.73 m2

orAlbuminuria 300 mg/d

or 200 mg/g crea (spot urine)

By Now You Should Know or at Least Have Regarding….

• The adequacy of the current antihypertensive regimen–Diuretic(s) appropriate to level of kidney function?–Enough diuretic on board? –Undesirable drug combinations prescribed?

• The number and types of antihypertensive agents likely needed topersistently keep BP lower than the target level

• The likely level of prior BP control

• Is secondary HTN a legitimate consideration?

Therapeutic Inertia: A Major Contributor to Poor BP Control in Hypertensives

Under Medical Care

When > 15 mm Hg systolic and/or > 10 mm Hg diastolic, monotherapy will often not be enough

Most Widely Available Fixed-Dose Single Pill Antihypertensive Drug Combinations

• Thiazide Diuretic plus:–ACE inhibitor–ARB–Aldosterone antagonist–Beta blocker–Direct renin inhibitor–Potassium-sparing diuretics (triamterene, amiloride)

• Calcium Antagonist plus:–ACE inhibitor–ARB

Therapeutic Coverage After “Missed” Doses

8 AM24º Dosing

Interval

8 AM

MissedDose

NextDoseTaken

6 PMVulnerable

Period1

1 Vulnerable period is where long t1/2 drugs provide superior residual BP control because of their slow offset of action

Titrate Antihypertensive Drugs Methodically, Though Titration More Often Than Every 4 Weeks is Typically Unnecessary

ATIME Study: Results

01020304050607080

Flack et al. Arch Intern Med. 2000;160:1842-1847.

% P

atie

nts

With

%

Pat

ient

s W

ith

BP

<140

/90

mm

Hg

BP

<140

/90

mm

Hg

3636

52526262

4141

5454

6868

PP<.001<.001

PP=.02=.02Slow Titration (q 6 wk)Slow Titration (q 6 wk)Fast Titration (q 2 wk)Fast Titration (q 2 wk)

11 22 33

N =N = 11831183 16631663 932932 14471447 780780 12721272Mean Dose (mg) =Mean Dose (mg) = 2020 2020 28.328.3 29.229.2 34.534.5 3535

Study VisitStudy Visit

Dosage Range:Dosage Range: 2020--80 mg80 mg

And, While Rapid Up-titration of Antihyhpertensive Drugs is Unnecessary, AVOID THERAPEUTIC INERTIA!!!!!!!!!!

Berlowitz et al. N Engl J Med. 1998;339:1957.

Management of HTN:New England VA Study (N=800)

If DBP ≥90 mm Hg and SBP ≥155 mm Hg, medications ↑ 26% of time

If DBP ≤90 mm Hg and SBP ≥165 mm Hg,medications ↑ 22% of time

Patients with poorly controlled BP seenmore often

Patients who received more therapy achieved better control

Detecting Chronic Kidney Disease: Don’t Depend On the Serum Creatinine

GFR EstimatorMDRD Estimate of Glomerular Filtration (EGFR) for White Women

SERUM CREATININEAGE 0.6 0.8 1 1.2 1.4 1.6 1.8 2

20 to 24 133.1 95.5 73.8 59.8 50.1 42.9 37.5 33.225 to 29 127.7 91.6 70.8 57.4 48 41.2 35.9 31.830 to 34 123.4 88.5 68.4 55.4 46.4 39.8 34.7 30.735 to 39 119.8 85.9 66.4 53.8 45.1 38.6 33.7 29.940 to 44 116.7 83.8 64.7 52.5 43.9 37.6 32.9 29.145 to 49 114.1 81.9 63.3 51.3 42.9 36.8 32.1 28.450 to 54 111.8 80.2 62 50.2 42 36 31.5 27.955 to 59 109.7 78.7 60.8 49.3 41.3 35.4 30.9 27.360 to 64 107.8 77.4 59.8 48.5 40.6 34.8 30.4 26.965 to 69 106.2 76.2 58.9 47.7 39.9 34.2 29.9 26.570 to 74 104.6 75.1 58 47 39.4 33.7 29.4 26.175 to 79 103.2 74 57.2 46.4 38.8 33.3 29 25.780 to 84 101.9 73.1 56.5 45.8 38.3 32.9 28.7 25.485 to 89 100.7 72.2 55.8 45.2 37.9 32.5 28.3 25.190 to 94 99.5 71.4 55.2 44.7 37.4 32.1 28 24.895 to 99 98.5 70.7 54.6 44.3 37 31.8 27.7 24.5

Generally Speaking, the Role of Race in Selecting Effective Antihypertensive Drug Therapy Has Been

Greatly Exaggerated

SBP Avg Change

20.0

African American(percent)

Mean -10.5Std Deviation 13.4Lower Quartile -2.2Upper Quartile -20.0Interquartile Range 17.8

39 27 15 3 -9 -21 -33 -45 -57

17.515.012.510.07.55.02.5

0

Caucasian(percent)

Mean -15.3Std Deviation 12.2Lower Quartile -7.3Upper Quartile -23.5Interquartile Range 16.2

20.017.515.012.510.07.55.02.5

0

Blood Pressure Response to Quinapril1-3 Follow-up Visits

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

Diuretics are Indispensable in Complex Antihypertensive Drug Regimens

Suggested Utilization of Diuretics According to Level of Kidney Function

STEP 1■ Loop diuretic■ Chlorthalidone (EGFR > low

30’s)■ Metolazone■ Torsemide

STEP 2■ Loop diuretic + chlorthalidone■ Loop diuretic + metolazone

EGFR= estimated glomerular filtration rate; step 2 interrupts renal sodium absorption at multiple sites within the nephron

STEP 1■ Thiazide diuretic■ Aldosterone antagonist

STEP 2■ Thiazide + aldosterone

antagonist or other K-sparing diuretic

EGFR

Low(<45 ml/min/1.73 m2)

Not Significantly Depressed(>50 ml/min/1.73 m2)

Dietary Na+ Restriction

BP agent

↑ Venous capacitance

↓ BP

↑ RenalNa+ retention

ExpandedECFV/PV

Ad libitumNa+ intake

DrugDiet

• Prevention of PV expansion during antihypertensive drug therapy is key to maintaining BP response

ECFV=extracellular fluid volume, PV=plasma volume.

Chlorthalidone Lowers Ambulatory Systolic Blood Pressure More than Hydrochlorothiazide at Week 8 (N=30)

-12.4-13.5

-7.4 -6.4

-16

-12

-8

-4

0Chl (25 mg) HCTZ (50 mg)

Ernst ME, et al. Hypertension 2006;47:352-358.

∆ mm Hg

24 hr ABPM ∆

Nighttime ABPM ∆

p = 0.054

p = 0.009

Office BP reductions in SBP trended greater for Chlorthalidone -17.1 vs. 10.8 mm Hg (P=NS)

Alterations in Kidney Function During Pharmacological Antagonism of the ReninAngiotensin System (with ACEI’s and ARB’s)

Maintenance of Relatively Constant lntraglomerular Pressure by Renal Autoregulation despite Variations in Mean Arterial Pressure

In chronic hypertension, the curve showing the relation of the intraglomerular pressure to the renal perfusion pressure (or mean arterial pressure) is shifted to the right. With the development of chronic renal failure, renal autoregulation changes in such a way that the intraglomerular pressure begins to vary more directly with changes in the mean arterial blood pressure. When this change occurs, the normal sigmoidalrelation becomes progressively more linear. As a result, increases in the mean arterial pressure cause exaggerated increases in the intraglomerular pressure, whereas declines in the mean arterial pressure cause exaggerated decreases. Because of the rightward shift in the lower end of the curve, antihypertensive therapy may be accompanied by a decline in the glomerular filtration rate at a level of blood pressure that would not affect a normal person. Renal dysfunction in this setting is hemodynamic in origin and reflects a lower intraglomerular pressure.

High

Low80 120 160

Normal

Chronichypertension with chronic

renal disease

Chronichypertension with normal

renal function

Mean Arterial Pressure (mm Hg)

Intr

aglo

mer

ular

Pres

sure

Undesirable Antihypertensive Drug Combinations

• ACE inhibitor + ARB– Modest incremental BP lowering– Heightened risk for hyperkalemia and renal dysfunction– No incremental reduction in HTN-related risk

• Beta blocker + non-dihydropyridine CA– Risk of bradycardia and/or depression nof LV systolic function

• Beta blocker + central adrenergic inhibitor– Modest incremental BP lowering– Significant risk of bradycardia and/or orthostatic hypotension

• Alpha blocker + central adrenergic inhibitor– Risk of orthostatic hypotension– Both agents work primarily on the sympathetic nervous system

Treating Hypertension in Patients With Limited Financial Means

• HCTZ, Chlorthalidone, furosemide (depressed GFR) and spironolactone are all generic and relatively inexpensive

• Generic long-acting calcium antagonists, for example, verapamil SR, are available

• Low-doses reserpine is a reasonable consideration as add-on therapy

• Generic ACE inhibitors can be utilized, unless limited by cough and/or angioedema, in patients with diabetes mellitus, CKD, and/or LV systolic dysfunction

• Peruse the low-dollar (3 – 4 bucks) BP drug co-pay list available at Wal-Mart, CVS, and other major pharmacy chains

Summary

• Treat patients as individuals and avoid favoring a therapy solely on the basis of race

• ALWAYS risk stratify patients, advise them of their goal BP, and place the goal BP level prominently in their chart

• There is rarely, if ever, an indication to start with more than 2 anti-hypertensive agents; however, understand when your patient is unlikely to be controlled with a single antihypertensive agent

• Avoid rapid-fire up-titration of antihypertensive drugs as this wastes patient’s time, creates unnecessary office visits, and pre-disposes to side-effects related to BP reductions that are too rapid

Summary Cont.

• Realize that many of decisions about anti-hypertensive drug therapy in daily practice relate to optimizing already prescribed regimens

• Monotherapy is relatively un-important in contemporary hypertension therapeutics as only a minority of patients will be adequately controlled – even initially – to below their goal BP

• Patients presenting with severe BP elevations infrequently need emergent BP reductions in the office or in the ER – and, those with the highest, most long-standing BP elevations are at the greatest short-term risk of harm from rapid BP lowering

Hypertension Case Management

Angela L. Brown, MDAssistant Professor of Medicine

Washington University in St. Louis School of Medicine

FACULTY DISCLOSURE

• Has received grant support from NIH: co-investigator

• Serves on the speaker bureau for Boehringer Ingelheim, Bristol-Myers Squibb Co., Forest Laboratories, GlaxoSmithKline, and Novartis Pharmaceuticals

Using a case-based approach, participants will be able to:

–Utilize current treatment guidelines to manage hypertension, and

–Direct hypertension therapy based on patient risk and evidence of target organ damage.

Objectives

Brown

Case #1

• 43 yo AA woman presents for evaluation and continued management of difficult to control hypertension. Has been on multiple medications that were discontinued due to ineffectiveness, not intolerances. Reports medical compliance.

• Complains of intermittent frontal headaches when BP is high, left chest discomfort with both rest and activity for several months, 5-pillow orthopnea, and dyspnea on exertion.

Brown

Case #1• PMH: HTN x 10 years

CHF - no other info available)CKD - baseline Cr unknownCVA ’06 – no residual signs No surgeriesG1P1-uncomplicated

• Meds: furosemide 80 – 160 mg bid, Minoxidil 10mg tid, clonidine 0.4mg tid; atenolol 100mg qd, aspirin 81mg qd

Brown

Case #1• FmHx: Mother died age 65 – MI, HTN

Father died young age – cause unknown6 sisters – all with HTN and DM

• SocHx: UnemployedSmokes several cigarettes per week, occ wears

nicotine patchDenies alcohol or illicit drugsTakes no OTC meds except occ tylenolDrinks one gallon tea and a 2-liter bottle of soda dailyDoes not add salt to food, eats out for majority of mealsNo structured exercise

Brown

Case #1

• VS: BP seated 166/104 right, 160/104 left, P 80 regular

wt 185#, ht 5’4”• HEENT: A-V nicking, disc margins sharp• Neck: JVD to angle of jaw, no carotid bruits, thyroid ok• Lungs: clear to auscultation• Heart: regular, S1,S2, S3, no m/g/r• Abdomen: soft, non-tender, no masses or bruits• Extremities: no edema, pulses 2+ and symmetrical• Neuro: nonfocal

Brown

Case #1

Where do you start?

Brown

Case #1

Labs: 141 106 23 Tprot 7.8 g/dL3.8 26 2.23 Ca2+ 9.5 mg/dL

12.3 TChol 151 mg/dl 9.3 233 TG 81 mg/dl

36 HDL 51 md/dlTSH 1.21 LDL 84 md/dlBNP 531 pg/ml CXR: cardiomegallyUA: 1.005, ph6.5, 1+ albumin, negative

EKG: NSR, 75 bpm, LVH, marked high lateral t-wave inversions c/w repolarization abnormality vsischemia Brown

2D2D--Echo: Echo: SubxipoidSubxipoid ViewView

Brown

2D2D--Echo: 4 Chamber ViewEcho: 4 Chamber View

Brown

Case #1 Case #1 –– Questions?Questions?

• What is the goal blood pressure?

• Does the patient have resistant hypertension?

• Will lifestyle changes make a difference?

• What would you do with her medications?

• What is her overall cardiovascular/renal risk?

• Do you want more information?Brown

Hypertension Case Management

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

Program Director, General Clinical Research Center/Clinical Hypertension ProgramCase Western Reserve University

FACULTY DISCLOSURE

• Has received grant/research support from AstraZeneca, GlaxoSmithKline, King Pharmaceuticals Company, Novartis, and Pfizer

• Serves as a consultant for AstraZeneca, Bayer, Bristol Myers Squibb, Encysive, GlaxoSmithKline, King Pharmaceuticals Company, Merck & Co., Novartis, and Pfizer

Effective BP Lowering and Target Organ Protection in Patients withCompromised Kidney Function

Errol D. Crook, MDAbraham A. Mitchell Professor and Chair, Department of Internal Medicine

Director, Center for Healthy CommunitiesUniversity of South Alabama College of Medicine

Faculty Disclosures

Has no financial or other relationships to disclose

Objectives

• To gain a comprehensive understanding of the diagnostic and therapeutic approach to lowering blood pressure and preservation of kidney function in hypertensives with compromised kidney function

• To understand the how to anticipate and avoid, or at least react to appropriately, common problems encountered when treating hypertension in patients with compromised kidney function

Hypertension in African Americans

• Prevalence of HTN among highest in world• African Americans develop HTN earlier in life and their

average BPs are much higher • Prevalence of HTN in African Americans in US among the

highest in world• African Americans have increased TOD

–320% increase in ESRD–80% higher stroke mortality rate–50% higher heart disease rate

12000 Heart and Stroke Statistical Update. Dallas, Tex: AHA;19992Morbidity & Mortality:1996 Chartbook on Cardiovascular, Lung, and Blood Diseases.

Washington, D.C.: NIH:NHLBI; 1996

Consequences of Hypertension in African Americans

•• 1.3 times greater rate of nonfatal stroke 1.3 times greater rate of nonfatal stroke •• 1.8 times greater rate of fatal stroke1.8 times greater rate of fatal stroke•• 1.5 times greater rate of CHD mortality1.5 times greater rate of CHD mortality•• 4.2 times greater rate of ESRD4.2 times greater rate of ESRD•• 2 times greater rate of HF2 times greater rate of HF

12000 Heart and Stroke Statistical Update. Dallas, Tex: AHA;19992Morbidity & Mortality:1996 Chartbook on Cardiovascular, Lung, and Blood Diseases.

Washington, D.C.: NIH:NHLBI; 1996

Stages of Renal Disease

Stage 1 GFR > 90 ml/min with presence of proteinuria or microalbuminuria

Stage 2 GFR between 60- 89 ml/min

Stage 3 GFR between 30 – 59 ml/min

Stage 4 GFR between 15 –29 ml/min

Stage 5 GFR < 15 ml/min (ESRD)

Prevalence of CKD by Stage of Disease

Stage Definition # in millions % of population

1 Albuminuria, GFR > 90 ml/min

~ 6.0 3.3

2 GFR 60 - 89 5.3 3.0

3 GFR 30 - 59 7.6 4.3

4 GFR 15 - 39 .4 0.2

5 GFR < 15 .3 0.1

NHANES III (1988 – 1994, USRDS 1998); CKD accounts for 11 – 16.5% of MedicareCost (AJKD 2006 Annual Data Report USRDS)

Equations to Predict GFR

MDRD GFR (mL/min/1.73 m2) = 170 x (SCr) -0.999 x (age) -0.176 x (BUN)-0.170 x (albumin) +0.318 x (0.762 if female) x (1.180 if black)

Modified (abbreviated) MDRD

Estimated GFR (mL/min/1.73 m2) = 186 x (SCr) -1.154 x (age) -0.203 x (0.742 if female) x (1.210 if African American)

Cockcroft–Gault Creatinine clearance (mL/min) =(140–age) x (weight) x (0.85 if female)

72 X SCr

24-hour urine collection

Creatinine clearance (mL/min) = UCr x volume (in mL)

SCr x 1440 (number minutes in 24 hours)

SCr, serum creatinine in mg/dL, age in years, BUN in mg/dL, weight in kilograms, albumin in g/dL., UCr, urine creatinine in mg/dL.

Hypertension Prevalence by GFR

75 7768

55

39 42

2115 12 10 6 6

0102030405060708090

15 30 45 60 90 120

GFR (ml/min)

Proportion of Population

(%)

>=140/90 or meds >=160/100

Issues to Discuss

• In patients with CKD, what is level of BP that protects against renal disease progression?

• In patients with CKD, what is level of BP that protects against CV events?

• Does it matter what BP lowering agent(s) we use to achieve the desired BP levels?

• Factors impacting answers to these questions: diabetes status, level of albuminuria /proteinuria, ethnicity (?)

Reasons to be Aggressive in Treatment of Hypertension in CKD

1) The adverse outcomes of CKD (kidney failure, cardiovascular disease, premature death) can be prevented or delayed

2) Treatment of earlier stages of CKD is effective in retarding progression to kidney failure and in preventing the systemic complications that develop during the course of progressive CKD.

3) Initiation of therapy for cardiovascular risk factors at earlier stages of CKD can be effective in reducing the very high cardiovascular morbidity and mortality of these patients.

NKF Recommendations for Treatment of Blood Pressure in Non-Diabetic Patients with Chronic Kidney Disease

• Target < 130 / 80 mm Hg–Determine urine protein-to-creatinine ratio

• BP > 130 / 80 mm Hg and urine protein-to-creatinineratio > 200 mg/g, start ACE inhibitor

• BP > 130 / 80 mm Hg and urine protein – to-creatinineratio < 200 mg/g, start diuretic and/or RAS inhibitor

• BP < 130 / 80 mm Hg and urine protein –to- creatinineratio > 1000 mg/g, start ACE inhibitor

NKF Recommendations for Treatment of Blood Pressure in Patients with Diabetes and CKD

• Target level of Blood pressure is < 130 / 80 mm Hg• Diabetic renal disease and BP > 130 / 80 mm Hg initiate ACE inhibitor or ARB

• Diabetic renal disease and BP < 130 / 80 mm Hg initiate ACE inhibitor.

Bakris et. al. NKF, Am J Kidney Dis 36: 646, 2000

JNC-7; Hypertension 42: 1206, 2003

K/DOQI-BP, Am J Kidney Dis 43:1-290, 2004

Bakris et. al. (2000) 36: 646

Level of Blood Pressure and Renal Survival in Diabetes

-10

-8

-6

-4

-2

094 96 98 100 102 104 106 108 110

MAP (mm Hg)

GFR

Dec

line

(ml/m

in/y

r)

0

.2

.4

.6

.8

1

Cum

. Sur

viva

l

0 20 40 60 80 100 120 140 160Time

Event Times (no)Cum. Survival (no)

Event Times (yes)Cum. Survival (yes)

Kaplan-Meier Cum . Survival Plot for f/u tim eCensor Variable : ESRD censorGrouping Variable: Reached Goal BP on F/u

Pts with Diabetes and CKD (N=272), BP Goal < 130/80 mm HgEndpoint: ESRD (P=0.0029)

Gavini & Crook. J AM Soc Nephrol (abstract) 15:576A, 2004

0

5

10

15

20

25

30

80 90 100

110

120

MAP (mm Hg)

Dou

blin

g of

Cr (p

er 100

pt

PlaceboCaptopril

Lewis et. al. Relationship Between BP and Diabetic Nephropathy

ARB’s and Diabetic Renal Disease

Drug Patient characteristics

Endpoint(s) Outcome

Losartan(RENAAL)

Type 2 DM, Urine Alb/Cr > 300, Cr 1.3-3 mg/dl

Mortality, doubling of Cr, ESRD

Losartan was better than placebo at reducing albuminuria, preserving renal function and reduced 1st time CHF hospitalizations

Irbesartan(IDNT)

Type 2 DM, urinary protein excretion of 900 mg/ 24 hours. Cr 1.0 -3.0 mg/dl in women and 1.2 –3.0 mg/dl in men.

Mortality, doubling of Cr, ESRD

Irbesartan lowered relative risk of reaching primary endpoint compared to placebo and amlodipine respectively. Resulted in a 24% and 21% slower rise in Cr than placebo and amlodipine respectively. No effect on CVD

Prevention of Progression of CKD: blood pressure or specific blood pressure lowering agent?

• IDNT: asked what level of BP is most protective for progression of CKD in T2DM?

–Baseline and achieved SBP predicted renal survival (reaching endpoint)

–Achieved SBP trumped baseline SBP–No effect of DBP (even > 100 mm Hg), PP or MAP on renal endpoint

–Additive effect of Irbesartan and low SBP–Pohl et. al. JASN (2005) 16: 3027

IDNT: asked what level of BP is most protective for progression of CKD in T2DM?

(Pohl et. al. JASN (2005) 16: 3027)

-0.6-0.3

00.30.60.91.21.5

<121 121 - 130 131 - 140 141-150 151-160 161-170 171-180 >180

SBP (over follow-up)

ln r

elat

i ve

ris

renal EP mortality

IDNT: asked what level of BP is most protective for progression of CKD in T2DM?

(Pohl et. al. JASN (2005) 16: 3027)

< 134 134 -140

141 -149

> 149

Amlopidineplacebo

Irbesartan0

0.30.60.91.21.51.82.12.42.7

rela

tive

ris k

( ren

al E

Quartile Avg SBP (f/u)

Treatment of Blood Pressure in Non-Diabetic Patients with CKD

• Several studies demonstrate efficacy of renin-angiotensin-system inhibition in this group

–AASK (JAMA (2002) 288:2421)–GISEN Group (Lancet 349: 1857 (2001)–MDRD (NEJM (1994) 330:877)–REIN (Lancet 365: 939, 2005)

Increasing Systolic BP Linked to End-Stage Renal Disease Risk: MRFIT

1 11.5

2.2

5

0

1

2

3

4

5

6

<117 117-123 124-130 131-140 >140

Klag et al. N Engl J Med. 1996;334:13-18.

PP=.009=.009PP<<.001.001

PP<<.001.001

Adj

uste

d R

elat

ive

Ris

k

Systolic BP (mm Hg)

Prevention of Progression of CKD: blood pressure or specific blood pressure lowering agent?

• RAS inhibition with ACEI or ARB slows progression of renal disease in patients with CKD and proteinuria.

–RENAAL, REIN, AASK, AIPRI, IDNT, Collaborative Study Group

• ALLHAT (CVD study): renal outcomes not varied by agent (Arch Intern Med (2005) 165:936)

–Meta-analysis heavily weighted by ALLHAT concludes that specific agent not important to renal disease progression (Casas, Lancet (2005) 366:2026)

0.5 1 1.5

1.12 (0.891.12 (0.89--1.40)1.40)

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

Favors Favors AmlodipineAmlodipine

Favors Favors LisinoprilLisinopril

1.11 (0.881.11 (0.88--1.38)1.38)

Favors Favors ChlorthalidoChlorthalido

nene

AmlodipineAmlodipine

LisinoprilLisinopril

ALLHAT: Secondary Endpoints: ESRD

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

Reasons to be Aggressive in Treatment of Hypertension in CKD

1) The adverse outcomes of CKD (kidney failure, cardiovascular disease, premature death) can be prevented or delayed

2) Treatment of earlier stages of CKD is effective in retarding progression to kidney failure and in preventing the systemic complications that develop during the course of progressive CKD.

3) Initiation of therapy for cardiovascular risk factors at earlier stages of CKD can be effective in reducing the very high cardiovascular morbidity and mortality of these patients.

Chronic Kidney Disease and

Cardiovascular Disease

Relationship of Renal Function to Cardiovascular Disease

Study, special characteristics Measure of Renal Function Associated With Outcome

Total Mortality

CVD mortality

CVD Risk/ Events

Hypertension Detection and Follow-Up Program, only hypertensive subjects

Baseline Cr > 1.7 mg/dl +

Hypertension Optimal Treatment, only hypertensive subjects

Estimated CrCl < 60 ml/min + +

Cardiovascular Health Study, > 65 yrs of age, population based

Baseline Cr > ~1.2 mg/dl +

Wannamethee, (16), middle aged men, normotensive and hypertensive

Baseline Cr > 1.3 mg/dl + + + (stroke)

Friedman, (17), Elderly, post CVA Baseline Cr > ~ 1.6 mg/dl +

Matts, (18), MI survivors, normotension Each 0.1 mg/dl Cr above normal + +

Heart Outcomes and Prevention Evaluation, High risk for CVD

Cr > 1.4 mg/dl, estimated CrCl > 65 ml/min + +(MI, CVA)

Schillaci (19), Hypertensive with normal Cr, free of CVD

Cr in reference range (highest quartiles) + +

Heart Estrogen / Progestin Replacement Study, postmenopausal female with CAD

Baseline Cr > 1.2 mg/dl +

Framingham, population based Baseline CrMale: Cr 1.5 – 3.0

Female: Cr 1.4 – 3.0

_ +

Multiple Risk Factor Intervention Study, Hypertension, no CVD

Baseline Cr _ _ _

Multiple Risk Factor Intervention Study Hypertension, no CVD

Increase in Cr from baseline at 6 years + +

Hillege (21) Baseline Calculated GFR (Cockcroft Gault), lowest quartile (< 44 ml/min)

+

Am J Med Sci 324:127-137, 2002

Level of Kidney Function and CVD Risk (ARIC JACC (2003) 41:47)

0

0.05

0.1

0.15

0.2

0.25

30 60 90 120 150

GFR (ml/min)

5-yr

Pre

d Pr

o

Albuminuria / Proteinuria and CVD

• Framingham:–Proteinuria: increased the mortality rate 3X; an independent

predictor of mortality in men; was strongly associated with hypertension (3X higher than in normotensives), diabetes and cardiac enlargement.

• MRFIT:–dipstick positive proteinuria was an independent risk factor for

all cause, CVD and coronary heart disease mortality.• Intervention as a Goal in Hypertension Treatment (INSIGHT):

(long acting dihydropyridine CCB and a diuretic on CVD events and death).

–Proteinuria was the most powerful predictor of CVD among all risk factors, including diabetes and previous MI.

• Albuminuria strongly associated with coronary CA and carotid IMT in T2DM (Freedman, JASN 16:2156, 2005)

Is albuminuria a modifiable CVD risk factor?

• In patients with diabetes therapies leading to decreases in albuminuria show associated improvements in renal survival.

• Albuminuria:creatinine is associated with coronary and carotid artery calcified plaque in T2DM (JASN 16:2156, 2005)

• LIFE (Losartan Intervention for Endpoint Reduction) (Hyperten 45:198, 2005).

–Increases in albuminuria -> increased CVD risk–Fall in albuminuria -> CV protection

Renal Dysfunction and Cardiovascular Outcomes

• Valsartan in Acute Myocardial Infarction Trial (VALIANT) (Anavekar et. al. NEJM (2004) 351:1285)

–Inverse relationship between initial renal function and subsequent risk of death in patients post MI complicated with LV dysfunction or CHF

• Community Based Sample from HMO (Kaiser) (Go et. al. NEJM (2004) 351:1296)

–Study of over 1 Million showing inverse relationship between renal function and CV death.

Diabetes and Cardiovascular Disease (or Diabetes is CVD)

• Diabetics have similar risk of CVD as non-diabetic with existing CVD.

• Diabetics with renal disease has CVD risk that is 6-7 fold that of diabetic without renal disease.

0

5

10

15

20

25

30

RR

CVD

1st Qtr

No DM, No CVD No DM, + CVD+ DM, no CKD +DM, + CKD

Trials Demonstrating Risk Reduction in CVD Outcomes with Lower BP in Diabetics

Study Achieved BP

HOT (felopidine) DBP 81.1 – 85.2

ABCD (nisoldipine & enalapril) 137/81 v 128/75

UKPDS (captopril & atenolol) 154/87 v 144/82

SHEP (diuretic) 155.1/71.1 v 144/67/7

SysEURO (nitrendipine) 155.1/71.1 v 151/79

Crook and Velusamy, Current HTN Reports, 2003

Hypertension Treatment and CVD in Diabetics With Renal Disease

• ABCD (Hypertensives): Enalapril lowered fatal and non-fatal MI–NEJM (1998) 338: 645

• ABCD (Hypertensive): Lower blood pressure (132/78 vs. 138/86)) group had less progression of retinopathy and lower rates of stroke

–(Diabetes Care (2002) 23 (suppl 2): B54• ABCD (Normotensive): Lower blood pressure group (128/75 vs.

137/81) had less progression of retinopathy and lower rates of stroke

–Kidney Int (2002) 61:1086

Hypertension Treatment and CVD in Diabetics With Renal Disease (2)

• UKPDS: Tight control (144/82 mm Hg) reduced risk for CVD by 34% vs less tight control (154/87 mm Hg).

–BMJ (1998) 317: 703 and (2000) 321:412• HOT: The lowest BP group (DBP = 81.1 mm Hg) had a 51%

reduced risk of major CVD events vs. higher target group (DBP = 85.2).

–Lancet (1998) 351:1755• SHEP, SysEur, SysChina: Rx of isolated systolic hypertension in

elderly lowers CVD risk in diabetics

Hypertension Treatment and CVD in Diabetics With Renal Disease (3)

• IDNT: Amlodipine lowered risk of MI in Type 2 diabetics with renal disease vs. Irbesartan

–Ann Int Med (2003) 138:542• RENAAL: Losartan lowered first time admits for CHF (NEJM

(2001) 345:861

Renal Dysfunction and Cardiovascular Outcomes

• Valsartan in Acute Myocardial Infarction Trial (VALIANT) (Anavekar et. al. NEJM (2004) 351:1285)

–Inverse relationship between initial renal function and subsequent risk of death in patients post MI complicated with LV dysfunction or CHF

• Community Based Sample from HMO (Kaiser) (Go et. al. NEJM (2004) 351:1296)

–Study of over 1 Million showing inverse relationship between renal function and CV death.

Valsartan in Acute Myocardial Infarction Trial (VALIANT)

(Anavekar et. al. NEJM (2004) 351:1285)

0.60.8

11.21.41.61.8

Adj Hazard Ratio

< 45 45 -59 60 - 74 > 74eGFR (ml/min/1.73 m2)

Death composite endpoint

Community Based Sample from HMO (Kaiser)(Go et. al. NEJM (2004) 351:1296)

0.61.62.63.64.65.66.6

Adj Hazard Ratio

> 60 45 -59 30 - 44 15 - 29 < 15eGFR (ml/min/1.73 m2)

Death CV Event Hospitalizations

Potential Mechanisms by Which Renal Disease Increases Cardiovascular Risk

• Increase in “conventional” CV Risk factors

– Anemia– Elevations in Blood Pressure– Dyslipidemia– Derangements of Ca++- PO4

homeostasis– Inflammation– Enhanced coagulation– Diabetes

• Increase in “non-conventional” Risk factors

– Albuminuria– Proteinuria– Homocysteine– Uric acid

Potential Mechanisms by Which Renal Disease Increases Cardiovascular Risk

• Renal disease may simply be a convenient, quantifiable surrogate for systemic vascular disease

• Patients with renal disease may not have CVD and CVD risk factors treated as aggressively

–Therapeutic nihilism

Worcester Heart Failure Study – Mortality in Heart Failure

Goldberg RJ, et. al. Arch Int Med (2007); 167: 490

• Characteristics more likely to be present in decedents (post hospital discharge for heart failure) upon hospital admission

–Older age, lower BMI, anemia, higher BUN, higher creatinine, history of stroke, renal disease, less likely to be on cardiac regimen (RAAS inhibition, ASA, beta-blocker)

Aldosterone Antagonism and Heart Failure

• Randomized Aldactone Evaluation Study (RALES) (NEJM (1999) 341: 709)

–NYHA Class 3 or 4 HF X >/= 6 wks, on ACEI and loop diuretic, LVEF < 35%, exclude Cr > 2.5 mg/dL

• Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) (NEJM (2003) 348:1309)

–AMI, LVEF < 40%, HF, Opt Rx, exclude Cr > 2.5 mg/dl.• Worsening of renal function not significant in either study, but some

studies show high risk for progression of CKD.–(Mayo Clin Proc (2005) 80:1623

Aldosterone Antagonism and Progression of CKD

• In rat remnant kidney model aldosterone contributes to progression of glomerular injury. Spironolactone did not replicate the protective effect of ACEI or ARB in the model.

– (Greene EL, et. al. J Clin Invest (1996) 98: 1063)

• Aldosterone antagonism in other animal models reduce proteinuria and nephrosclerosis.

• Reviewed in Ponda and Hostetter CJASN (2006) 1:668

IDNT: Achieved BP and CV outcomes in IDNT. CHF Events

(Berl et. al. JASN (2005) 16: 2170)

Independent Variable RR (95% CI) P

Lower achieved SBP (per 20 mm Hg) 0.75 (.63 - .89) .001

Assignment to Irbesartan (compared to amlodipine and placebo)

0.71 (.54 - .93) .013

Both lower SBP & Irbesartan 0.53 (.38 - .73) <0.0001

ARB use and SBP lowering are additive when lowering risk ofHeart Failure in IDNT.

Heart Failure and Renal Disease in ALLHATRahman, et. al. Ann Intern Med (2006) 144: 172.

02468

10121416

6-yr event rate / 100

GFR > 90 GFR 60 - 89 GFR < 60

Heart Failure by Rx Group

Chlorthalidone Amlopidine Lisinopril

*, p sig amlopidine compared to chlorthalidone**, p sig, lisinopril compared to chlorthalidone

**

**

Heart Failure Therapy in Patients with CKD

• Cooperative North Scandinavian Enalapril Survival Study (CONSENNSUS

• Mean eGFR 45 ml/min, median creatinine = 1.4 mg/dL• Those in enalapril group had 31% lower mortality at 1 yr.

–Am J Cardiol (1992) 70: 479–Most CHF studies do not enroll patients with CKD

CV Outcomes in AASK(Norris et. al. Am J Kidney Dis (2006) 48: 739)

• Low rates of CVD• No effect of treatment group or BP group• Factors found to be related to CV events in AASK

–PP, income, urine protein:creatinine > .22, duration of HTN, Abnormal ECG, urine sodium:potassiumratio

• Caveats: extremely low rate of CVD, Successful achievement of BP targets, excluded of 2.5 gm proteinuria and those with CHF, no relationship to baseline GFR.

What is appropriate Agent to Lower BP in Mild to Moderate Renal Disease?

• African American Study of Kidney Disease and Hypertension (AASK)

– African Americans with hypertension (18-70 yrs) with CRI (GFR 20 – 65 ml/min/1.73 m2 and no other cause of renal insufficiency.

– Goal of MAP 1) 102-107; 2) < 92– Rx: metoprolol (50-200 mg), ramipril (2.5 – 10 mg),

amlopidine (5 – 10 mg)– Endpoints: GFR slope, 50% reduction of GFR, ESRD, death

• In patients with urine protein:Cr > .2 ramipril was superior to amlodipine and metoprolol.

– 50% reduction in GFR, ESRD and death improved in ramiprilgroup compared to amlodipine.

– Lower BP was not superior to usual BP.

Treatment of Hypertension in CKD –Practical Considerations

• What drugs do I use?–ACE Inhibitor (ARB) and Diuretics are often necessary

–Remember comorbid conditions– Use whatever will get to goal.

• Which drugs do I avoid?• Combinations

Treatment of Hypertension in CKD –Practical Considerations

•What drugs do I use?•Which drugs do I avoid?•Combinations

Drugs to Avoid: Issues to Consider

• Use Calcium Channel Blockers in patients with significant proteinuria?

–Don’t use as first line agent (esp: dihydropyridines); less likely to decrease and may increase.

•AASK (non-diabetics), IDNT (Type 2 DM neph)•Amlopidine group with more rapid decline in GFR or more doubling of CR vs. ACE I and ARB respectively.

–However, when used with other agents proteinuria will decrease.

• Toto. J Clin Hypertens 7(4 suppl 1):15-20, 2004.

Drugs to Avoid as First Line Agents

• Negative inotrophes may not be tolerated in patients with CKD given higher prevalence rates of CHF in this population.

– (Rate lowering calcium antagonists and some b-blockers)

• Alpha antagonists (doxazosin) may increase risk of CHF as first line agent

–(ALLHAT, JAMA 283: 1967 – 1975, 2000 )

Drugs that Elevate Blood Pressure in Patients with CKD

• NSAIDs• Cyclosporine• Erythropoietin• Cocaine, nicotine, EtOH• Methyxanthines (theodur, caffeine)• Withdrawal of β-blocker, α-agonist, EtOH, Calcium antagonists

• Estrogen and Estrogen analogues

Treatment of Hypertension in CKD –Practical Considerations

• What drugs do I use?• Which drugs do I avoid?• Combinations

–JNC-7 and others recommend to start with 2 drugs in those with BP > 20/10 mm Hg above goal. Should consider combination pill.

Treatment of Hypertension in CKD –Practical Considerations

• Combinations

–Diuretics are great in combination with ACE inhibitors and ARBs.

–RAS inhibitors and calcium antagonists are effective.

–CCB’s and b-blockers are effective.

Treatment of Hypertension in CKD –Practical Considerations

• Ineffective Combinations

–RAS inhibitors with sympathetic nervous system inhibitors (β-blockers, α/β- blockers, α2-agonists)

–CCB’s with other directly vasodilators (hydralazine, minoxidil, nitrates)

Treatment of Hypertension in CKD (NKF Recommendations)(Am J Kidney Dis 43 (suppl): 1-290, 2004.

Type of Kidney Disease BP Target (mm Hg)

Preferred Agent for CKD with or without Hypertension

Other agents to reduce CVD risk and reach BP target

Diabetic Renal Disease < 130/ 80(< 125/75)

ACE inhibitor or ARB Diuretic preferred, then BB or CCB

Non- diabetic renal disease with spot urine protein:Cr ratio > 200 mg/g

<130/80(< 125/75)

ACE inhibitor Diuretic preferred, then BB or CCB

Non- diabetic renal disease with spot urine protein:Cr ratio < 200 mg/g

< 130/80 No preference Diuretic then ACE inh, ARB, BB, CCB

Disease in Kidney of Transplant recipient

< 130/80 No preference CCB, diuretic, BB, ACE inh, ARB

Blood Pressure Level is Much More Important than

Blood Pressure Medication!!!!

What is appropriate Agent to Lower BP in Patients with Mild to Moderate

Renal Disease?

ALLHAT, Diabetic Risk and Treatment of Hypertension

Agent Incidence of Diabetes over Follow-up

Chlorthalidone ~16%

Amlodipine ~10%

Lisinopril ~9%

ALLHAT, ACE Inhibitors and BP Control in African Americans

• African Americans randomized to lisinopril had a 4 mm Hg higher SBP than those on chlorthiadone.

–African Americans on lisinopril had higher rates of heart failure and stroke than those on chlorthiadone.

• Adjustment for BP differences reduced the relative risk of stroke and heart failure, but they remained statistically significant.

3.8

3.3

3.6

2.8

2.7

3

3.1

3

UKPDS

ABCD

MDRD

HOT

AASK

Number of Agents Needed

IDNT (<135/85)

IRMA2 (<135/85)

RENAAL (<140/90)

Adapted, with permission, from Bakris GL, et al. Am J Kidney Dis. 2000;36:646-661.

Multiple Agents Usually Required to Achieve BP Goals in Diabetic Patients

Level of baseline GFR and # of BP Meds to Achieve BP Goal

0.5

1

1.5

2

2.5

3

3.5

4

90-99 80-89 60-69 50-59 40-49

GFR (ml/min)

# of

BP

Med

Diabetic Non-Diabetic

K/DOQI Am J Kidney Dis 43(suppl): 1 -290, 2004.

Other Vexing Questions

• What do I do when the patient is very near ESRD?–Hyperkalemia–Will I speed up progression to dialysis?

• I’ve tried everything and the blood pressure is still up, what now?

• The level of proteinuria remains elevated, what can I do?

Treatment of Hypertension in patients with CKD - Summary

• CKD is common and is strong risk factor for CVD, including stroke.

• Most studies of the treatment of hypertension in patients with CKD have primarily been designed to look at renal survival, not CVD outcomes.

• African Americans have not been well represented in many of these studies with exception of ALLHAT, AASK, and RENAAL.

Treatment of Hypertension in patients with CKD – Summary (2)

• Inhibition of RAAS is clearly indicated in patients with CKD, especially if diabetes or even mild proteinuria(urine protein: creatinine > .2) is present.

• Patients with CKD require several drugs, on average, to achieve recommended goals, but goals should be sought aggressively.

Treatment of Hypertension in patients with CKD – Summary (3)

• African American patients with hypertension are at higher risk for both CKD/ESRD and CVD (MI, CHF, Stroke) and must be treated to goal.

• While the response to RAS inhibitors in African Americans may be decreased when compared to Caucasians, on average, they should be given RAS inhibitors when indicated.

Thanks

Questions

George L. Bakris, MD, F.A.H.A.Professor of Medicine

Director, Hypertensive Disease UnitUniversity of Chicago Pritzker School of Medicine

Chicago, IL

Blood Pressure ModulationBlood Pressure Modulation

ECF Volume Vasoconstriction

BP = Cardiac output x Total peripheral resistance

-

PGs ‘neutral lipid’

Kinins PAF NO

sympatheticnervous system

+

NaClreabsorption

+

Endothelin

+

ReninAngiotensin (II)

+

Aldosterone

+ +-

-

+

GFR

New Antihypertensive Agents and Potential Uses

Renin InhibitorsEndothelin AntagonistsARB-chlorthalidone combinationsOthers (in the wings)

Sowers JR. N Engl J Med. 2002;346:1999-2001.

AII Formed

(nmol/min/mg protein)

Others (non-ACE–, non-chymase–dependent)ACE-dependent

Chymase-dependent

Normal aorta (n = 9)

0

1

2

3

4

5

6

Atherosclerotic lesions(n = 8)

Aneurysm (n = 6)

**

† †

*P <0.01 vs normal aorta. †P <0.01 vs chymase-dependent A II-forming activity in the normal aorta.

Adapted from Ihara M et al. Hypertension. 1999;33:1399-1405.

Current Pharmacologic Interventions of the RAS

Angiotensinogen

A I

A II

Renin

AT1 AT2Receptors for angiotensin II

ACE

Aldosterone

A II

ACEIs 1

ARBs2

Aldosterone blockers 3

*P <0.001 vs placebo.Adapted from Biollaz J et al. J Cardiovasc Pharmacol. 1982;4:966-972.

A II Escape With Long-Term ACEI Therapy

Plas

ma

AC

E,

nmol

/mL/

min 100

806040200

* * * * * * * *

30

20

10

0

Plas

ma

A II,

pg

/mL

*

Placebo 4 h 24 h 1 2 3 4 5 6Months

Plasma A II levels increased with time, although plasma-converting enzyme

activity remained suppressed(n = 9 after 24 h)

Chymase-Dependent vs. ACE-Dependent AII Formation in Hearts of Various Species

Adapted from Balcells E et al. Am J Physiol. 1997;273:H1769-H1774.

A II Formation 

(%)

Mouse Rabbit Rat Dog Human0

40

60

80

100

20

ACE-dependentChymase-dependent

How Do We Improve RAS Inhibition?

Renin inhibition acts at the point of activation of the Renin System and neutralizes the PRA rise

Feedback Loop

AT1 Receptor

ReninAng I

Angiotensinogen

Ang II

Direct renin inhibitor

Biological effects

ACE

Non ACE pathways

PRA

Adapted from: Müller DN & Luft FC. 2006

• Glomerularvasoconstriction

• Inflammation• Fibrosis

Kidney

• Hypertrophy• Fibrosis• Vasoconstriction

Heart

• Vasoconstriction

Brain

• Hyperplasia hypertrophy• Inflammation• Oxidation• Fibrosis

Vessels

Renin

Aliskiren

Angiotensinogen

Renin secretion is regulated by 4 mechanisms

Distal tubule

Pressure in theafferent arteriole

1

Renin secretion is regulated by 4 mechanisms

Sympathetic nerve stimulation of the beta1 receptor in the JGA

Distal tubule2

Renin secretion is regulated by 4 mechanisms

Na+ at the macula densa Distal tubule3

Renin secretion is regulated by 4 mechanisms

Negative feedback by Ang IIDistal tubule

4

Unlike ACEIs and ARBs, aliskiren reducesAng I, Ang II and PRA

↑Aliskiren↑↑↑↑ARB↑↑↓↑ACEI

PRAReninAng IIAng I

Feedback Loop

AT1 Receptor

ReninAng I

Angiotensinogen

Ang II

Direct renin inhibitor

ARBs

ACE

Non ACE pathways

ACEIs

Azizi M et al. 2006

Renin

Aliskiren

Angiotensinogen

Can renin inhibitors be more organ protective than other RAAS blockers?

Possible Mechanisms• Reduced angiotensin II synthesis and reduce

aldosterone synthesis• Reduced compensatory activation of the RAAS

following administration of ACEIs, ARBs, diuretics

• Interference with angiotensin II production by renin and prorenin when bound to the (pro)renin receptor

Aliskiren (mg)

Aliskiren neutralizes the rise in PRA induced by other antihypertensive agents that stimulate renin release

Taylor et al. J Am Coll Cardiol 2007;49(9 Suppl A):370A

−50

50

150

Other treatment (mg)

−100

n=

Mean change from baseline in PRA at Week 8 (%)

100

0101

12

−75 −72 −75

111***

***p<0.0001 vs pooled placebo; †p<0.001, ‡p<0.0001 vs placeboaPlacebo from aliskiren/valsartan study

Pooledplacebo

Aliskiren

150 300 600

107 186 64

72

38

HCTZ

25

39

−62

25300

***

75

−44

74

Ramipril

30010 10

****** *** ***

18

51

Placeboa

320

Valsartan

320300

160

59

†

61

−44‡

Pooled analyses in >3,500 patients demonstrate that aliskiren provides dose-dependent reductions in BP

Dahlöf B, et al. 2007 (Pooled analysis)

***p<0.0001 vs placeboValues under bars represent least square mean reductions ± standard error of the mean; values in arrows represent placebo-subtracted reductions

Mean change from baseline in mean sitting BP after 8–12 weeks (mmHg)

0

−15

−5

−25

−10

−20

−6.2

***

DBP SBP

Placebo 150 mg

n=1180n=776 n=1603

−10.1−11.8

300 mgAliskiren

Placebo 150 mg 300 mgAliskiren

n=1180n=776 n=1603

***

−5.9

***−12.5

−15.2***

6.6 9.33.9 5.6

Aliskiren compared with ramiprilStudy design

†Optional up-titration of aliskiren or ramipril, with optional addition HCTZ 12.5 mg and up-titration of HCTZ, was performed in a sequential order for patients not achieving a BP of <140/90 mmHg. All treatments administered once daily.

Aliskiren 150 mg

Placebo

Aliskiren 300 mg

Ramipril 5 mg Ramipril 10 mg

Active-controlled treatment period (double-blind)†

n=420

n=422

+HCTZ 12.5

8 weeks

2–4 weeks

6 weeks 6 weeks 6 weeks

+HCTZ 25 mg

+HCTZ 12.5 +HCTZ 25 mg

Placebo

4 weeks

Re-randomizationRandomization

Placebo-controlled withdrawal period

(double-blind)

Andersen K, et al. 2008 (Study 2306)

Aliskiren-based treatment provides significantly greater BP reductions than ramipril-based treatment

Mean change from baseline in mean sitting BP (mmHg)

0

−15

−10

−20

−5

Ramipril-based therapyAliskiren-based therapy

Week 26n=420 n=422

−13.2−12.0

*

**

n=420 n=422

−17.9−15.2

Week 26

Andersen K, et al. 2008 (Study 2306)

*p<0.05, **p<0.01 vs ramiprilTreatment at Week 26 as per Week 12, with optional addition of HCTZ 12.5 or 25 mgn values represent number of patients randomized to each group

DBP SBP

Aliskiren provides superior BP-lowering compared with ramipril in patients with stage 2 hypertension (post-hoc

analysis)

Andersen K, et al. 2008 (Study 2306)

Stage 2 hypertension defined as SBP ≥160 mmHg*p<0.05; †p=0.0518 for superiority vs ramipril

Mean change from baseline in mean sitting BP at Week 12 (mmHg)†

0

−15

−5

−25

−10

−20

n=87n=88 n=87n=88

−12.7−10.2

−18.1

−22.3

DBP SBP

Aliskiren 150 or 300 mg Ramipril 5 or 10 mg

n=87n=87n=87

*

Aliskiren compared with ramipril and combination therapy in patients with diabetes and hypertension –

Study design

Single-blind

Washout

1 week 2–4 weeks 4 weeks

Placebo

4 weeks

n=282

n=278

n=277

Uresin Y, et al. 2007 (Study 2307)

Randomization

Double-blind

Aliskiren 150 mg Aliskiren 300 mg

Ramipril 5 mg Ramipril 10 mg

Aliskiren/ramipril150/5 mg

Aliskiren/ramipril300/10 mg

Aliskiren provides greater BP lowering compared to ramipril& additional BP lowering when combined with ramipril

Mean change from baseline in mean sitting BP at Week 8 (mmHg)

Aliskiren/ramipril

combinationRamipril

monoAliskiren

mono

−18

−60

−14

DBP SBP

−8−10−12

−16

Aliskiren/ramipril

combinationRamipril

monoAliskiren

mono

*p<0.05 for superiority vs ramipril monotherapy; †p<0.05 for superiority vs aliskiren monotherapy;‡p<0.05 for non-inferiority for aliskiren monotherapy vs ramipril monotherapyError bars indicate standard error from the mean

Uresin Y, et al. 2007 (Study 2307)

−20 *

n=274n=279n=275 n=274n=279n=275

−12.8

−10.7 −11.3

−16.6

−12.0

−14.7*

‡

†

* ‡

Aliskiren combined with HCTZ provides additional SBP lowering in patients with stage 2 hypertension

n=65 n=59

–15.5

–19.4

n=58 n=65

–17.3

§

‡

n=66 n=63 n=53 n=58

–23.2–24.8

§

–22.2†

Stage 2 hypertension defined as SBP ≥160 mmHg §p<0.05 vs both component monotherapies; †p<0.05 vs Aliskiren150 mg; ‡p<0.05 vs HCTZ 12.5 mg

–30

–20

–15

–10

HCTZ Combination

150 300 300 300150 15012.5 25 12.5 25 12.5 25

Aliskiren(mg)

HCTZ (mg)

Δ SBP from baseline at Week 8 (mean, mmHg)

–0

Rasilez®

–25

–5

Novartis, data on file (Study 2204)

–27.2

–18.9

1000

1

0.1

100

10

Aliskiren has a half-life of approximately 40 hours, making it suitable for once-daily dosing

Mean (plus SD) plasma aliskiren concentration profiles (n=30) after single oral administration of aliskiren to healthy subjects, semi-logarithmic scale

Concentration (ng/mL)

0Time (hours)

75 mg150 mg300 mg600 mg

1008020 40 60

Vaidyanathan S, et al. 2006 (Study 2205)

SBP returns to baseline levels more rapidly after discontinuation of ramipril compared with aliskiren

Baseline Week 1 Week 2 Week 3 Week 4

12

10

8

6

4

2

0

–2

Mean change in mean sitting SBP during the 4-week withdrawal period (mmHg)

*Following 26-weeks’ treatment, patients randomized to discontinuation received placebo for 4 weeks; †Patients continuing active treatment could be receiving aliskiren 150 or 300 mg, or ramipril 5 or 10 mg, with or without optional HCTZ (12.5 mg or 25 mg).

Aliskiren regimen discontinued (n=163)*Aliskiren regimen continued (n=170)†

Ramipril regimen discontinued (n=177)*Ramipril regimen continued (n=165)†

Andersen K, et al. 2008 (Study 2306)

Endothelin Production• Endothelin (ET-1) is a 21 amino acid peptide produced by the vascular

endothelium

• ET-1 INCREASES– Angiotensin II, Aldosterone– ADH– Thrombin– Reactive Oxygen Species

• ET-1 is DECREASED by– Prostacyclin– ANP– Nitric Oxide

BIG ET-1(39 amino acid)

ET-1(21 amino acid)endothelin converting enzyme

Doppler US images of the kidney in a single animal before (left)and after (right) 12 minutes of ET-1 infusion

Sehgal, CM. Radiology. 2001;219:419-426

Changes in Plasma Endothelin in Salt Replete and Salt Sensitive subjects

Elijovich and Laffer. Circulation (2001) 103, 263-268.

Darusentan in Resistant Hypertension

• Endothelin receptor affinity

– ETA: Ki = 0.18 nM– ETB: Ki = 216 nM

• Linear pharmacokinetics after oral administration • Half-life favors once-daily dosing

(S)‐2‐(4,6‐Dimethoxy‐pyrimidin‐2‐yloxy)‐3‐methoxy‐3,3‐diphenyl‐propanoic acid

COOH

ONO

N

O

O

Patient DemographicsParameter Darusentan

(N=76)Placebo (N=39)

Age, years† 62 ± 10 63 ± 11Male gender, n (%) 43 (57) 25 (64)Black race, n (%) 23 (30) 9 (23)Body mass index, kg/m2† 31.2 ± 5.0 32.6 ± 4.8Estimated GFR, mL/min/1.73 m2† 74.2 ± 24.3 79.3 ± 26.3Diabetes and/or CKD, n (%) 46 (61) 24 (62)

Diabetes, n (%) 36 (47) 19 (49)CKD, n (%) 20 (26) 9 (23)

Concomitant Antihypertensives, n (%)Diuretics 76 (100) 39 (100)Calcium channel blockers 56 (74) 29 (74)ACE inhibitors 36 (47) 22 (56)Angiotensin II receptor blockers 44 (58) 20 (51)Beta-blockers 53 (70) 25 (64)Other 15 (20) 5 (13)

† Data are means ± standard deviations.

Black HR et.al.J Clin Hypertens.2007;9:760–769

DAR-201 Baseline Values

Parameter (mmHg) Darusentan(N=76)

Placebo (N=39)

Sitting SBP 149.6 ± 12.7 149.0 ± 13.9Sitting DBP 82.4 ± 12.4 79.7 ± 14.1Sitting HR 66.7 ± 10.6 68.7 ± 11.2Mean 24-hour SBP 136.0 ± 13.7 138.1 ± 15.8Mean 24-hour DBP 77.6 ± 12.1 74.7 ± 11.3Data are means ± standard deviations.

Black HR et.al.J Clin Hypertens.2007;9:760–769

Primary Endpoints: Change from Baseline in SBP

Placebo-adjusted changes in DBP at Weeks 8 and 10 were -5.0 ± 1.9 mmHg (p = 0.003) and -6.3 ± 2.0 mmHg (p = 0.004), respectively.

∆ = -7.3 ± 3.0p = 0.048

∆ = -11.5 ± 3.1p = 0.015

-20

-15

-10

-5

0Week 8 Week 10

DarusentanPlacebo

Cha

nge

from

BL

in T

roug

h Si

tting

SB

P (m

mH

g, M

ean ±

SE)

Black HR et.al.J Clin Hypertens.2007;9:760–769

Subgroup Response: Change from Baseline to Week 10 in SBP

Darusentan Placebo

Cha

nge

from

BL

in T

roug

h Si

tting

SB

P (m

mH

g, M

ean ±

SE)

-20

-15

-10

-5

0

-10

-20

10

0

Age (in years)GenderMale Female

N=37 N=21 N=29 N=13<65 ≥65 ≥75

N=40 N=19 N=26 N=15 N=8N=5

∆ = -12.5 ± 4.0∆ = -9.5 ± 4.9

∆ = -11.4 ± 4.0∆ = -12.6 ± 4.9 ∆ = -15.7 ± 7.9

Black HR et.al.J Clin Hypertens.2007;9:760–769

Darusentan Placebo

Co-morbidity StatusRace

Cha

nge

from

BL

in T

roug

h Si

tting

SB

P (m

mH

g, M

ean ±

SE) Black Non-Black

-20

-15

-10

-5

0N=20 N=6 N=46 N=28

Diabetes CKD Neither

-20

-15

-10

-5

0N=32 N=17 N=15 N=8 N=25 N=13

∆ = -5.0 ± 7.8∆ = -13.5 ± 3.3

∆ = -10.6 ± 4.7∆ = -11.6 ± 6.3 ∆ = -8.6 ± 4.6

Subgroup Response: Change from Baseline to Week 10 in SBP

Black HR et.al.J Clin Hypertens.2007;9:760–769

ABPM Analysis

0 4 8 12 16 20 24

Ambulatory SBP Over Dosing Interval

Mean 24-hour BP

-15

-10

-5

0

SBP DBP

Cha

nge

from

BL

to W

eek

10(m

mH

g, M

ean ±

SE)

∆ = -9.2 ± 2.2p < 0.001

∆ = -7.2 ± 1.6p < 0.001

Clock HourDarusentanPlacebo

Mea

n H

ourly

SB

P (m

mH

g)

150

140

130

120

110

BaselinePlacebo – Week 10Darusentan – Week 10p values are unadjusted

DORADO study

All groups had significant drops in BP relative to Placebo; P<0.001

Weber M et.al. Late Breaker-Am Society Hypertension, May 2009

Interaction Between RAAS and ET

Clinical evidence for additive or synergistic effect

ET1 assumes a major hemodynamic role and contributes to end-organ damage mainly under experimental and clinical pathophysiological conditions

Blockade of ET1 via ETA assumes major vasoconstrictor role and contributes substantially to renal hemodynamics when intrarenal RAAS is blocked at the AT1 receptor in healthy humans

Combo drugs ARB +ETA and ARB+NEPI-being developed

Montanari et al Hypertension 2002;39:715-720; Riggleman A et al Hypertension 2001;38:105-109; Rajagopalan S et al Hypertension 1997;30:29-34; Berthold H et al Hypertension 1999;34:1254-1258

Summary• We can now effectively block the renin-angiotensin

system at the rate limiting step with renin inhibitors• Selective endothelin-A antagonists are effective in

treatment of resistant hypertension• Newer ARBs combined with chlorthalidone are on

the horizon• Combined ARBs/NEP inhibitors are also coming-

probably late 2010-2011

Optimal Utilization Diuretics in Antihypertensive Regimens –

Domenic A. Sica, MDProfessor of Medicine and Pharmacology

Virginia Commonwealth University, Medical College of Virginia

FACULTY DISCLOSURE

NEED INFORMATION HERE

CONCLUSION