Transcript Variables affecting creatinine metabolism

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
 92
20%
10%
20%
50%
Both BP
Groups
40%
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
AASK Trial Outcomes:
• 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
Distribution of Baseline Proteinuria*
for Randomized Patients
Percent of Patients
60
N= 1090
Mean= 0.33
STD= 0.52
Median= 0.08
50
40
30
1/3 of patients (n= 357) with UP/Cr > 0.22
2/3 of patients (n=733) with UP/Cr ≤ 0.22
20
10
0
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
Baseline Urine Protein/Creatinine Ratio (UP/Cr)
*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
% wi th Events
70
Baseline UP/Cr < 0.22
Baseline UP/Cr > 0.22
60
50
P < 0.001
40
30
20
10
0
0
6
12
18
24
30
36
42
Follow-up Month
48
54
60
Joint Effect of Baseline UP and Δ UP/Cr
Effects Per 2-fold UP/Cr
Patients
All
Baseline
UP/Cr
≤ 0.22
Baseline
UP/Cr
> 0.22
Base. UP/Cr
Δ UP/Cr
Base. UP/Cr
-0.66
-0.63
-0.41
ESRD
HR
2.11
1.72
1.94
Δ UP/Cr
-0.52
1.55
Base. UP/Cr
-0.91
2.20
Δ UP/Cr
-0.85
1.86
Predictor
GFR slope
(ml/min/yr/1.73m2)
Baseline UP/Cr
Association of Proteinuria with
GFR at Baseline
2.0
2.0
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0
-0.5 (N)
176
198
222
295
199
30
30-40
40-50
50-60
>60
-0.5
Mean Baseline GFR (ml/min/1.73m2)
Spearman r = - 0.46, p < 0.001, UP/Cr = urine protein/creatinine ratio
Box plots give 10th, 25th, 50th, 75th and 90th percentiles; '+' indicates mean.
Baseline UP/Cr Predicts Subsequent
Progression Independently of Initial GFR
(mean GFR slope, ml/min/1.73m2/yr (SE))
Baseline GFR Group (ml/min/1.73m2)
Baseline
UP/Cr
> 48
40-48
30-40
< 30
< 0.08
-1.21
-0.58
-1.49
-1.72
(0.19)
(0.38)
(0.39)
(0.50)
0.08-0.22
-2.25
-2.05
-2.06
-2.22
(0.41)
(0.70)
(0.69)
(0.47)
0.22-0.66
-2.95
-3.50
-2.73
-2.87
(0.52)
(0.48)
(0.44)
(0.61)
> 0.66
-3.36
-4.85
-5.77
-4.04
(0.55)
(0.94)
(0.66)
(0.41)
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.
Effect of Drug Group on Percent Change
in UP/Cr from Baseline to 12 Months
% Change
639
172
0
-63
-86
A B C
Baseline
UP/Cr
<0.08
A B C
0.08-0.22
A B C
0.22-0.66
A B C
>0.66
A = Ramipril, B = Metoprolol, C = Amlodipine
Boxes range from 25th to 75th percentiles
Effect of Drug Group on Absolute Change
in UP/Cr from Baseline to 12 Months
Absolute Change
1.5
1.0
0.5
0.0
-0.5
-1.0
Baseline
UP/Cr
A B C
A B C
A B C
A B C
<0.08
0.08-0.22
0.22-0.66
>0.66
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
172
Amlodipine
Ramipril
Metoprolol
% Change (SE)
122
82
49
22
0
-18
-33
0
6
12
18
24
30
36
42
48
Follow-up Month
Geometric mean urine protein/creatinine ratio declined faster in ramipril
and metoprolol groups than amlodipine group (p < 0.001)
Main Clinical Composite Outcome
Declining GFR Event, ESRD, or Death
Amlodipine
Metoprolol
Ramipril
40
% wi th Events
35
30
Ramipril vs. Metoprolol
RR = 22%, p = 0.042
25
20
15
10
Ramipril vs. Amlodipine:
RR= 38%, p=0.004
5
0
0
6
12
18
24
30
36
42
Follow-up Month
RR = % Risk Reduction, Adjusting for Baseline Covariates
48
54
60
Main Clinical Composite Outcome
Declining GFR Event, ESRD, or Death
Baseline UP/Cr  0.22
Amlodipine
Metoprolol
Ramipril
% wi th Events
40
35
30
Baseline UP/Cr > 0.22
Amlodipine
Metoprolol
Ramipril
25
20
15
10
5
0
0
12
24 36 48 60 0
Follow-up Month
12
24
36
48
60
Follow-up Month
Change in GFR from Baseline (ml/min/1.73m2)
Amlodipine Interaction p-values < 0.003
Baseline UP/Cr  0.22
16
Amlodipine
Ramipril
Metoprolol
Amlodipine
Ramipril
Metoprolol
12
Mean (SE) Change in GFR
Baseline UP/Cr > 0.22
8
4
0
-4
-8
-12
-16
0
12
24
36
Follow-up Month
48
0
12
24
36
Follow-up Month
48
Percent Change in Proteinuria
from Baseline
% Change (SE)
172
Lower BP Goal
Usual BP Goal
P < 0.001
122
82
49
22
0
-18
0
6
12
24
36
Follow-up Month
% change in geometric mean urine protein/creatinine ratio
48
Change in GFR from Baseline
Lower BP Goal
Usual BP Goal
0
ml/min/1.73m2
Mean (SE) Change in GFR
3
-3
-6
P = 0.24 for comparison
of total slope to 4 yrs
P = 0.33 for comparison of
chronic slopes
-9
-12
0
6
12
24
36
Follow-up Month
48
Composite Clinical Outcome
Declining GFR Event, ESRD or Death
40
Lower BP (Achieved: 128/78)
Usual BP (Achieved: 141/85)
% with Events
35
Low vs. Usual:
RR=2%, (p=0.85)
30
25
20
15
10
5
0
0
6
12
18
24
30
36
42
48
54
60
Follow-Up Time (Months)
RR=Risk Reduction, adjusted for baseline covariates
Main Clinical Composite Outcome
Declining GFR Event, ESRD or
Interaction p-valueDeath
with baseline UP: 0.007
Baseline UP/Cr  0.22
Low BP
Usual BP
% with Events
70
60
HR= 1.31, (p=0.11)
50
Baseline UP/Cr > 0.22
Low BP
Usual BP
HR=0.82, (p=0.18)
40
30
20
10
0
0
12 24 36 48 60 0
Follow-Up Month
12
24 36 48
Follow-Up Month
HR=Hazard Ratio adjusted for baseline covariates
60
AASK Trial-Based Assessment of Validity of
UP vs. True Endpoint (Scorecard)
Outcome
Treatment
Comparison
ACE vs. CCB
ACE vs. BB
Low vs. Usual
Δ UP
50% Δ GFR,
ESRD, Death
ACE
ACE
N.S. (Slight
trend for ACE)
ACE
Low BP
Null
Agreement of
Treatment
Effects
?
• 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
16
Amlodipine
Ramipril
Metoprolol
Amlodipine
Ramipril
Metoprolol
12
Mean (SE) Change in GFR
Baseline UP/Cr > 0.22
8
4
0
-4
-8
-12
-16
0
12
24
36
Follow-up Month
48
0
12
24
36
Follow-up Month
48
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
GFR
Treatment 1
Treatment 2
Acute
Phase
Chronic Phase
Follow-up time
Change in GFR from Baseline
16
Amlodipine
Ramipril
Metoprolol
12
ml/min/1.73m2
Mean (SE) Change in GFR
Baseline UP/Cr  0.22
8
4
0
-4
-8
-12
Total slope comparisons
Amlodipine vs metoprolol:  = 5.9, p < 0.001
Amlodipine vs ramipril:
 = 3.6, p = 0.006
-16
0
6
12
18
24
30
Follow-up Month
36
42
48
Change in GFR from Baseline
8
Amlodipine
Ramipril
Metoprolol
4
ml/min/1.73m2
Mean (SE) Change in GFR
Baseline UP/Cr > 0.22
0
-4
-8
-12
-16
-20
-24
Total slope comparisons
Amlodipine vs metoprolol:  = - 1.9, p = 0.087
Amlodipine vs ramipril:
 = - 6.0, p = 0.007
0
6
12
18
24
30
36
Follow-up Month
42
48
Change in GFR from Baseline
4
4
Low Goal
Usual Goal
2
m/lmin/1.73m2
Mean (SE) Change in GFR
Baseline UP/Cr  0.22
2
0
0
-2
-2
-4
-4
-6
-6
 Total Slope = - 0.76, p = 0.24
-8
-8
Base
line
F6
12
18
24
30
36
Follow-up Month
42
48