The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

ALLHAT study overview

Double-blind, randomized trial to determine whether the occurrence 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
CHD=coronary heart disease; MI=myocardial infarction ALLHAT Research Group. JAMA. 2002;288:2981-2997.

www.hypertensiononline.org

ALLHAT Study Design

Doxazosin n=9,062
Discontinued early at 3.3 yrs

Randomized n=42,418 Amlodipine n=9,048

1,357 (16.5%) stopped drug

Chlorthalidone n=15,255 YEAR 1

2,235 (16.1%) stopped drug

Lisinopril n=9,054
1,842 (22.6%) stopped drug

n=13,854

n=8,215

n=8,158

YEAR 5
Intent-toTreat Analysis

1,873 (30.2%) stopped drug

n=6,210

1,052 (27.9%) stopped drug

n=3,769

1,399 (38.8%) stopped drug

n=3,605

339 (2.2%) lost to follow-up 80 (0.5%) refused follow-up

n=15,255

200 (2.2%) lost to follow-up 58 (0.6%) refused follow-up

n=9,048

218 (2.4%) lost to follow-up 58 (0.6%) refused follow-up

n=9,054

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

www.hypertensiononline.org

ALLHAT 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

ALLHAT Baseline Characteristics

Chlorthalidone n=15,255
Mean BP (mmHg) Treated (90%) Untreated (10%) Mean age (yrs) Black (%) Women (%) Current smoking (%) 146 145 156 67 35 47 22 84 83 89

Amlodipine n=9,048
146 145 157 67 36 47 22 84 83 90

Lisinopril n=9,054
146 145 156 67 36 46 22 84 84 89

systolic diastolic systolic diastolic systolic diastolic

History of CHD (%)

Type 2 diabetes (%)

26
36

24
37

25
36
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BP=blood pressure CHD=coronary heart disease ALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT Mean Systolic and Diastolic Blood Pressure During Follow-up

Chlorthalidone Chlorthalidone

Systolic BP (mmHg)

Lisinopril

Diastolic BP (mmHg)

150 145 140 135 130

Amlodipine

90 85 80 75 70

Amlodipine Lisinopril
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.

6 0 1 Follow-up, yrs

SBP=systolic blood pressure DBP=diastolic blood pressure ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.org Copyright 2002, American Medical Association.

ALLHAT BP Controlled to <140/90 mmHg

Chlorthalidone Amlodipine Lisinopril

70
% Patients with BP <140/90 mmHg

60 50 40 30 20 10 0 Baseline Year 1
*

Year 2

Year 3

Year 4

Year 5

*P<0.001 for amlodipine vs chlorthalidone P<0.001 for lisinopril vs chlorthalidone ALLHAT Research Group. JAMA. 2002;288:2981-2997.

www.hypertensiononline.org

ALLHAT Treatment and Blood Pressure Control

1 Drug 2 Drugs
1.7

3 Drugs

2.0

100

Average # of drugs

Patients (%)

80
1.3

1.4

1.6 1.2 0.8 0.4 0

60 40 20 0

6 mos
49.8%

1 yr
55.2%

3 yr
62.3%

5 yr
65.6%

Blood pressure controlled <140/90 mmHg

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

www.hypertensiononline.org

ALLHAT Primary Outcome by Treatment Group

Cumulative Fatal CHD and Nonfatal MI event rate (%)
20 16 12 8 4 0
Chlorthalidone Amlodipine

Lisinopril

1
14477 8576 8535

2
13820 8218 8123

No. at Risk Chlorthalidone Amlodipine Lisinopril

3 4 5 Time to event, yrs

13102 7843 7711 11362 6824 6662 6340 3870 3832

6
2956 1878 1770

7
209 215 195

15255 9048 9054

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

www.hypertensiononline.org

ALLHAT CHD Death and Nonfatal MI

Relative Risk Favors Relative Risk Favors (95% CI) amlodipine chlorthalidone (95% CI) Favors Favors lisinopril chlorthalidone

TOTAL Age <65 Age 65 Men Women

0.98 (0.90-1.07) 0.99 (0.85-1.16)

0.99 (0.91-1.08) 0.95 (0.81-1.12)

0.97 (0.88-1.08)
0.98 (0.87-1.09) 0.99 (0.85-1.15) 1.01 (0.86-1.18) 0.97 (0.87-1.08) 0.99 (0.87-1.13) 0.97 (0.86-1.09)

1.01 (0.91-1.12)
0.94 (0.85-1.05) 1.06 (0.92-1.23) 1.10 (0.94-1.28) 0.94 (0.85-1.05) 1.00 (0.87-1.14) 0.99 (0.88-1.11)

Black
Nonblack Diabetic Nondiabetic

0.5

0.5

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

www.hypertensiononline.org

ALLHAT All-Cause Mortality

Relative Risk Favors Relative Risk Favors (95% CI) amlodipine chlorthalidone (95% CI) Favors Favors lisinopril chlorthalidone

TOTAL Age <65 Age 65 Men Women

0.96 (0.89-1.02) 0.96 (0.83-1.10)

1.00 (0.94-1.08) 0.93 (0.81-1.08)

0.96 (0.88-1.03)
0.95 (0.87-1.04) 0.96 (0.86-1.07) 0.97 (0.87-1.09) 0.94 (0.87-1.03) 0.96 (0.87-1.07) 0.95 (0.87-1.04)

1.03 (0.95-1.12)
0.99 (0.91-1.08) 1.02 (0.91-1.13) 1.06 (0.95-1.18) 0.97 (0.89-1.06) 1.02 (0.91-1.13) 1.00 (0.91-1.09)

Black
Nonblack Diabetic Nondiabetic

0.5

0.5

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

www.hypertensiononline.org

ALLHAT Combined CV Disease

Relative Risk Favors Relative Risk Favors (95% CI) amlodipine chlorthalidone (95% CI) Favors Favors lisinopril chlorthalidone

TOTAL Age <65 Age 65 Men Women

1.04 (0.99-1.09) 1.03 (0.94-1.12)

1.10 (1.05-1.16) 1.05 (0.97-1.15)

1.05 (0.99-1.12)
1.04 (0.98-1.11) 1.04 (0.96-1.13) 1.06 (0.96-1.16) 1.04 (0.97-1.10) 1.06 (0.98-1.15) 1.02 (0.96-1.09)

1.13 (1.06-1.20)
1.08 (1.02-1.15) 1.12 (1.03-1.21) 1.19 (1.09-1.30) 1.06 (1.00-1.13) 1.08 (1.00-1.17) 1.12 (1.05-1.19)

Black
Nonblack Diabetic Nondiabetic

0.5

0.5

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

www.hypertensiononline.org

ALLHAT Stroke by Treatment Group

Cumulative event rate (%)
10 8 6 4 2 0
Chlorthalidone Amlodipine

Lisinopril

No. at Risk 14515 13934 13309 11570 Chlorthalidone 15255 9048 8617 8271 7949 6937 Amlodipine 9054 8543 8172 7784 6765 Lisinopril ALLHAT Research Group. JAMA. 2002;288:2981-2997. Copyright 2002, American Medical Association.

3 4 5 Time to event, yrs

6385 3845 3891

6
3217 1813 1828

7
567 506 949

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ALLHAT Stroke
Relative Risk Favors Relative Risk Favors (95% CI) amlodipine chlorthalidone (95% CI) Favors Favors lisinopril chlorthalidone

TOTAL Age <65 Age 65 Men Women

0.93 (0.82-1.06) 0.93 (0.73-1.19)

1.15 (1.02-1.30) 1.21 (0.97-1.52)

0.93 (0.81-1.08)
1.00 (0.85-1.18) 0.84 (0.69-1.03) 0.93 (0.76-1.14) 0.93 (0.79-1.10) 0.90 (0.75-1.08) 0.96 (0.81-1.14)

1.13 (0.98-1.30)
1.10 (0.94-1.29) 1.22 (1.01-1.46) 1.40 (1.17-1.68) 1.00 (0.85-1.17) 1.07 (0.90-1.28) 1.23 (1.05-1.44)

Black
Nonblack Diabetic Nondiabetic

0.5

0.5

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

www.hypertensiononline.org

ALLHAT Heart Failure by Treatment Group

Cumulative event rate (%)
15 12 9 6 3 0
Chlorthalidone Amlodipine Lisinopril
P<0.001 for chlorthalidone vs amlodipine and chlorthalidone vs lisinopril

No. at Risk Chlorthalidone Amlodipine Lisinopril

1
14528 8535 8496

2
13898 8185 8096

15255 9048 9054

3 4 5 Time to event, yrs

13224 7801 7689 11511 6785 6698

6
3016 1780 1837

7
384 210 313

6369 3775 3789

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

www.hypertensiononline.org

ALLHAT Heart Failure

Relative Risk Favors Relative Risk Favors (95% CI) amlodipine chlorthalidone (95% CI) Favors Favors lisinopril chlorthalidone

TOTAL Age <65 Age 65 Men Women

1.38 (1.25-1.52) 1.51 (1.25-1.82)

1.20 (1.09-1.34) 1.23 (1.01-1.50)

1.33 (1.18-1.49)
1.41 (1.24-1.61) 1.33 (1.14-1.55) 1.47 (1.24-1.74) 1.33 (1.18-1.51) 1.42 (1.23-1.64) 1.33 (1.16-1.52)

1.20 (1.06-1.35)
1.19 (1.03-1.36) 1.23 (1.05-1.43) 1.32 (1.11-1.58) 1.15 (1.01-1.30) 1.22 (1.05-1.42) 1.20 (1.04-1.38)

Black
Nonblack Diabetic Nondiabetic

0.5

0.5

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

www.hypertensiononline.org

ALLHAT 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 ALLHAT Research Group. JAMA. 2002;288:2981-2997. HF=heart failure www.hypertensiononline.org

ALLHAT 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.org

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