1 Presenter Disclosure Information FINANCIAL DISCLOSURE: DSMB’s: Merck, Takeda Barry R. Davis, MD,...

1

Presenter Disclosure Information

FINANCIAL DISCLOSURE:DSMB’s: Merck, Takeda

Barry R. Davis, MD, PhDClinical Outcomes in Participants with Dysmetabolic Syndrome in ALLHAT

UNLABELED / UNAPPROVED USES DISCLOSURE:None

2

Clinical Outcomes in Participants with Dysmetabolic

Syndrome in ALLHATBarry R. Davis, MD, PhD & Henry R. Black, MD for the ALLHAT Collaborative Research Group

Presented at the

American Heart Association Meeting

November 8, 2004

ALLHATALLHAT

3

Randomized Designof ALLHAT

High-risk hypertensive patients

Consent / Randomize

(42,418)

Amlodipine

Chlorthalidone

Doxazosin

Lisinopril

Eligible for lipid-lowering

Not eligible for lipid-lowering

Consent / Randomize (10,355)

Pravastatin Usual care

Follow for CHD and other outcomes until death or end of study (up to 8 yr).

ALLHAT

4

Dysmetabolic SyndromeDysmetabolic Syndrome

ALLHAT reported overall superiority of ALLHAT reported overall superiority of thiazide-type treatment for first-step therapy thiazide-type treatment for first-step therapy of hypertensionof hypertension

Patients with dysmetabolic syndrome (DS) Patients with dysmetabolic syndrome (DS) are at especially high risk for many are at especially high risk for many hypertensive complicationshypertensive complications

Post hoc analyses from ALLHAT regarding Post hoc analyses from ALLHAT regarding treatment of hypertension in patients with treatment of hypertension in patients with and without DS are of interestand without DS are of interest

Definitions of DS vary (WHO, ATP III, etc.)Definitions of DS vary (WHO, ATP III, etc.)

ALLHATALLHAT

5

Dysmetabolic Syndrome (DS)

Any 3 or more of the following items:

• Glycemic disorder – History of diabetes– Baseline glucose

• BMI ≥30• Fasting triglycerides 150+ • HDL cholesterol <40 in men, <50 in women• High BP (“yes” for all ALLHAT participants)

• DS missing: # yes <3 and # yes + # missing ≥ 3

ALLHATALLHAT

6

Glycemic DisorderALLHATALLHAT

Fasting Glucose Nonfasting glucose

Missing

glucose<100 ≥100 <100 100-199 ≥200

Hx of diabetes

Yes Yes Yes Yes Yes Yes

No hx of diabetes

No Yes No Missing Yes Missing

7

Definitions ofDysmetabolic Syndrome

ALLHAT ATP III WHO AACE

Insulin resistance (any of following):

Fasting glucose ≥100 ≥110 IFG 110 - 126

Nonfasting glucose

≥200

History of diabetes Yes Yes

OGTT NA IGT

2-hr post-glucose >140

Obesity (any of following):

Abdominal obesity WC: >40” M, >35” F

W/H: >.9M >.85W

BMI ≥30 >30 ≥25

ALLHATALLHAT

ATP III – National Cholesterol Education Program’s Adult Treatment Panel III ReportWHO – World Health OrganizationAACE – American Association of Clinical Endocrinologists

IFG = Impaired fasting glucoseIGT = Impaired glucose toleranceWC = Waist circumferenceW/H = Waist / hip ratio

8

Definitions of Dysmetabolic Syndrome (continued)

ALLHATALLHAT

ALLHAT ATP III WHO AACE

Lipids (any of following):

Fasting TRIGs ≥150 ≥150 ≥150 ≥150

HDL <40 M <50 F <40 M <50 F <35M <39F <40 M <50 F

Blood pressure:

↑BP Yes ≥130/ ≥85 ≥140/ ≥90 ≥130/ ≥85

AHT medications Yes Yes

Other:

UA* Exr ≥20 or A/C** ≥30

Many+

* UA = Urinary albumin excretion rate** A/C = Albumin:creatinine ratio+ Family history of type 2 diabetes, hypertension or CVD; polycystic ovary syndrome; sedentary lifestyle; advancing age; ethnic groups having high risk for type 2 diabetes or CVD

9

Dysmetabolic Syndrome –Classification & Missing Values

DS No DS Missing Total

Chlor 8,315 54.5% 5,155 33.8% 1,785 11.7% 15,255

Amlod 4,915 54.3% 3,030 33.5% 1,103 12.2% 9,048

Lisin 4,953 54.7% 2,995 33.1% 1,106 12.2% 9,054

Total 18,183 54.5% 11,180 33.5% 3,994 12.0% 33,357

ALLHATALLHAT

10

Baseline Characteristics - Participants* With and Without DS

DS No DS

N 18,183 11,180Age – mean 66.1 68.0 **Women (%) 49.8 42.0 **Black (%) 28.4 34.6 **SBP – mean 146.1 146.6 **DBP – mean 83.8 84.4 **Current smokers (%) 17.8 27.4 **ASCVD (%) 46.5 58.4 **

*Randomized to chlorthalidone, amlodipine, or lisinopril.** p<.05

ALLHATALLHAT

11

Baseline Characteristics - Participants* With and Without DS

DS No DS

N 18,183 11,180

Fasting gluc - mean (sd) 135.2 (61.3) 102.6 (41.5) **

History of diabetes % 31.7 6.3 **

BMI – mean (sd) 32.0 (6.2) 26.5 (4.4) **

Fasting trig - mean (sd) 205.1 (148.4) 122.1 (84.6) **

HDL chol – mean (sd) 42.3 (12.2) 53.9 (15.5) **

*Randomized to chlorthalidone, amlodipine, or lisinopril.** p<.05

ALLHATALLHAT

12

Blood Pressure at 5 Yearsby Baseline DS Status

Chlor Amlod Lisin

SBP mean (sd)

DS 134 (15) 135 (15) 136 (18)*

No DS 133 (15) 134 (15) 136 (18)*

DBP mean (sd)

DS 75 (10) 74 (10)* 75 (10)

No DS 76 (10) 75 (10)* 76 (11)

SBP/DBP difference compared with chlorthalidone

DS --- +0.6 / +0.2* +1.9* / 0.0

No DS --- +0.9 / -1.0* +2.1* / 0.0

* p<0.05 compared with chlorthalidone

ALLHATALLHAT

13

Biochemical Measures at 4 Yearsin Participants with Dysmetabolic Syndrome

Chlor Amlod Lisin

TChol mg/dL

Mean

N

196.3

4,736

195.6

2,752

194.7

2,629

Fasting Glucose mg/dL

Mean

% 126+

N

137.5

43.1

2,809

134.7

41.8

1,674

131.1*

37.6*

1,523

Potassium mmol/L

Mean

N

4.1

4572

4.4*

2658

4.6*

2523

* p<0.05 compared with chlorthalidone

ALLHATALLHAT

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Biochemical Measures at 4 Yearsin Participants without Dysmetabolic Syndrome

Chlor Amlod Lisin

TChol mg/dL

Mean

N

197.4

2,924

194.6*

1,765

194.9*

1,606

Fasting Glucose mg/dL

Mean

% 126+

N

108.6

16.7

1,793

106.6

13.1*

1,057

107.7

16.4

989

Potassium mmol/L

Mean

N

4.1

2,849

4.4*

1,720

4.5*

1,570

* p<0.05 compared with chlorthalidone

ALLHATALLHAT

15

CHD by Treatment Group In Participants With DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

2

4

6

08

10

12

14

Cu

mu

lati

ve C

HD

Eve

nt

Rat

e, %

0 1 2 3 4 5 6

Years to CHD

HR (95% CI) p value

A/C 0.95 (0.84 – 1.07) 0.37

L/C 1.01 (0.90 – 1.13) 0.86

16

CHD by Treatment GroupIn Participants Without DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

2

4

6

8

10

12

14

Cu

mu

lati

ve C

HD

Eve

nt

Rat

e, %

0 1 2 3 4 5 6

Years to CHD

HR (95% CI) p value

A/C 1.05 (0.90 – 1.22) 0.53

L/C 1.02 (0.88 – 1.20) 0.78

17

CHD

All-cause mortality

Stroke

Heart Failure

Combined CVD

ESRD

FavorsChlorthalidone

FavorsAmlodipine

FavorsChlorthalidone

WithDysmetabolic Syndrome

WithoutDysmetabolic Syndrome

FavorsAmlodipine

0.50 1 2

0.81 (0.51 - 1.26)

1.05 (0.96 - 1.15)

1.45 (1.20 - 1.75)

1.04 (0.83 - 1.29)

0.93 (0.83 - 1.04)

1.05 (0.90 - 1.22)

0.50 1 2

1.27 (0.96 - 1.68)

1.05 (0.98 - 1.12)

1.32 (1.15 - 1.51)

0.87 (0.74 - 1.04)

0.97 (0.88 - 1.06)

0.95 (0.84 - 1.07)

Amlodipine/ChlorthalidoneRelative Risk and 95% Confidence IntervalsALLHAT

18

CHD

All-cause mortality

Stroke

Heart Failure

Combined CVD

ESRD

FavorsChlorthalidone

FavorsLisinopril

FavorsChlorthalidone

FavorsLisinopril

0.50 1 2

1.22 (0.92 - 1.63)

1.14 (1.06 - 1.21)

1.28 (1.12 - 1.47)

1.09 (0.93 - 1.28)

1.01 (0.93 - 1.12)

1.01 (0.90 - 1.13)

0.50 1 2

0.76 (0.48 - 1.21)

1.07 (0.98 - 1.17)

1.02 (0.83 - 1.25)

1.20 (0.97 - 1.48)

1.02 (0.91 - 1.14)

1.02 (0.88 - 1.20)

ALLHAT Lisinopril/ChlorthalidoneRelative Risk and 95% Confidence Intervals

WithDysmetabolic Syndrome

WithoutDysmetabolic Syndrome

19

Results by Baseline Dysmetabolic Syndrome -

Conclusions• Treatment group comparison results were

similar in participants with and without DS at baseline (i.e., there were no significant interactions)

• For both DS and non-DS participants, neither the CCB nor ACEI arms were superior to the diuretic arm

– For HF, diuretic was superior to CCB

• Results were similar with DS definition similar to ATP III

ALLHAT

20

Results - Overall

• Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy in patients with and without dysmetabolic syndrome.

ALLHAT

21

Additional Slides

(Not presented at AHA)

ALLHAT

22

BP Results by Treatment Group and Baseline DS

DS-Chlor DS–Amlod DS–Lisin

No DS–Chlor No DS–Amlod No DS–Lisin

ALLHATALLHAT

23

DS-Chlor DS–Amlod

No DS–Chlor No DS–Amlod

ALLHATALLHAT BP Results by Treatment Group and Baseline DS

Amlodipine vs Chlorthalidone

24

ALLHATALLHAT BP Results by Treatment Group and Baseline DS

Lisinopril vs Chlorthalidone

DS-Chlor DS–Lisin

No DS–Chlor No DS–Lisin

25

Outcomes in Participants with DS –Amlodipine Compared With Chlorthalidone

6-Year Rates per 100 (se)

# Events

RR (95% CI)

p

Chlor Aml Aml/Chl

CHD 11.5 (0.4)

771

10.9 (0.5)

434

0.95 (0.84 – 1.07)

0.37

Mortality 15.6 (0.5)

1,126

15.1 (0.6)

644

0.97 (0.88 – 1.06)

0.49

Stroke 5.7 (0.3)

386

5.2 (0.4)

201

0.87 (0.74 – 1.04)

0.12

Heart Failure 8.0 (0.4)

526

10.5 (0.5)

403

1.32 (1.15 – 1.51)

<0.001

Combined CVD

20.6 (0.5)

1,447

21.2 (0.7)

863

1.05 (0.98 – 1.12)

0.15

ESRD 1.8 (0.2)

135

2.4 (0.3)

97

1.27 (0.96 – 1.68)

0.09

ALLHAT

26

Outcomes in Participants with DS –Lisinopril Compared with Chlorthalidone

6-Year Rates per 100 (se)

# Events

RR (95% CI)

p

Chlor Lisin Lisin/Chl

CHD 11.5 (0.4)

771

11.4 (0.5)

457

1.01 (0.90 – 1.13)

0.86

Mortality 15.6 (0.5)

1,126

15.7 (0.6)

678

1.01 (0.93 – 1.12)

0.70

Stroke 5.7 (0.3)

386

6.1 (0.4)

248

1.09 (0.93 – 1.28)

0.27

Heart Failure 8.0 (0.4)

526

9.7 (0.5)

395

1.28 (1.12 – 1.47)

<0.001

Combined CVD

20.6 (0.5)

1,447

21.4 (0.7)

883

1.14 (1.06 – 1.21)

<0.001

ESRD 1.8 (0.2)

135

2.3 (0.3)

92

1.22 (0.92 – 1.63)

0.16

ALLHAT

27

Outcomes in Participants without DS –Amlodipine Compared with Chlorthalidone

6-Year Rates per 100 (se)

RR (95% CI)

p

Chlor Aml Aml/Chl

CHD 10.4 (0.5)

429

10.9 (0.7)

269

1.05 (0.90 – 1.22)

0.53

Mortality 17.6 (0.6)

795

17.0 (0.8)

441

0.93 (0.83 – 1.04)

0.23

Stroke 5.0 (0.4)

208

5.1 (0.5)

129

1.04 (0.83 – 1.29)

0.73

Heart Failure 6.8 (0.5)

258

8.6 (0.6)

215

1.45 (1.20 – 1.75)

<0.001

Combined CVD

17.6 (0.7)

732

17.3 (0.8)

448

1.05 (0.96 – 1.15)

0.28

ESRD 1.5 (0.2)

26

1.1 (0.2)

17

0.81 (0.51 – 1.26)

0.35

ALLHAT

28

Outcomes in Participants without DS –Lisinopril Compared with Chlorthalidone

6-Year Rates per 100 (se)

RR (95% CI)

p

Chlor Lisin Lisin/Chl

CHD 10.4 (0.5)

429

10.4 (0.7)

256

1.02 (0.88 – 1.20)

0.78

Mortality 17.6 (0.6)

795

18.3 (0.8)

476

1.02 (0.91-1.14)

0.72

Stroke 5.0 (0.4)

208

5.8 (0.5)

145

1.20 (0.97 – 1.48)

0.09

Heart Failure

6.8 (0.5)

258

6.6 (0.6)

153

1.02 (0.83 – 1.25)

0.84

Combined CVD

17.6 (0.7)

732

18.2 (0.9)

455

1.07 (0.98 – 1.17)

0.15

ESRD 1.5 (0.2)

26

1.0 (0.2)

16

0.76 (0.48 – 1.21)

0.26

ALLHAT

29

All-Cause Mortalityby Treatment Group

In Participants With DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

4

8

12

16

20

Cu

mu

lati

ve D

eath

Eve

nt

Rat

e, %

0 1 2 3 4 5 6

Years to Death

HR (95% CI) p value

A/C 0.97 (0.88 – 1.06) 0.49

L/C 1.01 (0.93 – 1.12) 0.70

30

All-Cause Mortalityby Treatment Group

In Participants Without DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

4

8

12

16

20

Cu

mu

lati

ve D

eath

Eve

nt

Rat

e, %

0 1 2 3 4 5 6

Years to Death

HR (95% CI) p value

A/C 0.93 (0.83 – 1.04) 0.23

L/C 1.02 (0.91-1.14) 0.72

31

Stroke by Treatment GroupIn Participants With DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

1

2

3

4

5

6

7

Cu

mu

lati

ve S

tro

ke E

ven

t R

ate,

%

0 1 2 3 4 5 6

Years to Stroke

HR (95% CI) p value

A/C 0.87 (0.74 – 1.04) 0.12

L/C 1.09 (0.93 – 1.28) 0.27

32

Stroke by Treatment GroupIn Participants Without DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

1

2

3

4

5

6

7

Cu

mu

lati

ve S

tro

ke E

ven

t R

ate,

%

0 1 2 3 4 5 6

Years to Stroke

HR (95% CI) p value

A/C 1.04 (0.83 – 1.29) 0.73

L/C 1.20 (0.97 – 1.48) 0.09

33

Heart Failure by Treatment GroupIn Participants With DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

2

4

6

8

10

12

Cu

mu

lati

ve H

F E

ven

t R

ate,

%

0 1 2 3 4 5 6

Years to HF

OR (95% CI) p value

A/C 1.32 (1.15 – 1.51) <0.001

L/C 1.28 (1.12 – 1.47) <0.001

34

Heart Failure by Treatment GroupIn Participants Without DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

2

4

6

8

10

12

Cu

mu

lati

ve H

F E

ven

t R

ate,

%

0 1 2 3 4 5 6

Years to HF

OR (95% CI) p value

A/C 1.45 (1.20 – 1.75) <0.001

L/C 1.02 (0.83 – 1.25) 0.84

35

Combined CVD by Treatment GroupIn Participants With DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

5

10

15

20

25

30

35

Cu

mu

lati

ve C

CV

D E

ven

t R

ate,

%

0 1 2 3 4 5 6

Years to CCVD

HR (95% CI) p value

A/C 1.05 (0.98 – 1.12) 0.15

L/C 1.14 (1.06 – 1.21) <0.001

36

Combined CVD by Treatment GroupIn Participants Without DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

5

10

15

20

25

30

35

Cu

mu

lati

ve C

CV

D E

ven

t R

ate,

%

0 1 2 3 4 5 6

Years to CCVD

HR (95% CI) p value

A/C 1.05 (0.96 – 1.15) 0.28

L/C 1.07 (0.98 – 1.17) 0.15

37

End Stage Renal Diseaseby Treatment Group

In Participants With DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

1

2

3

Cu

mu

lati

ve E

SR

D E

ven

t R

ate,

%

0 1 2 3 4 5 6

Years to ESRD

HR (95% CI) p value

A/C 1.27 (0.96 – 1.68) 0.09

L/C 1.22 (0.92 – 1.63) 0.16

38

End Stage Renal Diseaseby Treatment Group

In Participants Without DS at Baseline

ChlorthalidoneAmlodipineLisinopril

ALLHAT

0

1

2

3

Cu

mu

lati

ve E

SR

D E

ven

t R

ate,

%

0 1 2 3 4 5 6

Years to ESRD

HR (95% CI) p value

A/C 0.81 (0.51 – 1.26) 0.35

L/C 0.76 (0.48 – 1.21) 0.26

39

CHD

All-cause mortality

Stroke

Heart Failure

Combined CVD

ESRD

Favors Amlodipine0.50 1 2

1.27 (0.96 - 1.68)

1.05 (0.98 - 1.12)

1.32 (1.15 - 1.51)

0.87 (0.74 - 1.04)

0.97 (0.88 - 1.06)

0.95 (0.84 - 1.07)

Favors Chlorthalidone

ALLHATAmlodipine/Chlorthalidone

Relative Risk and 95% Confidence Intervals

Outcomes in Participants With Dysmetabolic Syndrome-

40

CHD

All-cause mortality

Stroke

Heart Failure

Combined CVD

ESRD

Favors Amlodipine0.50 1 2

0.81 (0.51 - 1.26)

1.05 (0.96 - 1.15)

1.45 (1.20 - 1.75)

1.04 (0.83 - 1.29)

0.93 (0.83 - 1.04)

1.05 (0.90 - 1.22)

Favors Chlorthalidone

ALLHATAmlodipine/Chlorthalidone

Relative Risk and 95% Confidence Intervals

Outcomes in Participants Without Dysmetabolic Syndrome

41

ESRD

Combined CVD

Heart Failure

Stroke

All-cause mortality

CHD

Favors Lisinopril

0.50 1 2

1.22 (0.92 - 1.63)

1.14 (1.06 - 1.21)

1.28 (1.12 - 1.47)

1.09 (0.93 - 1.28)

1.01 (0.93 - 1.12)

1.01 (0.90 - 1.13)

Favors Chlorthalidone

ALLHATLisinopril/Chlorthalidone

Relative Risk and 95% Confidence Intervals

Outcomes in Participants With Dysmetabolic Syndrome

42

CHD

All-cause mortality

Stroke

Heart Failure

Combined CVD

ESRD

Favors Lisinopril0.50 1 2

0.76 (0.48 - 1.21)

1.07 (0.98 - 1.17)

1.02 (0.83 - 1.25)

1.20 (0.97 - 1.48)

1.02 (0.91 - 1.14)

1.02 (0.88 - 1.20)

Favors Chlorthalidone

ALLHATOutcomes in Participants Without

Dysmetabolic SyndromeLisinopril/Chlorthalidone

Relative Risk and 95% Confidence Intervals