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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). Follow-up: Trial Phase: Approximately 3.5 – 6.5 years Cohort Phase: An additional 5 - 6 years. AASK Entry Criteria. African-American (self report)

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Implications of the AASK Study For Validity of Proteinuria as a Surrogate Endpoint

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  1. Implications of the AASK Study For Validity of Proteinuria as a Surrogate Endpoint

  2. AASK DESIGN (N = 1094 Patients) Follow-up: Trial Phase: Approximately 3.5 – 6.5 years Cohort Phase: An additional 5 - 6 years

  3. 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

  4. 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

  5. 60 N= 1090 Mean= 0.33 50 STD= 0.52 Median= 0.08 40 Percent of Patients 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) Distribution of Baseline Proteinuria* for Randomized Patients *Patients with UP/Cr > 2.5 excluded from randomization

  6. Individual-Level Association

  7. Association of Main Clinical Composite Outcome (GFR Event, ESRD, or Death) With Baseline Proteinuria 70 Baseline UP/Cr < 0.22 Baseline UP/Cr > 0.22 60 s t P < 0.001 n 50 e v E 40 h t 30 i w 20 % 10 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up Month

  8. Joint Effect of Baseline UP and Δ UP/CrEffects Per 2-fold UP/Cr

  9. 2.0 2.0 1.5 1.5 1.0 1.0 Baseline UP/Cr 0.5 0.5 0.0 0.0 176 198 222 295 199 -0.5 -0.5 (N) 30 30-40 40-50 50-60 >60 Mean Baseline GFR (ml/min/1.73m2) Association of Proteinuria with GFR at Baseline 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.

  10. Baseline UP/Cr Predicts Subsequent Progression Independently of Initial GFR (mean GFR slope, ml/min/1.73m2/yr(SE))

  11. 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.

  12. Effect of Drug Group on Percent Change in UP/Cr from Baseline to 12 Months 639 172 % Change 0 -63 -86 A B C A B C A B C A B C Baseline <0.08 0.08-0.22 0.22-0.66 >0.66 UP/Cr A = Ramipril, B = Metoprolol, C = Amlodipine Boxes range from 25th to 75th percentiles

  13. Effect of Drug Group on Absolute Change in UP/Cr from Baseline to 12 Months 1.5 1.0 0.5 Absolute Change 0.0 -0.5 -1.0 A B C A B C A B C A B C Baseline <0.08 0.08-0.22 0.22-0.66 >0.66 UP/Cr A = Ramipril, B = Metoprolol, C = Amlodipine

  14. 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.

  15. Percent Change in UP/Cr from Baseline 172 Amlodipine Ramipril 122 Metoprolol 82 49 % Change (SE) 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)

  16. s t n e v E h t i w % Ramipril vs. Amlodipine: RR= 38%, p=0.004 Main Clinical Composite Outcome Declining GFR Event, ESRD, or Death Amlodipine 40 Metoprolol 35 Ramipril 30 Ramipril vs. Metoprolol RR = 22%, p = 0.042 25 20 15 10 5 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up Month RR = % Risk Reduction, Adjusting for Baseline Covariates

  17. Baseline UP/Cr  0.22 Baseline UP/Cr > 0.22 Amlodipine Amlodipine 40 Metoprolol s Metoprolol 35 t Ramipril n Ramipril 30 e v E 25 h 20 t i w 15 % 10 5 0 0 12 24 36 48 60 0 12 24 36 48 60 Follow-up Month Follow-up Month Main Clinical Composite Outcome Declining GFR Event, ESRD, or Death

  18. Amlodipine 16 Amlodipine Ramipril Ramipril 12 Metoprolol Metoprolol 8 4 0 Mean (SE) Change in GFR -4 -8 -12 -16 0 12 24 36 48 0 12 24 36 48 Follow-up Month Follow-up Month Change in GFR from Baseline (ml/min/1.73m2) Amlodipine Interaction p-values < 0.003 Baseline UP/Cr > 0.22 Baseline UP/Cr  0.22

  19. Percent Change in Proteinuria from Baseline 172 Lower BP Goal Usual BP Goal 122 P < 0.001 82 % Change (SE) 49 22 0 -18 0 6 12 24 36 48 Follow-up Month % change in geometric mean urine protein/creatinine ratio

  20. Change in GFR from Baseline 3 Lower BP Goal Usual BP Goal 0 -3 Mean (SE) Change in GFR ml/min/1.73m2 -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 48 Follow-up Month

  21. Composite Clinical Outcome Declining GFR Event, ESRD or Death 40 Lower BP (Achieved: 128/78) Usual BP (Achieved: 141/85) 35 Low vs. Usual: 30 RR=2%, (p=0.85) 25 % with Events 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

  22. Baseline UP/Cr > 0.22 Baseline UP/Cr  0.22 Low BP 70 Low BP Usual BP 60 Usual BP HR= 1.31, (p=0.11) 50 HR=0.82, (p=0.18) 40 % with Events 30 20 10 0 0 12 24 36 48 60 0 12 24 36 48 60 Follow-Up Month Follow-Up Month Main Clinical Composite Outcome Declining GFR Event, ESRD or Death Interaction p-value with baseline UP: 0.007 HR=Hazard Ratio adjusted for baseline covariates

  23. AASK Trial-Based Assessment of Validity of UP vs. True Endpoint (Scorecard) ? • Effect modification of Low vs. Usual BP and Amlodopine • vs. Ramipril comparisons in general agreement between • treatment effects on UP and on progression endpoints.

  24. THANK YOU

  25. OTHER SLIDES

  26. Amlodipine 16 Amlodipine Ramipril Ramipril 12 Metoprolol Metoprolol 8 4 0 Mean (SE) Change in GFR -4 -8 -12 -16 0 12 24 36 48 0 12 24 36 48 Follow-up Month Follow-up Month Change in GFR from Baseline (ml/min/1.73m2) Baseline UP/Cr > 0.22 Baseline UP/Cr  0.22

  27. 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 Treatment 1 GFR Treatment 2 Acute Phase Chronic Phase Follow-up time

  28. Change in GFR from Baseline Baseline UP/Cr  0.22 16 Amlodipine Ramipril 12 Metoprolol 8 4 Mean (SE) Change in GFR ml/min/1.73m2 0 -4 Total slope comparisons -8 Amlodipine vs metoprolol:  = 5.9, p < 0.001 -12 Amlodipine vs ramipril:  = 3.6, p = 0.006 -16 0 6 12 18 24 30 36 42 48 Follow-up Month

  29. Change in GFR from Baseline Baseline UP/Cr > 0.22 8 Amlodipine 4 Ramipril Metoprolol 0 -4 Mean (SE) Change in GFR ml/min/1.73m2 -8 -12 -16 Total slope comparisons Amlodipine vs metoprolol:  = - 1.9, p = 0.087 Amlodipine vs ramipril:  = - 6.0, p = 0.007 -20 -24 0 6 12 18 24 30 36 42 48 Follow-up Month

  30. 4 4 Low Goal Usual Goal 2 2 0 0 -2 -2 -4 -4 -6  Total Slope = - 0.76, p = 0.24 -6 -8 -8 F6 12 18 24 30 36 42 48 Base line Follow-up Month Change in GFR from Baseline Baseline UP/Cr  0.22 Mean (SE) Change in GFR m/lmin/1.73m2

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