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

6/5/2006 - 1

ALLHAT

CARDIOVASCULAR DISEASE OUTCOMES IN HYPERTENSIVE PATIENTS STRATIFIED BY BASELINE GLOMERULAR FILTRATION

RATE (3 GROUPS by GFR)

6/5/2006 - 2

ALLHAT Introduction

• Over 13 million Americans are estimated to have chronic kidney disease (CKD)

• Patients with CKD are at very high risk for cardiovascular disease (CVD)

• There are limited data about the comparative effects of antihypertensive therapy on CVD outcomes in CKD patients

• 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

• 17.7% (n=7116) of ALLHAT participants had an estimated GFR <60 ml/min/1.73m2 at baseline

6/5/2006 - 3

ALLHAT Other Studies

• Many trials that studied patients with CKD do not have adequate assessment / reporting or power to evaluate CV events– HOPE demonstrated increased CV risk in patients

with renal insufficiency and that ramipril reduced risk in this subgroup compared to placebo

– IDNT and RENAAL showed similar CV event rates with ARB vs CCB (IDNT) and placebo (RENAAL), except hospitalization for first heart failure in RENAAL was lower with the ARB

– AASK (beta blocker, ACE, CCB) showed no difference in CV event rates

4

*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.

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*ALLHAT

6/5/2006 - 5

ALLHAT Relative Risk of Combined CVD by Baseline GFR Group

(Adjusted for Age, Race, Gender, BMI, SBP, DBP, HDL-cholesterol, LDL-cholesterol, fasting triglycerides, history of

diabetes, and cigarette smoking)

1.00 1.08

1.35

0.000.200.400.600.801.001.201.401.601.802.00

GFR90+ GFR60-89 GFR <60

RelativeRisk forincidentCVD

Estimated (eGFR) (ml/min/1.73 m2) calculated by simplified MDRD equation

* P <0.001 vs. GFR90+

*

*

6/5/2006 - 6

ALLHAT Blood Pressure at 4 Years by Treatment Group and Baseline GFR

GFR Chlor Amlod Lisin

SBP -mean (sd,N)

90 133.4 (15.2, 2276) 134.6 (14.4, 1462)* 135.6 (17.3, 1301)*

60-89 133.6 (15.5, 5310) 134.5 (14.6, 3127)* 135.2 (16.9, 3024)*

<60 135.5 (17.1, 1511) 135.9 (17.0, 869) 136.4 (18.2, 813)

DBP -mean (sd,N)

90 76.8 (9.5, 2276) 76.4 (9.0, 1462) 77.6 (10.1, 1301)*

60-89 76.5 (9.6, 5308) 75.8 (9.6, 3127)* 76.3 (10.2, 3024)

<60 75.6 (9.9, 1511) 74.2 (9.8, 869)* 75.7 (11.2, 813)

* p<0.05 compared with chlorthalidone

6/5/2006 - 7

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

6/5/2006 - 8

ALLHAT

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

Relative Risk (A/C)(95% CI) p valueChlorthalidone Amlodipine

GFR 90 8.7 (0.6)252 / 3648

7.6 (0.7)141 / 2274

0.90 (0.73 - 1.10)0.29

GFR 60-89 10.9 (0.4)740 / 8360

10.9 (0.6)427 / 4850

0.98 (0.87 – 1.10)0.72

GFR <60 15.2 (0.9)318 / 2613

16.0 (1.2)194 / 1516

1.06 (0.89 – 1.27)0.50

Total 11.5 (0.3)1362 / 15,255

11.3 (0.4)798 / 9048

0.98 (0.91 – 1.08)0.81

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

CHD (Nonfatal MI & Fatal CHD) by Baseline GFR & Treatment – Amlodipine vs Chlorthalidone

ALLHAT

6/5/2006 - 9

ALLHAT


Relative Risk (A/C)(95% CI) p valueChlorthalidone Lisinopril

GFR 90 8.7 (0.6)252 / 3648

9.0 (0.8)157 / 2204

1.04 (0.86 – 1.27)0.67

GFR 60-89 10.9 (0.4)740 / 8360

10.6 (0.6)421 / 4899

0.97 (0.86 – 1.09)0.59

GFR <60 15.2 (0.9)318 / 2613

15.1 (1.1)184 / 1533

1.00 (0.84 – 1.20)0.97

Total 11.5 (0.3)1362 / 15,255

11.4 (0.4)796 / 9054

0.99 (0.91 – 1.08)0.81


CHD (Nonfatal MI & Fatal CHD) by Baseline GFR & Treatment – Lisinopril vs Chlorthalidone

ALLHAT

6/5/2006 - 10

ALLHAT



GFR 90 10.0 (0.9)133 / 1667

9.2 (1.2)72 / 1026

0.88 (0.66 – 1.18)0.40

GFR 60-89 13.9 (0.8)304 / 2755

14.4 (1.1)184 / 1626

1.01 (0.84 – 1.21)0.96

GFR <60 19.3 (1.7)132 / 881

21.1 (2.4)83 / 506

1.07 (0.81 – 1.41)0.63

Total 13.5 (0.6)592 / 5528

13.8 (0.8)358 / 3323

0.99 (0.87 – 1.13)0.93


CHD (Nonfatal MI & Fatal CHD) by Baseline GFR & Treatment in Diabetic Participants –

Amlodipine vs Chlorthalidone

ALLHAT

6/5/2006 - 11

ALLHAT



GFR 90 10.0 (0.9)133 / 1667

9.7 (1.1)79 / 981

1.02 (0.77 – 1.35)0.87

GFR 60-89 13.9 (0.8)304 / 2755

13.2 (1.1)167 / 1563

0.98 (0.81 – 1.18)0.81

GFR <60 19.3 (1.7)132 / 881

18.3 (2.0)76 / 501

1.03 (0.78 – 1.37)0.83

Total 13.5 (0.6)592 / 5528

12.8 (0.7)339 / 3212

1.00 (0.87 – 1.14(0.97


CHD (Nonfatal MI & Fatal CHD) by Baseline GFR & Treatment in Diabetic Participants –

Lisinopril vs Chlorthalidone

ALLHAT

6/5/2006 - 12

ALLHAT



GFR 90 25.6 (0.9)803 / 3648

25.3 (1.1)487 / 2274

0.97 (0.86 – 1.08)0.56

GFR 60-89 29.6 (0.6)2125 / 8360

31.2 (0.8)1312 / 4850

1.06 (0.99 – 1.14)0.08

GFR <60 38.7 (1.2)870 / 2613

41.1 (1.5)537 / 1516

1.08 (0.97 – 1.20)0.18

Total 30.9 (0.5)3941 / 15,255

32.0 (0.6)2432 / 9048

1.04 (0.99 – 1.09)0.12

Combined CVD = CHD death, nonfatal MI, stroke, coronary revascularization procedures, hospitalized or treated angina, treated or hospitalized HF, and peripheral arterial disease (hospitalized, or outpatient revascularization)


Combined CVD by Baseline GFR & Treatment - Amlodipine vs Chlorthalidone

ALLHAT

6/5/2006 - 13

ALLHAT



GFR 90 25.6 (0.9)803 / 3648

29.1 (1.2)526 / 2204

1.11 (0.99 – 1.24)0.06

GFR 60-89 29.6 (0.6)2125 / 8360

31.3 (0.8)1330 / 4899

1.09 (1.02 – 1.17)0.02

GFR <60 38.7 (1.2)870 / 2613

41.3 (1.5)547 / 1533

1.12 (1.01 – 1.25)0.04

Total 30.9 (0.5)3941 / 15,255

33.3 (0.6)2514 / 9054

1.10 (1.05 – 1.16)<0.001



Combined CVD by Baseline GFR & Treatment – Lisinopril vs Chlorthalidone

ALLHAT

6/5/2006 - 14

ALLHAT



GFR 90 27.9 (1.3)402 / 1667

30.4 (1.8)256 / 1026

1.04 (0.89 – 1.22)0.61

GFR 60-89 34.3 (1.1)814 / 2755

35.2 (1.4)499 / 1626

1.03 (0.92 – 1.15)0.62

GFR <60 43.1 (2.0)326 / 881

50.4 (2.7)224 / 506

1.20 (1.01 – 1.42)0.04

Total 33.9 (0.8)1609 / 5528

36.2 (1.0)1030 / 3323

1.06 (0.98 – 1.15)0.12



Combined CVD by Baseline GFR & Treatmentin Diabetic Participants -

Amlodipine vs ChlorthalidoneALLHAT

6/5/2006 - 15

ALLHAT



GFR 90 27.9 (1.3)402 / 1667

31.4 (1.8)257 / 981

1.12 (0.95 – 1.31)0.17

GFR 60-89 34.3 (1.1)814 / 2755

35.0 (1.4)482 / 1563

1.07 (0.96 – 1.20)0.24

GFR <60 43.1 (2.0)326 / 881

44.2 (2.5)193 / 501

1.08 (0.90 – 1.29)0.40

Total 33.9 (0.8)1609 / 5528

35.5 (1.0)985 / 3212

1.08 (1.00 – 1.17)0.049



ALLHATCombined CVD by Baseline GFR & Treatment

in Diabetic Participants -Lisinopril vs Chlorthalidone

6/5/2006 - 16

ALLHAT



GFR 90 4.0 (0.4)118 / 3648

3.5 (0.5)70 / 2274

0.95 (0.70 – 1.27)0.71

GFR 60-89 5.2 (0.3)366 / 8360

4.7 (0.4)185 / 4850

0.85 (0.71 – 1.02)0.08

GFR <60 7.6 (0.6)157 / 2613

8.8 (1.0)100 / 1516

1.12 (0.87 – 1.44)0.38

Total 5.6 (0.2)675 / 15,255

5.4 (0.3)377 / 9048

0.93 (0.82 – 1.06)0.28


ALLHAT Stroke by Baseline GFR & Treatment - Amlodipine vs Chlorthalidone

6/5/2006 - 17

ALLHAT



GFR 90 4.0 (0.4)118 / 3648

5.7 (0.6)101 / 2204

1.43 (1.10 – 1.87)0.01

GFR 60-89 5.2 (0.3)366 / 8360

5.9 (0.4)239 / 4899

1.12 (0.95 – 1.31)0.19

GFR <60 7.6 (0.6)157 / 2613

7.9 (0.8)99 / 1533

1.10 (0.86 – 1.42)0.45

Total 5.6 (0.2)675 / 15,255

6.3 (0.3)457 / 9054

1.15 (1.02 – 1.30)0.02


Stroke by Baseline GFR & Treatment –Lisinopril vs Chlorthalidone

ALLHAT

6/5/2006 - 18

ALLHAT



GFR 90 4.4 (0.6)55 / 1667

3.9 (0.8)33 / 1026

0.98 (0.63 – 1.50)0.92

GFR 60-89 7.7 (0.6)176 / 2755

6.4 (0.7)83 / 1626

0.77 (0.59 – 1.00)0.05

GFR <60 8.7 (1.1)63 / 881

10.9 (1.7)42 / 506

1.17 (0.79 – 1.72)0.44

Total 7.1 (0.4)314 / 5528

6.6 (0.5)172 / 3323

0.90 (0.75 – 1.08)0.26


ALLHATStroke by Baseline GFR & Treatment

in Diabetic Participants -Amlodipine vs Chlorthalidone

6/5/2006 - 19

ALLHAT



GFR 90 4.4 (0.6)55 / 1667

7.0 (1.1)53 / 981

1.66 (1.14 – 2.43)0.01

GFR 60-89 7.7 (0.6)176 / 2755

7.8 (0.8)99 / 1563

1.00 (0.78 – 1.28)1.00

GFR <60 8.7 (1.1)63 / 881

8.3 (1.5)33 / 501

0.94 (0.62 – 1.43)0.78

Total 7.1 (0.4)314 / 5528

7.6 (0.6)193 / 3212

1.07 (0.90 – 1.28)0.45


ALLHATStroke by Baseline GFR & Treatment


6/5/2006 - 20

ALLHAT



GFR 90 5.1 (0.5)147 / 3648

6.4 (0.6)121 / 2274

1.34 (1.02 – 1.71)0.02

GFR 60-89 6.7 (0.4)435 / 8360

9.8 (0.5)380 / 4850

1.55 (1.34 – 1.79)<0.001

GFR <60 13.1 (0.9)259 / 2613

15.0 (1.2)174 / 1516

1.18 (0.96 – 1.44)0.11

Total 7.7 (0.3)870 / 15,255

10.2 (0.4)706 / 9048

1.40 (1.26 – 1.55)<0.001


ALLHAT Heart Failure by Baseline GFR & Treatment -Amlodipine vs Chlorthalidone

6/5/2006 - 21

ALLHAT



GFR 90 5.1 (0.5)147 / 3648

6.1 (0.6)110 / 2204

1.25 (0.97 – 1.61)0.08

GFR 60-89 6.7 (0.4)435 / 8360

6.9 (0.4)278 / 4899

1.10 (0.94 – 1.28)0.25

GFR <60 13.1 (0.9)259 / 2613

15.8 (1.1)191 / 1533

1.29 (1.06 – 1.58)0.01

Total 7.7 (0.3)870 / 15,255

8.7 (0.4)612 / 9054

1.20 (1.08 – 1.33)0.001


ALLHAT Heart Failure by Baseline GFR & Treatment - Lisinopril vs Chlorthalidone

6/5/2006 - 22

ALLHAT



GFR 90 6.5 (0.8)87 / 1667

8.0 (1.1)65 / 1026

1.23 (0.88 – 1.71)0.22

GFR 60-89 9.9 (0.7)203 / 2755

13.4 (1.0)177 / 1626

1.54 (1.24 – 1.90)<0.001

GFR <60 15.6 (1.6)104 / 881

22.0 (2.4)87 / 506

1.55 (1.14 – 2.11)0.005

Total 9.7 (0.5)410 / 5528

13.1 (0.7)347 / 3323

1.46 (1.25 – 1.69)<0.001


ALLHATHeart Failure by Baseline GFR & Treatment

in Diabetic Participants -Amlodipine vs Chlorthalidone

6/5/2006 - 23

ALLHAT



GFR 90 6.5 (0.8)87 / 1667

8.1 (1.0)68 / 981

1.35 (0.97 – 1.88)0.07

GFR 60-89 9.9 (0.7)203 / 2755

9.1 (0.9)119 / 1563

1.04 (0.82 – 1.31)0.77

GFR <60 15.6 (1.6)104 / 881

20.5 (2.2)81 / 501

1.44 (1.05 – 1.97)0.02

Total 9.7 (0.5)410 / 5528

10.9 (0.7)284 / 3212

1.21 (1.03 – 1.42)0.02


ALLHATHeart Failure by Baseline GFR & Treatment


6/5/2006 - 24

ALLHAT Discussion

• ALLHAT confirms increased risk for CVD in patients with reduced GFR.

• The overall study results of no difference in the primary outcome for the lisinopril vs. chlorthalidone and amlodipine vs. chlorthalidone comparisons was consistent across diabetes, GFR, and diabetes-GFR subgroups.

ALLHAT

6/5/2006 - 25

ALLHAT Conclusion

• Amlodipine and lisinopril are not superior to chlorthalidone in preventing fatal CHD/non fatal MI

• Chlorthalidone and amlodipine are similar but chlorthalidone is superior to lisinopril in reducing combined CVD events independent of level of renal function.

ALLHAT

In high risk hypertensive patients with impaired renal function:

Documents

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