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