The The AAntihypertensive and ntihypertensive and LLipid-ipid-LLowering Treatment owering Treatment

to Prevent to Prevent HHeart eart AAttack ttack TTrialrialALLHAT study overviewDouble-blind, randomized trial to determine whether theoccurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (amlodipine,lisinopril, or doxazosin) compared with a diuretic (chlorthalidone)

Cohort• 42,418 patients (55 years old) from 623 sites in North America

– Stage 1 or 2 hypertension – 1 additional risk factor for CHD

• Comparisons between chlorthalidone and amlodipine and chlorthalidone and lisinopril have been reported together, excluding the doxazosin arm (n=9,062), which was terminated early

ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.orgCHD=coronary heart disease; MI=myocardial infarction

ALLHAT Study DesignALLHAT Study Design

n=13,854n=13,8542,235 (16.1%) stopped drug

Chlorthalidone Chlorthalidone n=15,255n=15,255

AmlodipineAmlodipinen=9,048n=9,048

Randomizedn=42,418

n=15,255 n=15,255 339 (2.2%) lost to follow-up80 (0.5%) refused follow-up

n=9,048n=9,048200 (2.2%) lost to follow-up58 (0.6%) refused follow-up

n=6,210n=6,2101,873 (30.2%) stopped drug

n=9,054 n=9,054 218 (2.4%) lost to follow-up58 (0.6%) refused follow-up

n=8,215n=8,215 1,357 (16.5%) stopped drug

n=3,769n=3,7691,052 (27.9%)stopped drug

YEAR 1n=8,158n=8,158

1,842 (22.6%) stopped drug

n=3,605n=3,6051,399 (38.8%) stopped

drug

LisinoprilLisinopriln=9,054n=9,054

YEAR 5

ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.org

Intent-to-Treat

Analysis

Doxazosinn=9,062

Discontinuedearly at 3.3 yrs

ALLHAT EndpointsALLHAT Endpoints

Primary endpoint• Composite of fatal coronary heart disease (CHD) or nonfatal

myocardial infarction (MI)Other predefined endpoints

– all-cause mortality– stroke– combined CHD – nonfatal MI, CHD death, coronary

revascularization, hospitalized angina– combined cardiovascular disease – combined CHD, stroke,

lower extremity revascularization, treated angina, fatal/ hospitalized/treated congestive heart failure, hospitalized or outpatient peripheral arterial disease

– other – renal

ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.org

Chlorthalidone n=15,255

Amlodipine n=9,048

Lisinopril n=9,054

systolic diastolic systolic diastolicsystoli

cdiastolic

Mean BP (mmHg) 146 84 146 84 146 84

Treated (90%) 145 83 145 83 145 84

Untreated (10%) 156 89 157 90 156 89

Mean age (yrs) 67 67 67

Black (%) 35 36 36

Women (%) 47 47 46

Current smoking (%) 22 22 22

History of CHD (%) 26 24 25

Type 2 diabetes (%) 36 37 36

ALLHAT Baseline CharacteristicsALLHAT Baseline Characteristics

ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.orgBP=blood pressure CHD=coronary heart disease

70

75

80

85

90

130

135

140

145

150

ALLHAT Mean Systolic and Diastolic Blood ALLHAT Mean Systolic and Diastolic Blood Pressure During Follow-upPressure During Follow-up

Systo

lic B

P (

mm

Hg

)

Follow-up, yrs0 1 2 3 4 5 6 0 1 2 3 4 5 6

Dia

sto

lic B

P (

mm

Hg

)

Chlorthalidone

Amlodipine

Lisinopril

Chlorthalidone

Amlodipine

Lisinopril

ALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association. www.hypertensiononline.org

SBP=systolic blood pressure DBP=diastolic blood pressure

Compared to chlorthalidone:

DBP significantly lower in amlodipine group (~1 mmHg).

Compared to chlorthalidone:

SBP significantly higher in amlodipine (~1 mmHg) and

lisinopril (~2 mmHg) groups.

0

10

20

30

40

50

60

70

Baseline Year 1 Year 2 Year 3 Year 4 Year 5

ALLHAT BP Controlled ALLHAT BP Controlled to <140/90 mmHgto <140/90 mmHg

LisinoprilAmlodipineChlorthalidone

www.hypertensiononline.org

†

ALLHAT Research Group. JAMA. 2002;288:2981-2997.

% P

ati

en

ts w

ith

B

P <

140/9

0 m

mH

g

*P<0.001 for amlodipine vs chlorthalidone†P<0.001 for lisinopril vs chlorthalidone

††

*†*†

0

20

40

60

80

100

0

0.4

0.8

1.2

1.6

2

ALLHAT Treatment ALLHAT Treatment and Blood Pressure Controland Blood Pressure Control

6 mos 1 yr 3 yr 5 yr

1 Drug 2 Drugs 3 Drugs

Pati

en

ts (

%)

Cushman WC, et al. J Clin Hypertens. 2002;4:393-405. www.hypertensiononline.org

Avera

ge #

of d

rug

s

Blood pressure controlled <140/90 mmHg

49.8% 55.2% 62.3% 65.6%

1.41.4

1.71.7

2.02.0

1.31.3

0

4

8

12

16

20

ALLHAT Primary OutcomeALLHAT Primary Outcomeby Treatment Groupby Treatment Group

Cu

mu

lati

ve F

ata

l C

HD

an

d

Non

fata

l M

I even

t ra

te (

%)

Time to event, yrs0 1 2 3 4 5 6

1525590489054

7No. at Risk

ChlorthalidoneAmlodipine

Lisinopril

1447785768535

1382082188123

1310278437711

1136268246662

634038703832

295618781770

209215195

Chlorthalidone

Amlodipine

Lisinopril

www.hypertensiononline.orgALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association.

Relative Risk(95% CI)

Relative Risk(95% CI)

TOTAL0.98

(0.90-1.07)

0.99 (0.91-1.08)

Age <650.99

(0.85-1.16)0.95

(0.81-1.12)

Age 650.97

(0.88-1.08)1.01

(0.91-1.12)

Men0.98

(0.87-1.09)0.94

(0.85-1.05)

Women0.99

(0.85-1.15)1.06

(0.92-1.23)

Black1.01

(0.86-1.18)1.10

(0.94-1.28)

Nonblack0.97

(0.87-1.08)0.94

(0.85-1.05)

Diabetic0.99

(0.87-1.13)1.00

(0.87-1.14)

Nondiabetic0.97

(0.86-1.09)0.99

(0.88-1.11)0.5 1 2 0.5 1 2

ALLHAT ALLHAT CHD DeathCHD Death and and Nonfatal MINonfatal MI

www.hypertensiononline.org

Favorslisinopril

Favorschlorthalidone

Favorsamlodipine

Favorschlorthalidone

ALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association.

Relative Risk(95% CI)

Relative Risk(95% CI)

TOTAL0.96

(0.89-1.02)

1.00 (0.94-1.08)

Age <650.96

(0.83-1.10)0.93

(0.81-1.08)

Age 650.96

(0.88-1.03)1.03

(0.95-1.12)

Men0.95

(0.87-1.04)0.99

(0.91-1.08)

Women0.96

(0.86-1.07)1.02

(0.91-1.13)

Black0.97

(0.87-1.09)1.06

(0.95-1.18)

Nonblack0.94

(0.87-1.03)0.97

(0.89-1.06)

Diabetic0.96

(0.87-1.07)1.02

(0.91-1.13)

Nondiabetic0.95

(0.87-1.04)1.00

(0.91-1.09)0.5 1 2 0.5 2

ALLHAT ALLHAT All-Cause MortalityAll-Cause Mortality

www.hypertensiononline.org

Favorslisinopril

Favorschlorthalidone

Favorsamlodipine

Favorschlorthalidone

1ALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association.

Relative Risk(95% CI)

Relative Risk(95% CI)

TOTAL1.04

(0.99-1.09)

1.10 (1.05-1.16)

Age <651.03

(0.94-1.12)1.05

(0.97-1.15)

Age 651.05

(0.99-1.12)1.13

(1.06-1.20)

Men1.04

(0.98-1.11)1.08

(1.02-1.15)

Women1.04

(0.96-1.13)1.12

(1.03-1.21)

Black1.06

(0.96-1.16)1.19

(1.09-1.30)

Nonblack1.04

(0.97-1.10)1.06

(1.00-1.13)

Diabetic1.06

(0.98-1.15)1.08

(1.00-1.17)

Nondiabetic1.02

(0.96-1.09)1.12

(1.05-1.19)0.5 2 0.5 2

ALLHAT ALLHAT Combined CV DiseaseCombined CV Disease

www.hypertensiononline.org

Favorsamlodipine

Favorschlorthalidone

Favorslisinopril

Favorschlorthalidone

1 1ALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association.

0

2

4

6

8

10

ALLHAT StrokeALLHAT Strokeby Treatment Groupby Treatment Group

0 1 2 3 4 5 6

1525590489054

7No. at Risk

ChlorthalidoneAmlodipine

Lisinopril

1451586178543

1393482718172

1330979497784

1157069376765

638538453891

321718131828

567506949

Cu

mu

lati

ve e

ven

t ra

te (

%)

Chlorthalidone

Amlodipine

Lisinopril

Time to event, yrs

www.hypertensiononline.orgALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association.

Relative Risk(95% CI)

Relative Risk(95% CI)

TOTAL0.93

(0.82-1.06)

1.15 (1.02-1.30)

Age <650.93

(0.73-1.19)1.21

(0.97-1.52)

Age 650.93

(0.81-1.08)1.13

(0.98-1.30)

Men1.00

(0.85-1.18)1.10

(0.94-1.29)

Women0.84

(0.69-1.03)1.22

(1.01-1.46)

Black0.93

(0.76-1.14)1.40

(1.17-1.68)

Nonblack0.93

(0.79-1.10)1.00

(0.85-1.17)

Diabetic0.90

(0.75-1.08)1.07

(0.90-1.28)

Nondiabetic0.96

(0.81-1.14)1.23

(1.05-1.44)0.5 1 2 0.5 2

ALLHAT ALLHAT StrokeStroke

www.hypertensiononline.org

Favorsamlodipine

Favorschlorthalidone

Favorslisinopril

Favorschlorthalidone

1ALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association.

0

3

6

9

12

15

ALLHAT Heart Failure ALLHAT Heart Failure by Treatment Groupby Treatment Group

0 1 2 3 4 5 6

1525590489054

7No. at Risk

ChlorthalidoneAmlodipine

Lisinopril

1452885358496

1389881858096

1322478017689

1151167856698

636937753789

301617801837

384210313

Cu

mu

lati

ve e

ven

t ra

te (

%)

Chlorthalidone

Amlodipine

Lisinopril

Time to event, yrs

www.hypertensiononline.org

P<0.001 for chlorthalidone vs amlodipine and chlorthalidone vs lisinopril

ALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association.

Relative Risk(95% CI)

Relative Risk(95% CI)

TOTAL1.38

(1.25-1.52)

1.20 (1.09-1.34)

Age <651.51

(1.25-1.82)1.23

(1.01-1.50)

Age 651.33

(1.18-1.49)1.20

(1.06-1.35)

Men1.41

(1.24-1.61)1.19

(1.03-1.36)

Women1.33

(1.14-1.55)1.23

(1.05-1.43)

Black1.47

(1.24-1.74)1.32

(1.11-1.58)

Nonblack1.33

(1.18-1.51)1.15

(1.01-1.30)

Diabetic1.42

(1.23-1.64)1.22

(1.05-1.42)

Nondiabetic1.33

(1.16-1.52)1.20

(1.04-1.38)0.5 2 0.5 2

ALLHAT ALLHAT Heart FailureHeart Failure

www.hypertensiononline.org

Favorsamlodipine

Favorschlorthalidone

Favorslisinopril

Favorschlorthalidone

1 1ALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association.

ALLHAT ConclusionsALLHAT Conclusions• Better control of systolic BP was achieved with

chlorthalidone than with amlodipine or lisinopril

• There were no differences in risk for CHD death/nonfatal MI between chlorthalidone and amlodipine or lisinopril

• In secondary endpoints, chlorthalidone was associated with lower risk for – stroke, combined CVD, and HF compared with

lisinopril– HF compared with amlodipine

MI=myocardial infarction CHD=coronary heart disease HF=heart failurewww.hypertensiononline.orgALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT ImplicationsALLHAT Implications

• Unless contraindicated, or unless specific indications are present that would favor use of another drug class, diuretics should be the initial drug of choice in antihypertensive regimens

• Only 30 percent of patients achieve both systolic BP <140 mmHg and diastolic BP <90 mmHg on monotherapy

• Many high-risk hypertensive patients will require 2 or more drugs for BP control

www.hypertensiononline.orgALLHAT Research Group. JAMA. 2002;288:2981-2997.