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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