1

U.S. Department of Health and Human

Services

National Institutes of Health

National Heart, Lung, and Blood Institute

Major Outcomes in High Risk Major Outcomes in High Risk Hypertensive Patients Randomized to Hypertensive Patients Randomized to

Angiotensin-Converting Enzyme Inhibitor Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diureticor Calcium Channel Blocker vs Diuretic

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

The ALLHAT Collaborative Research GroupThe ALLHAT Collaborative Research Group

Sponsored by the National Heart, Lung, and Blood Sponsored by the National Heart, Lung, and Blood Institute (NHLBI)Institute (NHLBI)

ALLHAT

www.allhat.org JAMA 2002;288:2981-2997 JAMA 2002;288:2981-2997

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AntihypertensiveTrial Design

• Randomized, double-blind, multi-center clinical trial

• Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic

• 42,418 high-risk hypertensive patients ≥ 55 years

ALLHAT

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BackgroundBackground

• In addition to their BP lowering potential all In addition to their BP lowering potential all antihypertensive agents have other antihypertensive agents have other important mechanisms of action and important mechanisms of action and indications.indications.

• These actions may convey benefits or risks These actions may convey benefits or risks independent of BP loweringindependent of BP lowering

• By having a common BP goal for all By having a common BP goal for all treatment arms, ALLHAT aimed to evaluate treatment arms, ALLHAT aimed to evaluate the health effects of these non-BP actionsthe health effects of these non-BP actions

ALLHAT

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Secondary Outcomes

• All-cause mortality

• Stroke

• Combined CHD – nonfatal MI, CHD death, coronary revascularization, hospitalized angina

• Combined CVD – (CHD, stroke, coronary revascularizations, heart failure [treated non-hospitalized, hospitalized, fatal], angina (treated non-hospitalized, hospitalized), peripheral arterial disease (revascularization procedure)

ALLHAT

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Secondary Outcomes(Continued)

ALLHAT

•HQOL (Health-related quality of life)

•GI Bleeding

•Costs

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Step 1Treatment Protocol

Step 1 Agent Initial Dose* Dose 1* Dose 2* Dose 3*

Chlorthalidone 12.5 12.5 12.5 25

Amlodipine 2.5 2.5 5 10

Lisinopril 10 10 20 40

Doxazosin 1 2 4 8

* mg/day

ALLHAT

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Step 2 Agents: Dose 1* Dose 2* Dose 3*

Reserpine 0.05 qdor 0.1 qod

0.1 qd 0.2 qd

Clonidine (oral) 0.1 bid 0.2 bid 0.3 bid

Atenolol 25 qd 50 qd 100 qd

Step 3 Agent:

Hydralazine 25 bid 50 bid 100 bid

*All doses in mg

ALLHATStep Up

Treatment Protocol

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Baseline Characteristics

Chlorthalidone 15,255

Amlodipine 9,048

Lisinopril 9,054

Mean SBP/DBP 146 / 84 146 / 84 146 / 84 Treated (90%) Untreated (10%)

145 / 83156 / 89

145 / 83157 / 90

145 / 84156 / 89

Mean age, y 67 67 67Black, % 35 36 36Women, % 47 47 46Current smoking % 22 22 22History of CHD, % 26 24 25Type 2 diabetes, % 36 37 36

ALLHAT

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On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group

0.0

20.0

40.0

60.0

80.0

100.0

%

Chlor 87.1 84.7 82.7 80.8 80.5Aml 87.6 85.2 83.2 80.5 80.4Lis 82.4 78.4 77.1 74.8 72.6

1 Year 2 Years 3 Years 4 Years 5 Years

ALLHAT

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BP Results by Treatment GroupALLHAT

Compared to chlorthalidone:

SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg).

Compared to chlorthalidone:

DBP significantly lower in the amlodipine group (~1 mm Hg).

BL 6M 1Y 3Y 5Y

C 146.2 138.2 136.6 134.6 134.1

A 146.2 140.0 138.3 135.4 134.9

L 146.4 141.4 139.7 136.4 136.1

BL 6M 1Y 3Y 5Y

C 84.0 80.1 79.2 77.1 75.4

A 83.9 79.7 78.5 76.1 74.5

L 84.1 80.8 79.7 77.2 75.4

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Blood Pressure ControlBlood Pressure Control

31

58 60 64 67 67

92%91%90%88%86%

68% 66656258

27

55

0

20

40

60

80

100

0 1 2 3 4 5

Years of Follow-up

Perc

ent

DBP<90 SBP<140 BP<140/90

ALLHATALLHAT

1.41.6 1.7 1.8

2.0

1.6 = mean number of drugs= mean number of drugs

Cushman, et al. J Clin Hypertens 2002;Cushman, et al. J Clin Hypertens 2002;4:393-4044:393-404

@ 5 years:@ 5 years:62% were on 62% were on >>2 drugs2 drugs30% were on 1 drug and controlled30% were on 1 drug and controlled

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Biochemical Results

Chlorthalidone Amlodipine LisinoprilSerum cholesterol- mg/dL

Baseline 216.1 (43.8) 216.5 (44.1) 215.6 (42.4)

4 Years 197.2 (42.1) 195.6 (41.0)* 195.0 (40.6)*

Serum cholesterol - > 240 mg/dL Baseline 3838 (26.5) 2284 (26.6) 2178 (25.4)

4 Years 1223 (14.4) 673 (13.4) 603 (12.8)

Serum potassium – mmol/LBaseline 4.3 (0.7) 4.3 (0.7) 4.4 (0.7)*

4 Years 4.1 (0.7) 4.4 (0.7)* 4.5 (0.7)*

Serum potassium – <3.5mEq/LBaseline 493 (3.4) 292 (3.4) 223 (2.6)

4 Years 707 (8.5) 93 (1.9) 37 (0.8)

* p<.05 compared to chlorthalidone† Ann Intern Med. 1999;130:461-470

ALLHAT

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ALLHATUSE OF POTASSIUM SUPPLEMENTATION

2.2 0.6

0.8

3.6

1.1

1.1

4.6

2.1

1.6

5.4

2.6

1.7

7.9

3.5

2.3

11

5.9

4

0

2

4

6

8

10

12

Year 1 Year 2 Year 3 Year 4 Year 5 Year 6

Chlorthalidone Amlodipine Lisinopril

% o

n po

tass

ium

sup

pl.

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Biochemical Results – Fasting Glucose – mg/dLChlorthalidone Amlodipine Lisinopril

TotalBaseline 123.5 (58.3) 123.1 (57.0) 122.9 (56.1)

4 Years 126.3 (55.6) 123.7 (52.0) 121.5 (51.3)*

Among baseline nondiabetics with baseline <126 mg/dLBaseline 93.1 (11.7) 93.0 (11.4) 93.3 (11.8)

4 Years 104.4 (28.5) 103.1 (27.7) 100.5 (19.5)*

Diabetes Incidence (follow-up fasting glucose 126 mg/dL)4 Years 11.6% 9.8%* 8.1%*

*p<.05 compared to chlorthalidone

ALLHAT

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Renal Outcomes

C A L A/C L/CESRD(Rate/100 # events)

1.8 (0.1)193

2.1 (0.2)129

2.0(0.2)126

RR=1.12 p=.98

RR=1.11p=0.38

GFR (4 Year)Mean (sd)

70.0 (19.7)

75.1 (20.7)

70.7 (20) p<.001 p=0.03

ALLHAT

C = Chlorthalidone; A = Amlodipine; L = Lisinopril

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Years to CHD Event0 1 2 3 4 5 6 7

Cumulative CHD Event Rate

0

.04

.08

.12

.16

.2

Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group

RR (95% CI) p value

A/C 0.98 (0.90-1.07) 0.65L/C 0.99 (0.91-1.08) 0.81

ChlorthalidoneAmlodipineLisinopril

ALLHAT

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Cumulative Event Rates for Stroke by ALLHAT Treatment Group ALLHAT

Cumulative Stroke Rate

Years to Stroke0 1 2 3 4 5 6 7

0

.02

.04

.06

.08

.1

Number at risk: Chlor 15,255 14,515 13,934 13,309 11,570 6,385 3,217 567 Amlo 9,048 8,617 8,271 7,949 6,937 3,845 1,813 506 Lisin 9,054 8,543 8,172 7,784 6,765 3,891 1,828 949

RR (95% CI) p valueA/C 0.93 (0.81-1.06) 0.28L/C 1.15 (1.02-1.30) 0.02

ChlorthalidoneAmlodipineLisinopril

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Stroke – Subgroup Comparisons – RR (95% CI)ALLHAT

Amlodipine Better Chlorthalidone Better0.50 1 2

Non-Diabetic 0.96 (0.81, 1.14)

Diabetic 0.90 (0.75, 1.08)

Non-Black 0.93 (0.79, 1.10)

Black 0.93 (0.76, 1.14)

Women 0.84 (0.69, 1.03)

Men 1.00 (0.85, 1.18)

Age >= 65 0.93 (0.81, 1.08)

Age < 65 0.93 (0.73, 1.19)

Total 0.93 (0.82, 1.06)

Lisinopril Better Chlorthalidone Better0.50 1 2

Non-Diabetic 1.23 (1.05, 1.44)

Diabetic 1.07 (0.90, 1.28)

Non-Black 1.00 (0.85, 1.17)

Black 1.40 (1.17, 1.68)

Women 1.22 (1.01, 1.46)

Men 1.10 (0.94, 1.29)

Age >= 65 1.13 (0.98, 1.30)

Age < 65 1.21 (0.97, 1.52)

Total 1.15 (1.02, 1.30)

P = .01 for interaction

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Cumulative Event Rates for All-Cause Mortality by ALLHAT Treatment Group ALLHAT

Cumulative Mortality Rate

Years to Death0 1 2 3 4 5 6 7

0

.05

.1

.15

.2

.25

.3RR (95% CI) p value

A/C 0.96 (0.89-1.02) 0.20L/C 1.00 (0.94-1.08) 0.90

Number at risk: Chlor 15,255 14,933 14,564 14,077 12,480 7.185 3,523 428 Amlo 9,048 8,847 8,654 8,391 7,442 4,312 2,101 217 Lisin 9,054 8,853 8,612 8,318 7,382 4,304 2,121 144

RR (95% CI) p valueA/C 0.96 (0.89-1.02) 0.20L/C 1.00 (0.94-1.08) 0.90

ChlorthalidoneAmlodipineLisinopril

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Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group ALLHAT

Cumulative Combined CVD Event Rate

Years to Combined CVD Event0 1 2 3 4 5 6 7

0

.1

.2

.3

.4

.5

Number at risk: Chlor 15,255 13,752 12,594 11,517 9,643 5,167 2,362 288 Amlo 9,048 8,118 7,451 6,837 5,724 3,049 1,411 153 Lisin 9,054 7,962 7,259 6,631 5,560 3,011 1,375 139

RR (95% CI) p valueA/C 1.04 (0.99-1.09) 0.12L/C 1.10 (1.05-1.16) <0.001

ChlorthalidoneAmlodipineLisinopril

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Combined CVD – Subgroup Comparisons – RR (95% CI)ALLHAT

Amlodipine Better Chlorthalidone Better0.50 1 2

Non-Diabetic 1.02 (0.96, 1.09)

Diabetic 1.06 (0.98, 1.15)

Non-Black 1.04 (0.97, 1.10)

Black 1.06 (0.96, 1.16)

Women 1.04 (0.96, 1.13)

Men 1.04 (0.98, 1.11)

Age >= 65 1.05 (0.99, 1.12)

Age < 65 1.03 (0.94, 1.12)

Total 1.04 (0.99, 1.09)

Lisinopril Better Chlorthalidone Better0.50 1 2

Non-Diabetic 1.12 (1.05, 1.19)

Diabetic 1.08 (1.00, 1.17)

Non-Black 1.06 (1.00, 1.13)

Black 1.19 (1.09, 1.30)

Women 1.12 (1.03, 1.21)

Men 1.08 (1.02, 1.15)

Age >= 65 1.13 (1.06, 1.20)

Age < 65 1.05 (0.97, 1.15)

Total 1.10 (1.05, 1.16)

P = .04 for interaction

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Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group ALLHAT

Cumulative CHF Rate

Years to HF0 1 2 3 4 5 6 7

0

.03

.06

.09

.12

.15RR (95% CI) p value

A/C 1.38 (1.25-1.52) <.001L/C 1.19 (1.07-1.31) <.001

ChlorthalidoneAmlodipineLisinopril

Number at risk: Chlor 15,255 14,528 13,898 13,224 11,511 6,369 3,016 384 Amlo 9,048 8,535 8,185 7,801 6,785 3,775 1,780 210 Lisin 9,054 8,496 8,096 7,689 6,698 3,789 1,837 313

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Overall ConclusionsALLHAT

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.