The Challenge Medication Usage Are we using appropriate doses

1
The Challenge Medication Usage Are we using
appropriate doses ?

• Domenic A. Sica, MD
• Chairman
• Division of Clinical Pharmacology and
  Hypertension
• Division of Nephrology
• Professor of Medicine and Pharmacology
• Virginia Commonwealth University
• Health Systems
• Richmond, Virginia

2
Pathophysiology of Chronic Hypertension
Inappropriately high sympathetic outflow
Inappropriately high cardiac outflow
Abnormal venoconstriction and high venus return
Inappropriately high renin release
Abnormal renal salt/water handling
Courtesy of JL Izzo, Jr, MD.
3
DoseResponse and DoseAdverse Event Relationship
for an Antihypertensive
DoseTherapeutic Response Relationship
100
DoseAdverse Response Relationship
Maximum Tolerated Adverse Effect
Effect()
Minimum Useful Effect
Therapeutic Range
0
Dose
4
Rationale for Combination of an ACE inhibitor of
an ARB With a Diuretic
Diuretic Effects
JG Cells
Renin
Angiotensin I
? ReninRelease
Volume Depletion
Angiotensin II
ARB
AT1 Receptor
DistalTubule
Na Diuresis
Vasoconstriction
Less Na Reabsorbed
5
Stages and Prevalence of CKD(Age gt20)
Prevalence N (1000s)
GFR (mL/min/1.73 m2)
Description
Stage
NKF Clinical Practice Guidelines for CKD. Am J
Kidney Dis. 200239S17S31.
6
DIURETICS
Thiazides Inhibit active exchange of Cl-Na in
the cortical diluting segment of the ascending
loop of Henle
Cortex
K-sparing Inhibit reabsorption of Na in
the distal convoluted and collecting tubule
Loop diuretics Inhibit exchange of Cl-Na-K in
the thick segment of the ascending loop of Henle
Medulla
Loop of Henle
Collecting tubule
7
Hypertension, Renal Disease, and Drug
Considerations

• Domenic A. Sica, MD
• Chairman
• Division of Clinical Pharmacology and
  Hypertension
• Division of Nephrology
• Professor of Medicine and Pharmacology
• Virginia Commonwealth University
• Health Systems
• Richmond, Virginia

8
Projections for the Year 2010Incident
Point-Prevalent ESRD Patients
700
661,330
Number of Patients
Projection
600
95 Confidence Interval
500
Point prevalence
400
Number of Patients, thousands
R2 99.7
372,407
300
172,667
326,217
200
98,953
86,825
Incidence
100
R2 99.8
0
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
2010
USRDS 2000 Annual Data Report. Bethesda, Md. 2000.
9
Adjusted ESRD Incident Rates, by Primary
Diagnosis and Diabetes in the General Population
Prevalence of Diabetes in the General Population
Incident Rates in the ESRD Population
350
9
Glomerulonephritis
300
Cystic Kidney
8
250
All
7
Diabetes
200
Rate per Million Population
Percent of Population
Hypertension
150
6
100
5
50
0
4
81
83
85
87
89
91
93
95
97
99
01
91
92
93
94
95
96
97
98
99
00
01
90
Incident ESRD patients rates adjusted for age,
gender, race. Data on the prevalence of
diabetes in the general population obtained from
the CDCs Behavioral Risk Factor Surveillance
System. United States Renal Data Sytem. 2003
Annual Data Report Graphics. Available at
http//www.usrds.org/slides.htm. Accessed 31
October 2003.
10
CVD Mortality Markedly Increased in ESRD
CVD mortality 1020 times higher in ESRD than
the general population 120 times higher for
ESRD patients aged 25 to 34
100
Dialysis male Dialysis female Dialysis
black Dialysis white GP male GP female GP
black GP white
10
1
Annual Mortality,
0.1
0.01
2534
3544
4554
5564
6574
7584
gt85
Age, years
GP General population.
Reprinted with permission from Foley RN et al. Am
J Kidney Dis. 199832(suppl 3)S112S119.
11
All-Cause Mortality in the General Medicareand
Dialysis Populations (Pts Age 65)
CVD No CVD
Deaths/1000 pt-yr at risk
Non-CKD
CKD
Dialysis
12
Stages of CKD and CVD
CHF
ESRD
End-Stage
ASCVD events
CRI (? GFR)
Progression
CADLVH
AlbuminuriaProteinuria
Initiation
At Risk
Elderly, DM, HBP
Elderly, DM, HBP
CVD
CKD
Sarnak MJ, Levey AS. Am J Kidney Dis.
200035S117-S131.
13
Stages of Chronic Kidney Disease NKF K/DOQI
Classification
GFR (mL/min/1.73 m2) 130 90 60 30 15 0
Stage I CKD risk factors/damagewith
preservedGFR
Stage II Mild ?kidneyfunction
Stage III Moderate ?kidneyfunction
Stage IV Severe ?kidneyfunction
Stage V Kidneyfailure,ESRD
? Risk of RCN, dialysis, and death
Prevalence 5.8 12.3 4.3 0.2 0.1n
(x1000) 10,259 21,794 7,553 363 300
CKDchronic kidney disease, ESRDend-stage renal
disease, GFRglomerular filtration rate, NKF
K/DOQINational Kidney Foundation Kidney Disease
Outcomes Quality Initiative, RCNradiocontrast
nephropathy Adapted from National Kidney
Foundation. Am J Kidney Dis. 200239(2suppl
2)S1-S246.
14
Serum creatinine and GFR relationship
Cut point for drug accumulation
Creatinine clearance
15
What Is Known

• Specific indications for agents blocking the
  renin-angiotensin-aldosterone system (RAAS)
• Chronic kidney disease with proteinuria
• Congestive heart failure
• Equivalence of classes for most other outcomes
• Need for adequate diuresis or sodium restriction
• Safety of calcium channel blockers for both
  cardiac and renal outcomes.
• Need for multiple agents for most patients

16
Long-term Decline in GFR is Correlated With Poor
Control of Blood Pressure 9 Studies on
Nephropathy Progression
MAP (mmHg)
95
97
99
107
101
103
105
109
111
113
115
117
119
121
0
2
4
GFR (ml/min/yr) (mmHg)
6
8
Untreated HTN
10
12
140/90
130/85
14
Trials marked by are non-diabetic renal
disease patients.
Graph (Bakris GL. J Clin Hypertens. 1999)
Trials
(Parving HH, et al. Br Med J. 1989) (Viberti GC,
et al. JAMA. 1993) (Klaur S, et al. N Engl J Med.
1993) (Herbert L, et al. Kidney Int. 1994)
(Lebovitz H, et al. Kidney Int. 1994) (Moschio G,
et al. N Engl J Med. 1996) (Bakris GL, et al.
Kidney Int. 1996) (Bakris GL, et al.
Hypertension. 1997) (GISEN Group, Lancet. 1997)
17
The Need for Sodium Restriction or Adequate
Diuresis

• Most classes of antihypertensive agents lead, by
  compensation for lower BP, to sodium retention.
  This may substantially blunt the
  anti-hypertensive effect
• JNC 7 recommends that most patients should
  receive a regimen including a thiazide type
  diuretic, either alone or with other agents.
• This is particularly important in patients with
  high sodium intakes, in particular
  African-American patients. In African-Americans,
  adequate diuresis restores a responsiveness to
  RAAS blockers similar to that in Caucasians

18
Rationale for Combination of an ACE inhibitor of
an ARB With a Diuretic
Diuretic Effects
JG Cells
Renin
Angiotensin I
? ReninRelease
Volume Depletion
Angiotensin II
ARB
AT1 Receptor
DistalTubule
Na Diuresis
Vasoconstriction
Less Na Reabsorbed
19
Safety of Calcium Channel Blockers

• Concern has been expressed in the past about the
  safety of CCBs with respect to both cardiac and
  renal outcomes
• The ALLHAT found amlodipine to be equivalent to
  chlorthalidone and lisinopril in cardiac outcomes
• The IDNT in a randomized comparison found no
  beneficial or adverse impact of amlodipine (other
  than BP reduction) on renal outcomes or
  proteinuria
• The RENAAL in a secondary analysis found no
  beneficial or adverse impact on renal outcomes of
  use of any CCBs

20
Angiotensin II and Diabetic Renal Disease
3. Abnormal matrix metabolism
Afferent arteriole
decrease angiotensin II modulation
1. Deficientautoregulation
control of systemic arterial pressure
Glomerulus
Bowmans capsule
Efferent arteriole
2. Increased efferent resistance
decrease intrarenalangiotensin II effect
21
Renin-Angiotensin System
Angiotensinogen
(-)
Renin
Angiotensin I
Bradykinin
ACE
Non-renin
Non-ACE
Angiotensin II
Inactive kinins
?BP
AT1
AT2

• Vasoconstriction
• Aldosterone secretion
• Catecholamine release
• Proliferation
• Hypertrophy

• Vasodilation
• Inhibition of cell growth
• Cell differentiation
• Injury response
• Apoptosis

Ellis ML et al. Pharmacotherapy.
199616849-860. Carey RM et al. Hypertension.
200035155-163.
22
ACEIs and ARBs in Chronic Renal Failure Renal and
Pharmacokinetic Differences
Parameter ACEIs
ARBs Proteinuria ?? ?? Uric acid
? ?? Glomerular filtration
rate ? ? Hyperkalemia ?? ? Dose titration
suggested Yes No BP reduction ?? ?? Systemic
accumulation Yes No AT2 receptor stimulation ? ??
Occurs only with losartan
23
What Is Not Yet Known

• Appropriate doses of ACEIs or ARBs in proteinuric
  kidney disease and CHF, and how to target the
  optimal doses
• Benefits of combining ACEIs and ARBs in
  proteinuric kidney disease and CHF
• Appropriate BP targets (lt140 mm Hg) in patients
  with proteinuric and non-proteinuric kidney
  disease
• Appropriate BP targets (lt140 mm Hg) for optimal
  vascular (CAD and stroke) outcomes

24
Dosing of RAAS Blockers for Renal Protection

• The currently established dose ranges for all
  ACEIs and ARBs were based on maximum BP reduction
• There is no reason to assume that the maximal
  dose for BP control will also be the appropriate
  dose for renal protection (or protection against
  CHF)
• It is unlikely that trials such as the IDNT or
  RENAAL, with hard clinical end points, will be
  undertaken to establish the optimal doses of
  these agents.

25
DoseResponse and Antiproteinuric Relationship
for an ACE inhibitor or an Angiotensin-receptor
blocker
DoseTherapeutic Response Relationship
100
DoseAdverse Response Relationship
Maximum Tolerated Adverse Effect
Effect,
Minimum Useful Effect
Therapeutic Range
0
Dose
26
Characteristics of ACE Inhibitors

• Dosing
• Once daily versus multiple
• Variable trough-to-peak ratios
• Pharmacokinetics
• Terminal elimination phase
• Route of elimination
• Renal or renal/hepatic
• Physical characteristics
• Lipophilicity
• Plasma ACE or plasma/tissue ACE binding
• Ethnicity
• Some have been studied to have documenteddifferen
  tial effects in black patients

The clinical significance of tissue ACE
inhibition has not been established in humans.
27
Inhibiting ACE at Two RAS Sites Circulation and
Tissue
Circulating ACE10 of ACE
Tissue ACE90 of ACE
Angiotensin I
Angiotensin I
ACE Inhibition
ACE
ACE
Angiotensin II
Angiotensin II
Degrades Bradykinin
PeripheralVasoconstriction
Negative Feedbackon Renin Secretion
Bradykinin
Stimulates AldosteroneSecretion
StimulatesNitric Oxide(NO)
StimulatesProstaglandinRelease
ACE angiotensin-converting enzyme RAS
renin-angiotensin system. Kang PM et al. Am Heart
J. 19941271388-1401. Gibbons GH. Am J Cardiol.
1997793-8. Dzau VJ. Arch Intern Med.
1993153937-942.
VasodilatorGrowth InhibitorAntiatherogenicAntit
hromboticAnti-inflammatoryAntioxidant
28
Pharmacology ofAngiotensin Receptor Blockers
Half-Life Bioavailability Volume of
Renal/Hepatic Drug (h) () Distribution
Clearance
Candesartan 9 15 0.13 L/kg 60/40 Eprosartan 5 13 1
3 L 30/70 Irbesartan 11-15 60-80 53-93
L 1/99 Losartan 2 33 34 L 10/90 E-3174 6-9 12
L 50/50 Olmesartan 10-15 28 17 L 45/55 Telmisartan
24 42-58 500 L 1/99 Valsartan 6 ?25 17 L 30/70
29
Role of Angiotensin II in Glomerular
Function in Renal Failure RENAL FAILURE -
TREATED
Increased Filtration
Reduced blood pressure
DecreasedGlomerularPressure
Decrease in Afferent Arteriolar Blood Flow
Glomerulus
Angiotensin II
Efferent ArteriolarDilation
Blood Flow
30
What Is Not Yet Known

• Appropriate doses of ACEIs or ARBs in proteinuric
  kidney disease and CHF, and how to target the
  optimal doses
• Benefits of combining ACEIs and ARBs in
  proteinuric kidney disease and CHF
• Appropriate BP targets (lt140 mm Hg) in patients
  with proteinuric and non-proteinuric kidney
  disease
• Appropriate BP targets (lt140 mm Hg) for optimal
  vascular (CAD and stroke) outcomes

31
Angiotensin Receptor Blocker and ACE Inhibitor
Combination TherapyPRINCIPLES

• Pharmacokinetic considerations
• Sequence effect
• Dose-response relationships
• Time of day of dosing
• Point-in-time for assessment of additive response
  and parameters measured

32
COOPERATE Study Design

• Design Randomized, double-blind trial in 263
  patients with nondiabetic renal disease
• Primary Composite of time to doubling of serum
  Endpoint creatinine concentration or ESRD
• Randomization Losartan 100 mg/day AHT as
  needed
• Trandolapril 3 mg/day AHT as needed
• Duration 3 yrs
• Target BP SBP lt130 mmHg
• DBP lt80 mmHg

Antihypertensive therapy (excluding other ACEIs
or other ARBs).
Nakao N et al. Lancet. 2003361117124.
33
COOPERATE UAER
3
Trandolapril Losartan Combination
2
Median Urinary Protein Excretion, g/day
1
0
0
5
15
20
30
35
10
25
40
Months After Randomization
Baseline
Reprinted with permission from Nakao N et al.
Lancet. 2003361117124.
34
COOPERATE Primary Endpoint
Doubling of Serum Creatinine or Progression to
ESRD
Trandolapril Losartan Combination
30
25
20
Proportion Reaching Endpoint,
15
10
5
P 0.02
0
0
5
12
18
24
30
36
Months After Randomization
Number at Risk
47
59
65
79
84
88
89
Losartan
58
63
72
75
83
85
86
Trandolapril
67
73
76
83
86
87
88
Combination
Reprinted with permission from Nakao N et al.
Lancet. 2003361117124.
35
What Is Not Yet Known

• Appropriate doses of ACEIs or ARBs in proteinuric
  kidney disease and CHF, and how to target the
  optimal doses
• Benefits of combining ACEIs and ARBs in
  proteinuric kidney disease and CHF
• Appropriate BP targets (lt140 mm Hg) in patients
  with proteinuric and non-proteinuric kidney
  disease
• Appropriate BP targets (lt140 mm Hg) for optimal
  vascular (CAD and stroke) outcomes

36
AASK Enrollment
2801 Screened
1094 Randomized
441 Randomized to receive metoprolol
436 Randomized to receive ramipril 3 Did not
receive ramipril 433 Received ramipril as assigned
217 Randomized to receive amlodipine 6 Did
not receive amlodipine 211 Received amlodipine as
assigned
20 No follow-up GFR 50 No GFR in final year of
follow-up 0 Withdrawn 47 Dialysis 18 Death
7 No follow-up GFR 23 No GFR in final year of
follow-up 0 Withdrawn 32 Dialysis 13 Death
Ongoing
321 Active participants
149 Active participants
AASK Study Group. JAMA. 200128527192728.
37
AASK Risk Reduction in GFR Decline, ESRD, or
Death With ACEI, ?-Blockade, or CCB
0
10
19
22
Risk Reduction
20
Metoprolol vs amlodipine P.19
Ramipril vs metoprolol P.005
30
37
38
40
Metoprolol vs amlodipine P.003
16
Ramipril vs amlodipine P.042
Ramipril vs amlodipine P.004
50
Patients with existing kidney damage(baseline
UP/C lt0.22)
Decrease from baseline GFR of 50, or 25
mL/min/1.73 m2. Agodoa LY et al. JAMA.
200128527192728.
38
AASK Blood Pressure Results

• Patients randomized to standard vs aggressive BP
  lowering
• Standard target 140/90 mm Hg
• Aggressive target 125/75 mm Hg
• Findings underscore importance of BP control even
  in patients with minimal renal dysfunction
• Aggressive BP lowering beyond usual levels did
  not further slow renal disease progression

Wright JT et al. Arch Intern Med.
200216216361643. Wright JT et al. JAMA.
200228824212431.
39
What Is Not Yet Known

• Appropriate doses of ACEIs or ARBs in proteinuric
  kidney disease and CHF, and how to target the
  optimal doses
• Benefits of combining ACEIs and ARBs in
  proteinuric kidney disease and CHF
• Appropriate BP targets (lt140 mm Hg) in patients
  with proteinuric and non-proteinuric kidney
  disease
• Appropriate BP targets (lt140 mm Hg) for optimal
  vascular (CAD and stroke) outcomes

40
CVD Risk Factors in CKD

• Hypertension
• Diabetes/metabolic syndrome
• Dyslipidemia
• Inflammation
• Endothelial dysfunction
• Hyperhomocysteinemia
• Hyperparathyroidism Ca2/PO4
• Uric acid elevations
• Anemia
• LVH
• Smoking
• Physical inactivity
• Sleep apnea

41
Target Blood Pressure
For Individuals With
BP Goal
Hypertension(no diabetes or renal disease)
lt140/90 mmHg (JNC 7)
lt130/80 mmHg (ADA, JNC 7)
Diabetes Mellitus
Renal Disease with proteinuria gt1 gram/24 hours
or diabetic kidney disease
lt135/85 mmHglt125/75 mmHg (NKF)
Chobanian AV et al. JAMA. 200328925602571.
American Diabetes Association. Diabetes Care.
200225134147. National Kidney Foundatrion. Am
J Kidn Dis. 200239(suppl 1)S1S266.
42
(No Transcript)
43
Altered Loop Diuretic Pharmacodynamics in
Diuretic Resistance
Sica DA et al. Clin Pharmacokinet 199630229-249.
44
Trends in ESRD Incidence Rates by Primary
Diagnosis, and Rate of Diabetes in the General
Population
Incidence Rates in the ESRD Population
Prevalence of Diabetes in the General Population
All
Rate/million population
Rate/1000 population
DM
HTN
GN
PCK
96
Year
Year
45
Adjusted ESRD Incident Rates, by Age and
Race/Ethnicity
Age
Race/Ethnicity
1,600
0-19
White
20-44
Black
1,200
45-64
Native American
65-74
Asian
Rate per Million Population
75
800
Hispanic
All
400
0
81
83
85
87
89
91
93
95
97
99
01
81
83
85
87
89
91
93
95
97
99
01
Incident ESRD patients rates by age unadjusted
for gender race, rates by race ethnicity
adjusted for age gender. For Hispanic patients
we present data beginning in 1996, the first full
year after the April 1995 introduction of the
revised Medical Evidence form, which contains
more specific questions on race ethnicity.
United States Renal Data Sytem. 2003 Annual Data
Report Graphics. Available at
http//www.usrds.org/slides.htm. Accessed 31
October 2003.
46
Cardiovascular Mortality Rates in Prevalent ESRD
Patients
100
16
89.3 (2001 Actual)
80
12
60
8
Bars Deaths per 1,000 Pt Years at Risk
Symbols Change from Previous Year
52 (2010 Target)
40
4
20
0
0
-4
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Deaths from CV Disease
Period prevalent ESRD patients unadjusted. The
Death Notification form was revised in September
1990 to include more detailed categories for
cause of death prior to this time CV deaths were
often classified as being of other causes.
Because of this, data for CV other deaths
prior to 1991 have been omitted here. United
States Renal Data Sytem. 2003 Annual Data Report
Graphics. Available at http//www.usrds.org/slid
es.htm. Accessed 31 October 2003.
47
Diuretic Therapy
48
Clinical Trials in Patients With Disorders
Related to Hypertension
CVA/ Dementia
LVH
Heart failure/
Post-MI
Renal disease
Dyslipidemia
Diabetes
Atherosclerosis
LIFE
HR Black, 2003.
49
Albuminuria

• Associated with myocardial infarction and stroke
• Reflects endothelial damage
• Part of the cardiometabolic syndrome
• Progression of micro- to macroalbuminuria
  predicts progression of renal disease

Microalbuminuria 30300 mg/day
50
Association of Microalbuminuria and
Cardiovascular Morbidity and Mortality in Type 2
Diabetes
Niskanen et al, 1993
Neil et al, 1993
Stehouwer et al, 1990
Stiegler et al, 1992
Patrick et al, 1990
Subtotal
Macleod et al, 1995
Total
1
2
5
10
20
50
100
0.5
Odds ratios of CV morbidity and mortality in
patients withtype 2 diabetes with
microalbuminuria vs. normoalbuminuria
Dinneen SF, et al. Arch Intern Med.
199715714131418.
51
Microalbuminuria and Ischemic Heart Disease Risk
6
5
Micro-albuminuria
5.3
4
Normo-albuminuria
Relative Risk of IHD
3
3.3
2
2.2
2.5
1
1.5
1.0
0
SBP lt140
SBP 140160
SBP gt160
Borch-Johnsen K, et al. Arterioscler Thromb Vasc
Biol. 19991919921997.
52
Proteinuria Predicts CV Mortality, Stroke,and
CHD Events in Type 2 Diabetes
A U-Prot lt150 mg/L
B U-Prot 150300 mg/L
C U-Prot gt 300 mg/L
P lt 0.001 for trend
A
B
Survival Curves for CV Mortality
Incidence,
C
Overall P lt 0.001
Stroke
CHD Events
Months
U-Prot urinary protein concentration. Miettinen
H, et al. Stroke. 19962720332039.
53
Influence of Drug Accumulation on Blood Pressure
in Heart Failure and Renal Disease
Afferent arteriole
Glomerulus
Bowmans capsule
BP ?
Untreated
Efferent arteriole
Afferent arteriole
Afferent arteriole
Glomerulus
Glomerulus
Bowmans capsule
Bowmans capsule
BP ??
BP ?
Efferent arteriole
Efferent arteriole
ARBs
ACEIs
Difference due to drug accumulation with ACEIs,
not class effect.
54
Glomerulotubular Structure and Drug Handling
Tubular transport and/or metabolism
Filtration
Capillary Loop
Endothelial Cell
Afferent Arteriole
Efferent Arteriole
Juxtaglomerular Apparatus
55
Diabetes The Most Common Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Other
Glomerulonephritis
Diabetes
10
13
Hypertension
27
50.1
Number of Dialysis Patients, thousands
520,240
No. of patients
281,355
Projection
95 CI
243,524
r2 99.8
United States Renal Data System. Annual data
report. 2000.
56
The Impact of ACEI Treatment on CHF End
PointsGarg Metaanalysis

• Metaanalysis of results of 32 trials including
  7,105 patients from trials in which any of a
  number of ACEIs were compared with placebo in
  treatment of patients with CHF (AHA Stage II
  IV)
• Overall 23 reduction of risk of mortality
  (plt0.001), 35 reduction of mortality or
  hospitalization (plt0.001). Non-significant trend
  to benefit on other CV outcomes
• Effects in diabetic subgroup similar to results
  in entire cohort
• Effects of all ACEI were similar ie, a class
  effect
• Major benefits seen on deaths from CHF,
  especially in patients with worst CHF, and in
  first 3 mo of Rx
• NO COMMENT ON IMPACT ON BLOOD PRESSURE!!!

Garg R, Yusuf S. JAMA.19952731450-1456.
57
Studies Confirming the Benefits of RAAS Blockade
in Kidney Diseases With Proteinuria

• Diabetic kidney disease
• Type 1 Captopril (Lewis) Study
• Type 2 IDNT and RENAAL Studies (overt
  proteinuria)
• Type 2 IRMA-2 (microalbuminuria)
• Non-diabetic kidney disease
• AIPRI
• REIN Studies
• Jafar metaanalysis of studies of non-diabetic
  kidney disease (Ann Intern Med. 2003139244-252)
  confirms effect of ACEI independent of blood
  pressure effect.

58
What We Need to Learn1

• Optimal doses of RAAS blockers for renal effect
  remain to be determined. It is likely that these
  studies will be based on minimization of
  proteinuria, a surrogate for renal risk

59
What We Need to Learn2

• Optimal doses of RAAS blockers for renal effect
  remain to be determined. It is likely that these
  studies will be based on minimization of
  proteinuria, a surrogate for renal risk
• We need further studies of the combination of
  ACEIs and ARBs, especially for kidney protection

60
Evidence From Trials With Kidney Patients
Randomized to Different BP Goals

• Patients with various non-diabetic renal diseases
  were randomized either to a MAP of 108 (140/90)
  or to 92 (125/75) mm Hg
• Patients with type 2 diabetes were randomized to
  DBP of 90 or 75 mm Hg
• A-A patients with hypertensive renal disease were
  randomized to MAPs of 108 (140/90) or 92 (125/75)
  mm Hg

MDRD
ABCD
AASK
61
MDRD Impact of BP Goal on Rate of Progression as
a Function of Proteinuria
Usual BP Low BP
Study A
Study B
Mean rates of GFR decline (mL/min/yr)
n420
n104
n54
n136
n63
n32
lt1
13
gt3
lt1
13
gt3
Baseline urine protein (g/d)
Klahr S. N Engl J Med. 1994 330877.
62
MDRD Impact of Usual and Low BP Group Assignment
on Slope of BP
Usual BP Low BP
Decline in GFR (mL/min)
Month
Klahr S et al. N Engl J Med. 1994 330877.
63
AASK Comparison of BP Goal and Change in GFR
(mL/min/1.73m2) from Baseline
3
0
-3
Mean (SE) Change in GFR
Usual Goal
-6
-9
Low Goal
-12
0
6
12
24
36
48
Follow-up (mo)
64
A Major Limitation of Studies of BP Reduction on
CV Outcomes

• There have been no studies of the impact of
  randomizing diabetic patients to systolic BP
  targets lt140 mm Hg
• Two trials have looked at randomizing diabetic
  patients to diastolic BP targets lt90 mm Hg. But
  in these trials the systolic BP achieved in the
  low diastolic BP group was ?140 mm Hg
• Therefore most evidence on the impact of SBP
  levels lt140 mm Hg come from secondary,
  correlative, analyses

65
IDNT Impact of Mean Follow-up Systolic BP on
Risk of All Cause Mortality
1.5
1.0
RRofdeath
0.5
0.0
-0.5
-1.0
lt121
121-130
131-140
141-150
151-160
161-170
171-180
gt180
Average Follow-up Seated SBP (mm Hg)
66
What We Need to Learn3

• Optimal doses of RAAS blockers for renal effect
  remain to be determined. It is likely that these
  studies will be based on minimization of
  proteinuria, a surrogate for renal risk
• We need further studies of the combination of
  ACEIs and ARBs, especially for kidney protection
• We need a randomized trial to establish once and
  for all the safety and efficacy of different SBP
  goals lt140 mm Hg for renal and cardiac outcomes,
  and to determine which patients will benefit from
  more aggressive goals

67
AASK Overview
Objective Compare ACEI (ramipril), calcium
channel blocker (amlodipine) and beta blocker
(metoprolol) on progression of hypertensive renal
disease.

• Interventions Participants received either
• amlodipine, 510 mg/d (N 217)
• ramipril, 2.510 mg/d (N 436) or
• metoprolol, 50200 mg/d (N 441)
• other agents were added to achieve either MAP
  102107 or ?92 mmHg

African American Study of Kidney Disease and
Hypertension. Random distribution.
Agodoa LY, et al. JAMA. 200128527192728.
68
AASK Study Baseline Patient Characteristics
Amlodipine(N 217)
Ramipril (N 436)
Age, y Women, GFR (mL/min per 1.73m2) Serum
creatinine (mg/dL) Men Women Urine protein g/d
(UP/Cr) Men Women
54.2 49.8 38.8 40.1 46.1 46.8 2.18 2.27 1.76 1.75
0.34 0.30 0.32 0.30
(Adapted from Agodoa LY, et al. JAMA 2001)
69
AASK Study Antihypertensive Therapy andBP
During Follow-up
Ramipril
Amlodipine
151.0
150.0
134.5
134.4
134.0
132.9
SBP DBP
95.7
96.0
84.0
83.1
82.2
Mean BP (mm Hg)
81.4
Baseline(n436)
Mo 3(n375)
Follow-upafter 3rd mo(n418)
Baseline(n217)
Mo 3(n189)
Follow-upafter 3rd mo(n209)
AASK Study Group. JAMA. 200128527192728.
70
AASK Study Relative Risk Reduction With Ramipril
vs Amlodipine
38P0.005
Amlodipine Ramipril
41P0.007
38P0.01
44P0.01
41P0.03
Eventsperperson-yr
31P0.31
GFR
ESRD
Death
GFR orESRD
ESRDor death
GFR, ESRD, or death
AASK Study Group. JAMA. 200128527192728.
71
AASK Study Mean Change in GFR Basedon Urinary
Protein to Creatinine Ratio
Baseline UP/Cr gt0.22
Baseline UP/Cr ?0.22
10
10
0
5
-5
? in GFR(mL/minper 1.73 m2/y)
0
-10
-5
Amlodipine
-20
Ramipril
-10
-25
0
3
12
24
36
0
3
12
36
24
Months
Months
AASK Study Group. JAMA. 200128527192728.
72
Influence of Drug Accumulation on Blood Pressure
in Heart Failure and Renal Disease
Afferent arteriole
Glomerulus
Bowmans capsule
BP ?
Untreated
Efferent arteriole
Afferent arteriole
Afferent arteriole
Glomerulus
Glomerulus
Bowmans capsule
Bowmans capsule
BP ??
BP ??
Efferent arteriole
Efferent arteriole
ARBs
ACEIs
Difference due to drug accumulation with ACEIs,
not class effect.
73
Case Study No. 1 History

• 62-year-old AA female
• 18-year history of DM
• 5-year history of poorly-controlled HTN
• Smokes and occasionally uses alcohol
• Family history positive for DM, MI, renal failure
• Previous adverse reaction to baby aspirin

74
Case Study No. 1 Medications

• Previous Meds
• HCTZ (d/cd due to hypokalemia)
• Nifedipine GITS (d/cd due to dizziness,
  flushing, and edema)
• NPH Insulin, 50U SQ qd
• Current Meds
• Atenolol 100 mg qd
• NPH insulin, 33U SQ qd

75
Case Study No. 1 Physical Exam

• Overweight female
• BP 180/102 mmHg
• Pulse 92 bpm
• Diabetic retinopathy
• Lungs clear
• Grade 1/6 SEM
• 2 pedal edema

76
Case Study No. 1 Laboratory Exam

• Serum K 5.2 mEq/L
• Serum Cr 2.7 mg/dL
• 2 proteinuria on dipstick
• 7.5 g protein in 24-h collection
• Hemoglobin A1C 7.2
• LDL cholesterol 200 mg/dL
• HDL cholesterol 30 mg/dL

77
Case Study No. 1 Teaching Points

• What factors most likely led to hypokalemia when
  this patient was administered hydrochlorothiazide?
  
• What factors contribute to her current level of
  hyperkalemia? Is this degree of hyperkalemia a
  contraindication to the use of an ACE inhibitor?
• Why does she have a decreasing insulin
  requirement?
• What might be the most effective way to diminish
  protein excretion in this patient?
• Is antiplatelet therapy recommended, and if so,
  which agent?

78
Case Study No. 1 Teaching Points, cont.

• How should the lipid abnormality be treated?
• What type of adjuvant antihypertensive therapy
  should be offered? Is non-pharmacologic therapy
  a viable option?
• Is ARB therapy useful in this patient type?
• Would fixed-dose combination therapy be of
  benefit in the management of this patients HTN
  and/or end-organ disease?

79
Case Study No. 2 History

• 62-year-old AA male
• Long-term history of poorly-controlled HTN due to
  lack of compliance
• Recent MI 6 months ago
• Patient states he was unable to tolerate dose
  increases necessary to adequately control BP,
  which has never been lower than 170/98

80
Case Study No. 2 Physical Exam

• BP 160/95 mmHg
• 2/6 SEM along left sternal border
• Bibasilar rales
• 1 bilateral pedal edema

81
Case Study No. 2 Test Results

• Echocardiogram
• Hypocontractility
• LVH
• EF 33
• 2 mitral regurgitation
• 2 tricuspid regurgitation
• CXR
• Cardiomegaly and interstitial edema
• Labs
• Serum Cr 2.2 mg/dL

82
Case Study No. 2 Teaching Points

• Whats the role of diuretic therapy in the
  management of this patients HTN?
• How do ACEs/ARBs fit into this patients
  management?
• After initiation of pharmacotherapy, lab tests
  show a rise in serum Cr to 5.0 mg/dL. What is the
  next therapeutic step?
• Despite maximum titrated doses of ACE/ARB,
  symptoms do not resolve. What additional
  management strategies should be considered?
• The patient develops angioneurotic edema while
  taking an ACE inhibitor. What is the next
  therapeutic step?
• Disease progression leads to refractory edema.
  What management steps should be considered to
  overcome his diuretic resistance?