Implications of the AASK Study For Validity of Proteinuria as a Surrogate Endpoint
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Transcript of Implications of the AASK Study For Validity of Proteinuria as a Surrogate Endpoint
Implications of the AASK Study For Validity of
Proteinuria as a Surrogate Endpoint
AASK DESIGN (N = 1094 Patients)
ACEi
Ramipril
CCB
Amlodipine
Beta Blocker
Metoprolol
All Drug
Groups
Usual BP
MAP Goal
102-107
20% 10% 20% 50%
Low BP MAP Goal
9220% 10% 20% 50%
Both BP
Groups40% 20% 40% 100%
Follow-up:Trial Phase: Approximately 3.5 – 6.5 years Cohort Phase: An additional 5 - 6 years
AASK Entry Criteria– African-American (self report)
– 18-70 yr old with DBP > 95 mmHg
– GFR 20 - 65 ml/min/1.73 m2
– Non-diabetic
– Baseline urine protein/creatinine < 2.5
• Primary Renal Outcome– Rate of decline (slope) in iothalomate GFR in
ml/min/1.73m2/year • Secondary (Clinical) Composite Outcome
– 50% or > 25 ml/min reduction from baseline GFR– ESRD– Death
• Other Secondary Outcomes– ESRD or Death– ESRD alone
• Long-term Follow-up of Trial + Cohort– Doubling of SCR or ESRD– Doubling of SCR, ESRD, or Death
AASK Trial Outcomes:
Distribution of Baseline Proteinuria*for Randomized Patients
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6
N= 1090
Mean= 0.33STD= 0.52Median= 0.08
Per
cen
t o
f P
atie
nts
0
10
20
30
40
50
60
Baseline Urine Protein/Creatinine Ratio (UP/Cr)
1/3 of patients (n= 357) with UP/Cr > 0.222/3 of patients (n=733) with UP/Cr ≤ 0.22
*Patients with UP/Cr > 2.5 excluded from randomization
Individual-Level Association
Association of Main Clinical Composite Outcome (GFR Event, ESRD, or Death)
With Baseline Proteinuria
Baseline UP/Cr < 0.22Baseline UP/Cr > 0.22
% w
ith
Eve
nts
0
10
20
30
40
50
60
70
Follow-up Month0 6 12 18 24 30 36 42 48 54 60
P < 0.001
Joint Effect of Baseline UP and Δ UP/CrEffects Per 2-fold UP/Cr
Patients Predictor GFR slope(ml/min/yr/1.73m2)
ESRD
HR
AllBase. UP/Cr -0.66 2.11
Δ UP/Cr -0.63 1.72
Baseline UP/Cr ≤ 0.22
Base. UP/Cr -0.41 1.94
Δ UP/Cr -0.52 1.55
Baseline UP/Cr > 0.22
Base. UP/Cr -0.91 2.20
Δ UP/Cr -0.85 1.86
Spearman r = - 0.46, p < 0.001, UP/Cr = urine protein/creatinine ratioBox plots give 10th, 25th, 50th, 75th and 90th percentiles; '+' indicates mean.
176 198 222 295 199(N)
Bas
elin
e U
P/C
r
-0.5
0.0
0.5
1.0
1.5
2.0
Mean Baseline GFR (ml/min/1.73m2) 30 30-40 40-50 50-60 >60
-0.5
0.0
0.5
1.0
1.5
2.0
Association of Proteinuria withGFR at Baseline
Baseline GFR Group (ml/min/1.73m2)
Base-line UP/Cr
> 48 40-48 30-40 < 30
< 0.08 -1.21 (0.19)
-0.58(0.38)
-1.49(0.39)
-1.72(0.50)
0.08-0.22 -2.25(0.41)
-2.05(0.70)
-2.06(0.69)
-2.22(0.47)
0.22-0.66 -2.95(0.52)
-3.50(0.48)
-2.73(0.44)
-2.87(0.61)
> 0.66 -3.36(0.55)
-4.85(0.94)
-5.77(0.66)
-4.04(0.41)
Baseline UP/Cr Predicts Subsequent Progression Independently of Initial GFR
(mean GFR slope, ml/min/1.73m2/yr (SE))
AASK and Trial-Based Approach
• Provides three independent treatment comparisons to test if treatment effects on Δ UP predict treatment effects on clinical endpoints
• Time-to-event endpoints more relevant than primary slope endpoint from perspective of validating UP/Cr as a surrogate endpoint.
% C
han
ge
-86
-63
0
172
639
A B C A B C A B C A B C
Effect of Drug Group on Percent Changein UP/Cr from Baseline to 12 Months
A = Ramipril, B = Metoprolol, C = Amlodipine
<0.08 0.08-0.22 0.22-0.66 >0.66BaselineUP/Cr
Boxes range from 25th to 75th percentiles
Effect of Drug Group on Absolute Changein UP/Cr from Baseline to 12 Months
<0.08 0.08-0.22 0.22-0.66 >0.66BaselineUP/Cr
Ab
so
lute
Ch
an
ge
-1.0
-0.5
0.0
0.5
1.0
1.5
A B C A B C A B C A B C
A = Ramipril, B = Metoprolol, C = Amlodipine
AASK and Trial-Based Approach
• Much greater treatment effects on absolute ΔUP at higher baseline UP levels also allows AASK to be used to determine if larger treatment effects on ΔUP correspond to larger effects on clinical endpoints.
Percent Change in UP/Cr from Baseline
Geometric mean urine protein/creatinine ratio declined faster in ramipril and metoprolol groups than amlodipine group (p < 0.001)
% C
han
ge
(SE
)
-33
-18
0
22
49
82
122
172
Follow-up Month0 6 12 18 24 30 36 42 48
Metoprolol
RamiprilAmlodipine
Main Clinical Composite OutcomeDeclining GFR Event, ESRD, or Death
% w
ith
Eve
nts
MetoprololRamipril
Amlodipine
0
5
10
15
20
25
30
35
40
Follow-up Month0 6 12 18 24 30 36 42 48 54 60
Ramipril vs. Amlodipine: RR= 38%, p=0.004
Ramipril vs. MetoprololRR = 22%, p = 0.042
RR = % Risk Reduction, Adjusting for Baseline Covariates
Main Clinical Composite Outcome Declining GFR Event, ESRD, or Death
Amlodipine
RamiprilMetoprolol
0
5
10
15
20
25
30
35
40
Follow-up Month0 12 24 36 48 60
Baseline UP/Cr 0.22 Baseline UP/Cr > 0.22
Amlodipine
RamiprilMetoprolol
Follow-up Month
0 12 24 36 48 60
% w
ith
Eve
nts
Change in GFR from Baseline (ml/min/1.73m2)Amlodipine Interaction p-values < 0.003
Baseline UP/Cr 0.22
MetoprololRamiprilAmlodipine
Mea
n (
SE
) C
han
ge
in G
FR
-16
-12
-8
-4
0
4
8
12
16
Follow-up Month0 12 24 36 48
MetoprololRamipril
Amlodipine
Follow-up Month0 12 24 36 48
Baseline UP/Cr > 0.22
Percent Change in Proteinuria from Baseline
Lower BP GoalUsual BP Goal
%
Ch
ang
e (S
E)
-18
0
22
49
82
122
172
Follow-up Month0 6 12 24 36 48
P < 0.001
% change in geometric mean urine protein/creatinine ratio
Change in GFR from BaselineM
ean
(S
E)
Ch
ang
e in
GF
Rm
l/m
in/1
.73m
2
Lower BP GoalUsual BP Goal
-12
-9
-6
-3
0
3
Follow-up Month0 6 12 24 36 48
P = 0.24 for comparison of total slope to 4 yrsP = 0.33 for comparison of chronic slopes
RR=Risk Reduction, adjusted for baseline covariates
% w
ith
Eve
nts
Composite Clinical OutcomeDeclining GFR Event, ESRD or Death
Low vs. Usual:RR=2%, (p=0.85)
Lower BP (Achieved: 128/78)Usual BP (Achieved: 141/85)
0
5
10
15
20
25
30
35
40
Follow-Up Time (Months)0 6 12 18 24 30 36 42 48 54 60
Main Clinical Composite Outcome
Declining GFR Event, ESRD or Death
HR=Hazard Ratio adjusted for baseline covariates
Follow-Up Month
% w
ith E
vent
s
HR= 1.31, (p=0.11)
Low BP
Usual BP
0
10
20
30
40
50
60
70
0 12 24 36 48 60
Baseline UP/Cr 0.22 Baseline UP/Cr > 0.22
HR=0.82, (p=0.18)
Low BPUsual BP
Follow-Up Month0 12 24 36 48 60
Interaction p-value with baseline UP: 0.007
AASK Trial-Based Assessment of Validity of UP vs. True Endpoint (Scorecard)
Treatment Comparison
Outcome
Δ UP50% Δ GFR, ESRD, Death
Agreement of Treatment
Effects
ACE vs. CCB ACE ACE
ACE vs. BBN.S. (Slight
trend for ACE)ACE
Low vs. Usual Low BP Null
?
• Effect modification of Low vs. Usual BP and Amlodopine vs. Ramipril comparisons in general agreement between treatment effects on UP and on progression endpoints.
THANK YOU
OTHER SLIDES
Change in GFR from Baseline (ml/min/1.73m2)
Baseline UP/Cr 0.22
MetoprololRamiprilAmlodipine
Mea
n (
SE
) C
han
ge
in G
FR
-16
-12
-8
-4
0
4
8
12
16
Follow-up Month0 12 24 36 48
MetoprololRamipril
Amlodipine
Follow-up Month0 12 24 36 48
Baseline UP/Cr > 0.22
AASK Outcomes• Mean GFR decline evaluated separately in
first 3 months (acute phase) and after 3 months (chronic phase) due to expectation of acute hemodynamic effects
GF
R
AcutePhase
Chronic Phase
Treatment 1
Treatment 2
Follow-up time
Change in GFR from BaselineBaseline UP/Cr 0.22
MetoprololRamiprilAmlodipine
Mea
n (
SE
) C
han
ge
in G
FR
m
l/m
in/1
.73m
2
-16
-12
-8
-4
0
4
8
12
16
Follow-up Month0 6 12 18 24 30 36 42 48
Amlodipine vs metoprolol: = 5.9, p < 0.001Amlodipine vs ramipril: = 3.6, p = 0.006
Total slope comparisons
Change in GFR from Baseline Baseline UP/Cr > 0.22
MetoprololRamipril
Amlodipine
Mea
n (S
E)
Cha
nge
in G
FR
m
l/min
/1.7
3m2
-24
-20
-16
-12
-8
-4
0
4
8
Follow-up Month0 6 12 18 24 30 36 42 48
Total slope comparisonsAmlodipine vs metoprolol: = - 1.9, p = 0.087Amlodipine vs ramipril: = - 6.0, p = 0.007
Change in GFR from BaselineBaseline UP/Cr 0.22
Mea
n (S
E)
Cha
nge
in G
FR
m/lm
in/1
.73m
2
Baseline
Low Goal
Usual Goal
-8
-6
-4
-2
0
2
4
Follow-up Month
F6 12 18 24 30 36 42 48-8
-6
-4
-2
0
2
4
Total Slope = - 0.76, p = 0.24