6 / 5 / 2006 - 1 1 RENAL DISEASE OUTCOMES IN HYPERTENSIVE PATIENTS STRATIFIED INTO 3 GROUPS BY BASELINE GLOMERULAR FILTRATION RATE (GFR) ALLHAT

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RENAL DISEASE OUTCOMES IN HYPERTENSIVE PATIENTS

STRATIFIED INTO 3 GROUPS BY BASELINE GLOMERULAR FILTRATION

RATE (GFR)

ALLHAT

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Introduction

• Hypertension is the second most common cause of end-stage renal disease (ESRD) in the US

• Hypertension is a key factor contributing to progression of chronic kidney disease

• Successful treatment of hypertension is important in slowing down progression of renal disease

ALLHAT

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Background

• In diabetic (DM) and nondiabetic (NDM) hypertensive patients with established chronic renal insufficiency and proteinuria, inhibition of the renin angiotensin axis is suggested to be superior to conventional therapy in slowing decline in renal function

• Few studies directly compared effects of different classes of antihypertensive drug therapy on decline in renal function in hypertensive patients with mild reduction in glomerular filtration rate (GFR).

ALLHAT

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Overall Results –Renal Outcomes

• In the ALLHAT study population as a whole, no difference was noted in the risk of ESRD with chlorthalidone compared to amlodipine and lisinopril

• Estimated GFR was higher at the end of the study in patients randomized to amlodipine compared to chlorthalidone.

ALLHAT

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ObjectiveALLHAT

Post-hoc analysis of the ALLHAT study to determine whether treatment with a calcium channel blocker or an ACE inhibitor, each versus a diuretic, lowers incidence of renal outcomes in high risk hypertensive patients stratified by baseline GFR.

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Normal GFR (90)

Mild GFR (60-

89)

Moderate or severe GFR

(<60)

N 8,126 18,109 5,662

Mean age, y 63.3 67.3** 70.7**

Black non-Hisp, % 43.1 27.7** 25.5**

Women, % 46.6 44.5** 52.3**

Mean SBP 146 146 147**

Mean DBP 85 84** 83**

Type 2 diabetes, % 45.2 32.8** 33.4**

History of CHD, % 21.2 26.3** 30.5**

Baseline Characteristics StratifiedBy Estimated GFR*

*Estimated (eGFR) (ml/min/1.73 m2) calculated by simplified MDRD equation (Levey et al., J Am Soc Nephrol 11, A 0828. 2000.)

**p<.05 compared with normal GFR

NOTE: Within each GFR stratum, there was no significant difference in these characteristics between patients assigned to amlodipine or lisinopril compared with patients assigned to chlorthalidone.

ALLHAT

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eGFR During the Course of the Study (Baseline eGFR ≥90)

70

80

90

100

110

Chlorthalidone 102.5 93.4 91.9 86.9

Amlodipine 102.7 98.6 97.7 93.3

Lisinopril 102.7 94.5 93.4 88.3

Baseline (n=8126)

1 Year (n=5282)

2 Year (n=5188)

4 Year (n=4409)

*

* *

* p<0.05 vs. ChlorthalidoneEstimated GFR (eGFR) calculated from the simplified MDRD equation

*

ALLHAT

*

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eGFR During the Course of the Study (Baseline eGFR 60-89)

65.0

70.0

75.0

80.0


Amlodipine 75.2 76.7 75.9 73.0

Lisinopril 75.1 73.2 72.5 69.1

Baseline (n=18109)

1 Year (n=12264)

2 Year (n=12011)

4 Year (n=10262)

* **


ALLHAT

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eGFR During the Course of the Study (Baseline eGFR <60)

40.0

45.0

50.0

55.0

60.0


Amlodipine 50.6 54.9 54.3 51.5

Lisinopril 50.1 51.1 50.6 48.3

Baseline (n=5662)

1 Year (n=3583)

2 Year (n=3421)

4 Year (n=2718)

* **


ALLHAT

ALLHAT Evaluating Treatment Effects by Subgroup

Significant Test for Treatment x Subgroup Interaction?

Yes No

Significant treatment difference within 1 or more subgroups?

Yes Interaction No interaction

No Interaction No interaction

Interaction – Use subgroup estimates of treatment effects

No interaction – Use estimate of treatment effect in total population

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End Stage Renal Disease by Baseline Diabetes & Treatment – Amlodipine vs Chlorthalidone

6-year rates per 100 (se)& total events / N Relative Risk (A/C)

(95% CI) p valueChlorthalidone Amlodipine

Diabetic participants

2.7 (0.3)109 / 5,528

3.6 (0.4)86 / 3,323

1.30 (0.98 – 1.73)p = 0.07

Nondiabetic participants

1.3 (0.2)84 / 9,727

1.0 (0.1)43 / 5,725

0.86 (0.60 – 1.25)p = 0.43

Total 1.8 (0.1)193 / 15,255

2.1 (0.2)129 / 9,048

1.12 (0.89 – 1.40)P = 0.33

Differences among treatment group effects by baseline history of diabetes are not statistically significant.

ALLHAT

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End Stage Renal Disease by Baseline GFR & Treatment – Amlodipine vs Chlorthalidone


(95% CI)p valueChlorthalidone Amlodipine

GFR 90 0.27 (0.10)11 / 3648

0.60 (0.22)9 / 2274

1.31 (0.54 – 3.17)p = 0.54

GFR 60-89 0.84 (0.14)47 / 8360

1.24 (0.21)41 / 4850

1.47 (0.97 – 2.23) p = 0.07

GFR <60 6.23 (0.59)124 / 2613

5.69 (0.76)65 / 1516

0.92 (0.68 – 1.24)p = 0.57

Differences among treatment group effects by baseline GFR group are not statistically significant.

ALLHAT

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End Stage Renal Disease by Baseline GFR & Treatment – Amlodipine vs Chlorthalidone – Diabetic Participants



GFR 90 0.54 (0.21)8 / 1,667

0.76 (0.39)5 / 1,026

1.03 (0.34 – 3.16) p = 0.95

GFR 60-89 1.38 (0.30)26 / 2,755

2.62 (0.54)27 / 1,626

1.72 (1.01 – 2.95)p = 0.05

GFR <60 10.05 (1.25)68 / 881

11.55 (1.84)44 / 506

1.11 (0.77 – 1.63)p = 0.56


ALLHAT

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End Stage Renal Disease by Baseline Diabetes & Treatment – Lisinopril vs Chlorthalidone

6-year rates per 100 (se)& total events / N Relative Risk

(95% CI)p valueChlorthalidone Lisinopril


2.7 (0.3)109 / 5,528

3.3 (0.4)73 / 3,212

1.17 (0.87 – 1.57)p = 0.31


1.3 (0.2)84 / 9,727

1.3 (0.2)53 / 5,842

1.05 (0.74 – 1.48)p = 0.78

Total 1.8 (0.1)193 / 15,255

2.0 (0.2)126 / 9,054

1.11 (0.88 – 1.38)P = 0.38


ALLHAT

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ALLHAT

End Stage Renal Disease by Baseline GFR & Treatment – Lisinopril vs Chlorthalidone



GFR 90 0.27 (0.10)11 / 3,648

0.40 (0.15)7 / 2,204

1.08 (0.42 – 2.78) p = 0.88

GFR 60-89 0.84 (0.14)47 / 8,360

1.06 (0.18)37 / 4,899

1.34 (0.87 – 2.06)p = 0.18

GFR <60 6.23 (0.59)124 / 2,613

6.00 (0.76)70 / 1,533

0.98 (0.73 – 1.31)p = 0.89


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ALLHAT

End Stage Renal Disease by Baseline GFR & Treatment – Lisinopril vs Chlorthalidone – Diabetic Participants



GFR 90 0.54 (0.21)8 / 1,667

0.27 (0.19)2 / 981

0.43 (0.09 – 2.04)p = 0.29

GFR 60-89 1.38 (0.30)26 / 2,755

2.35 (0.49)25 / 1,563

1.74 (1.00 – 3.01)p = 0.05

GFR <60 10.05 (1.25)68 / 881

11.12 (1.79)41 / 501

1.07 (0.73 – 1.58)p = 0.72


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Events per 100& total events / N

Relative Risk (A/C)



5.0279 / 5,528

4.9164 / 3,323

0.98 (0.80 – 1.19)p = 0.82


2.2214 / 9,727

1.692 / 5,725

0.73 (0.57 – 0.93)p = 0.01

Total 3.2493 / 15,255

2.8256 / 9,048

0.87 (0.74 – 1.01)p = 0.08


ALLHATEnd Stage Renal Disease or 50% or

Greater Decline in GFRby Baseline Diabetes & Treatment –

Amlodipine vs Chlorthalidone

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Relative Risk (A/C)p valueChlorthalidone Amlodipine

GFR 90 3.1112 / 3,648

2.046 / 2,274

0.65 (0.46 – 0.92)p = 0.02

GFR 60-89 2.3190 / 8,360

2.2106 / 4,850

0.96 (0.76 – 1.22)p = 0.74

GFR <60 6.9180 / 2,613

5.990 / 1,516

0.85 (0.66 – 1.11)p = 0.23



Greater Decline in GFRby Baseline GFR & Treatment –Amlodipine vs Chlorthalidone

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Relative Risk (A/C)p valueChlorthalidone Amlodipine

GFR 90 4.677 / 1,667

2.930 / 1,026

0.62 (0.40 – 0.96)p=0.03

GFR 60-89 3.699 / 2,755

4.268 / 1,626

1.17 (0.85 – 1.60)p=0.33

GFR <60 10.9%96 / 881

11.1%56 / 506

1.02 (0.72 – 1.44)p=0.92



Greater Decline in GFR by Baseline GFR & Treatment – Diabetic Participants

Amlodipine vs Chlorthalidone

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Relative Risk (L/C)p valueChlorthalidone Lisinopril


5.0279 / 5,528

5.2168 / 3,212

1.04 (0.85 – 1.26)p = 0.71


2.2214 / 9,727

2.3132 / 5,842

1.03 (0.83 – 1.28)p = 0.81

Total 3.2493 / 15,255

3.3300 / 9,054

1.03 (0.89 – 1.20)P = 0.65



Greater Decline in GFRby Baseline Diabetes & Treatment –

Lisinopril vs Chlorthalidone

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GFR 90 3.1112 / 3,648

2.657 / 2,204

0.84 (0.61 – 1.16)p = 0.28

GFR 60-89 2.3190 / 8,360

2.6125 / 4,899

1.13 (0.90 – 1.41)p = 0.31

GFR <60 6.9180 / 2,613

6.9106 / 1,533

1.00 (0.78 – 1.29)p = 0.98



Greater Decline in GFRby Baseline GFR & Treatment –


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GFR 90 4.677 / 1,667

3.635 / 981

0.76 (0.51 – 1.15)p=0.20

GFR 60-89 3.699 / 2,755

4.367 / 1,563

1.20 (0.88 – 1.65)p=0.26

GFR <60 10.996 / 881

12.161 / 501

1.13 (0.81 – 1.60)p=0.47



Greater Decline in GFR by Baseline GFR & Treatment – Diabetic Participants


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Summary

• The overall study results of no difference in ESRD and the composite (ESRD/50% decline in GFR) for the lisinopril vs. chlorthalidone and amlodipine vs. chlorthalidone comparisons was consistent across diabetes, GFR, and diabetes-GFR subgroups.

ALLHAT

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Discussion

• High risk hypertensive patients are at higher risk for CVD than ESRD

• Risk of ESRD is higher in diabetic participants, and those with reduced GFR at baseline

• Since risk of CVD is much higher than risk for ESRD in CKD patients, choices of therapy need to be guided by effects on CVD outcomes

Combined CVD Events ESRD events

# events 8887 448

Six year event rate /100

30.9-33.3 1.8-2.1

ALLHAT

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Strengths & Limitations

• Strength -– The number of patients with moderate

reduction in GFR, and the number of patients developing ESRD are higher in ALLHAT compared to any other renal study, including AASK, RENAAL and IDNT

• Limitation – – Proteinuria is an independent predictor of

decline in renal function. Information about proteinuria was not available in ALLHAT participants.

ALLHAT

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Conclusion

In high risk hypertensive patients with reduced GFR, amlodipine and lisinopril are not superior to chlorthalidone in reducing the rate of development of ESRD and significant decrements in GFR

ALLHAT

Documents

6 / 5 / 2006 - 1 1 RENAL DISEASE OUTCOMES IN HYPERTENSIVE PATIENTS STRATIFIED INTO 3 GROUPS BY BASELINE GLOMERULAR FILTRATION RATE (GFR) ALLHAT