1

U.S. Department of Health and Human

Services

National Institutes of Health

National Heart, Lung, and Blood Institute

Major Outcomes in High Risk Hypertensive Patients Randomized to

Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic

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

The ALLHAT Collaborative Research Group

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

ALLHAT

JAMA. 2002;288:2981-2997

2

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

3

Secondary Objectives: Subgroups

Pre-specified

–Age 65+

–Women

–African-Americans

–Diabetic patients

Post-hoc

–Baseline CHD

ALLHAT

4

Secondary Outcomes

• All-cause mortality

• Stroke

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

• Combined CVD – combined CHD, stroke, lower extremity revascularization, treated angina, fatal / hospitalized / treated CHF, hospitalized or outpatient PAD

• Other – renal (reciprocal serum creatinine, ESRD, estimated GFR) and cancer

ALLHAT

5

Sites in ALLHAT

• 623 clinical sites

• United States, Canada, Puerto Rico, US Virgin Islands

• VA, private & group general medicine practices, community health centers, HMOs, specialty practices

• Variety of research experience

ALLHAT

6

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

7

Inclusion Criteria forAntihypertensive Trial

• Age/sex: men and women aged > 55 years

• BP eligibility:

–Untreated systolic and/or diastolic hypertension ( 140/90 mm Hg but 180/110 mm Hg at two visits)

–Treated hypertension

• ≤ 160/100 mm Hg on 1-2 antihypertensive drugs at Visit 1

• ≤ 180/110 mm Hg at Visit 2, when medication may have been partially withdrawn

–No washout period was required in ALLHAT.

ALLHAT

8

ALLHAT Inclusion Criteria:Risk Factors

At least one of the following:

• Myocardial infarction or stroke: at least 6 months old, or age-indeterminate

• History of revascularization procedure

• Major ST segment depression or T-wave inversion

• Other documented ASCVD

ALLHAT

9

ALLHAT Inclusion Criteria: Risk Factors

At least one of the following (cont.)

• Type 2 diabetes mellitus

• HDL cholesterol < 35 mg/dL on any 2 or more determinations in past 5 years

• Left ventricular hypertrophy (past 2 years)

– ECG, or echo (septum + posterior wall thickness 25 mm)

• Current cigarette smoking

ALLHAT

10

Major Exclusion Criteria

• MI, stroke, or angina within 6 months

• Symptomatic CHF or ejection fraction < 35%

• Known renal insufficiency - creatinine 2 mg/dL

• Requiring diuretics, CCB, ACEI, or alpha blockers for reasons other than hypertension

ALLHAT

11

Sample Size Assumptions & Statistical Methods

• 83% power to detect 16% reduction in risk for primary outcome

• 2-sided α=.0178 (z=2.37)– Accounts for multiple comparisons

• Analysis according to “intent to treat”• Cumulative event rates – Kaplan-Meier• Differences between event curves - Log-rank

tests & Cox proportional hazards (PH) model• PH assumption tested by log-log plots, tests with

treatment by time interaction– If violated, 2 x 2 table used

ALLHAT

12

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

13

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

Reserpine 0.05 qd

or 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

14

Safety Outcomes

• Angioedema

• Hospitalization for gastrointestinal bleeding

– Records from the VA hospitalization database

– Records from the Center for Medicare & Medicaid Services (CMS) database (participants age 65 or older)

ALLHAT

15

Decision to Dropan ALLHAT Arm

• January 24, 2000 – NHLBI Director accepts the recommendation of an independent review group to terminate doxazosin arm

– Futility of finding a significant difference for primary outcome

– Statistically significant 25 percent higher rate of major secondary endpoint, combined CVD outcomes

ALLHAT

16

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0.05

0.10

0.15

0.20

0.25

0.30

0 1 2 3 4

Cu

mu

lati

ve E

ven

t R

ate

Years of Follow-up

doxazosin

chlorthalidone

Cardiovascular Disease

C: 15,268D: 9,067

12,990 7,382

9,4435,285

4,8272,654

2,0101,083

Rel Risk 1.25

z = 6.77, p < 0.0001

95% CI1.17-1.33

ALLHAT

JAMA. 2000;283:1967-1975

17

0.00

0.02

0.04

0.06

0.08

0.10

0 1 2 3 4

Cu

mu

lati

ve E

ven

t R

ate

Years of Follow-up

doxazosinchlorthalidone

Heart Failure

C: 15,268D: 9,067

13,644 7,845

5,5313,089

2,4271,351

9,541 5,457

Rel Risk 2.04

z = 10.95, p < 0.0001

95% CI1.79-2.32

ALLHAT

JAMA. 2000;283:1967-1975

18

Comparison of Doxazosin with Chlorthalidone -

Conclusions

• Doxazosin is not recommended as first-line therapy in hypertension.

• ALLHAT does not allow an assessment of the effect of doxazosin compared with placebo on the incidence of CVD.

• The use of doxazosin as a step-up drug for treating hypertension was not tested in this trial.

• These findings are likely to apply to all alpha-blockers.

ALLHAT

JAMA. 2000;283:1967-1975

19

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 / 83

156 / 89

145 / 83

157 / 90

145 / 84

156 / 89

Mean age, y 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

20

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 80.5

Aml 87.6 85.2 83.2 80.5 80.4

Lis 82.4 78.4 77.1 74.8 72.6

1 Year 2 Years 3 Years 4 Years 5 Years

ALLHAT

21

Full Crossovers by Antihypertensive Treatment Group

0.0

5.0

10.0

15.0

%

Chlor 5.1 6.7 7.7 8.2 9.0

Amlodipine 2.8 4.5 5.0 6.0 6.9

Lisinopril 3.5 5.1 6.0 7.0 8.5

1 Year 2 Years 3 Years 4 Years 5 Years

ALLHATChlorthalidone: not on assigned medicine or open-label diuretic, but on open-label calcium channel blocker or ACE-inhibitorAmlodipine: not on assigned medicine or open-label calcium channel blocker, but on open-label diureticLisinopril: not on assigned medicine or open-label ACE-inhibitor, but on open-label diuretic

22

On Step 2 or Step 3 Treatment by Antihypertensive Treatment Group

0.0

20.0

40.0

60.0

80.0

100.0

%

Chlor 26.7 32.2 35.6 38.0 40.7

Aml 25.9 32.0 35.2 36.9 39.5

Lis 32.6 36.3 38.8 40.7 43.0

1 Year 2 Years 3 Years 4 Years 5 Years

ALLHAT

23

BP Results by Treatment Group

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).

ALLHAT

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

24

Biochemical Results

Chlorthalidone Amlodipine Lisinopril

Serum cholesterol- mg/dL, mean (SD)

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 potassium – mmol/L, mean (SD)

Baseline 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)*

Estimated GFR† – mL/min/1.73m2 ,mean (SD)

Baseline 77.6 (19.7) 78.0 (19.7) 77.7 (19.9)

4 Years 70.0 (19.7) 75.1 (20.7)* 70.7 (20.1)*

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

ALLHAT

25

Biochemical Results – Fasting Glucose – mg/dL

Chlorthalidone Amlodipine Lisinopril

Total –mean (SD)

Baseline 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/dL – mean (SD)

Baseline 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

26

Follow-Up

Chlorthalidone Amlodipine Lisinopril

Randomized 15,255 9,048 9,054

Known alive 12,530 (82.1%) 7,479 (82.7%) 7,412 (81.9%)

Confirmed deaths

2,203 (14.4%) 1,256 (13.9%) 1,314 (14.5%)

Deaths pending confirmation

103 (0.7%) 55 (0.6%) 52 (0.6%)

Lost 339 (2.2%) 200 (2.2%) 218 (2.4%)

Refused 80 (0.5%) 58 (0.6%) 58 (0.6%)

Person-years

(% obs/exp)

99% 99% 99%

ALLHAT

27

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 2,956 209 Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 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) 0.65

L/C 0.99 (0.91-1.08) 0.81

ALLHAT

ChlorthalidoneAmlodipineLisinopril

28

Nonfatal MI + CHD Death – Subgroup Comparisons – RR (95% CI)ALLHAT

Amlodipine Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 0.97 (0.86, 1.09)

Diabetic 0.99 (0.87, 1.13)

Non-Black 0.97 (0.87, 1.08)

Black 1.01 (0.86, 1.18)

Women 0.99 (0.85, 1.15)

Men 0.98 (0.87, 1.09)

Age>=65 0.97 (0.88, 1.08)

Age <65 0.99 (0.85, 1.16)

Total 0.98 (0.90, 1.07)

Lisinopril Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 0.99 (0.88, 1.11)

Diabetic 1.00 (0.87, 1.14)

Non-Black 0.94 (0.85, 1.05)

Black 1.10 (0.94, 1.28)

Women 1.06 (0.92, 1.23)

Men 0.94 (0.85, 1.05)

Age >= 65 1.01 (0.91, 1.12)

Age < 65 0.95 (0.81, 1.12)

Total 0.99 (0.91, 1.08)

29

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

Cumulative Event Rates for Stroke by ALLHAT Treatment Group

RR (95% CI) p value

A/C 0.93 (0.81-1.06) 0.28

L/C 1.15 (1.02-1.30) 0.02

ALLHAT

ChlorthalidoneAmlodipineLisinopril

30

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

Amlodipine Better Chlorthalidone Better

0.50 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 Better

0.50 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

31

Cumulative Mortality Rate

Years to Death0 1 2 3 4 5 6 7

0

.05

.1

.15

.2

.25

.3

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

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

RR (95% CI) p value

A/C 0.96 (0.89-1.02) 0.20

L/C 1.00 (0.94-1.08) 0.90

ALLHAT

ChlorthalidoneAmlodipineLisinopril

32

All-Cause Mortality – Subgroup Comparisons – RR (95% CI)ALLHAT

Amlodipine Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 0.95 (0.87, 1.04)

Diabetic 0.96 (0.87, 1.07)

Non-Black 0.94 (0.87, 1.03)

Black 0.97 (0.87, 1.09)

Women 0.96 (0.86, 1.07)

Men 0.95 (0.87, 1.04)

Age >= 65 0.96 (0.88, 1.03)

Age < 65 0.96 (0.83, 1.10)

Total 0.96 (0.89, 1.02)

Lisinopril Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 1.00 (0.91, 1.09)

Diabetic 1.02 (0.91, 1.13)

Non-Black 0.97 (0.89, 1.06)

Black 1.06 (0.95, 1.18)

Women 1.02 (0.91, 1.13)

Men 0.99 (0.91, 1.08)

Age >= 65 1.03 (0.95, 1.12)

Age < 65 0.93 (0.81, 1.08)

Total 1.00 (0.94, 1.08)

33

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

Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group

RR (95% CI) p value

A/C 1.04 (0.99-1.09) 0.12

L/C 1.10 (1.05-1.16) <0.001

ALLHAT

ChlorthalidoneAmlodipineLisinopril

34

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

Amlodipine Better Chlorthalidone Better

0.50 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 Better

0.50 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

35

Cumulative CHF Rate

Years to HF0 1 2 3 4 5 6 7

0

.03

.06

.09

.12

.15

Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group

RR (95% CI) p value

A/C 1.38 (1.25-1.52) <.001

L/C 1.19 (1.07-1.31) <.001

ALLHAT

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

36

Heart Failure – Subgroup Comparisons – RR (95% CI)ALLHAT

Amlodipine Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 1.33 (1.16, 1.52)

Diabetic 1.42 (1.23, 1.64)

Non-Black 1.33 (1.18, 1.51)

Black 1.47 (1.24, 1.74)

Women 1.33 (1.14, 1.55)

Men 1.41 (1.24, 1.61)

Age >= 65 1.33 (1.18, 1.49)

Age < 65 1.51 (1.25, 1.82)

Total 1.38 (1.25, 1.52)

Lisinopril Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 1.20 (1.04, 1.38)

Diabetic 1.22 (1.05, 1.42)

Non-Black 1.15 (1.01, 1.30)

Black 1.32 (1.11, 1.58)

Women 1.23 (1.05, 1.43)

Men 1.19 (1.03, 1.36)

Age >= 65 1.20 (1.06, 1.35)

Age < 65 1.23 (1.01, 1.50)

Total 1.20 (1.09, 1.34)

37

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.

38

Other Conclusions

• Neither amlodipine (representing CCB) nor lisinopril (representing ACEI) was superior to chlorthalidone (representing thiazide-type diuretics) in preventing major coronary events or increasing overall survival.

• Although chlorthalidone did not differ from amlodipine in overall CVD event prevention, it was superior to amlodipine (by about one-fourth) in preventing heart failure, overall and for hospitalized or fatal cases.

ALLHAT

39

Other Conclusions

• Chlorthalidone was superior to lisinopril in preventing aggregate CV events, principally stroke, HF, angina, and coronary revascularization

• Chlorthalidone was superior to doxazosin (representing alpha-blockers) in preventing CV events, including both HF and other CVD.

ALLHAT

40

Other Conclusions

• Given the large sample size, almost all biochemical differences between treatment groups at 4 years were statistically significant.

• Total cholesterol 1-2 mg/dL higher in chlorthalidone compared to amlodipine and lisinopril.

• Serum potassium 0.3-0.4 mmol/L lower in chlorthalidone compared to amlodipine and lisinopril.

– Potassium <3.5 mmol/L 6-8% higher among those randomized to chlorthalidone

• Fasting glucose 3 mg/dL higher in chlorthalidone than amlodipine group, 5 mg/dL higher in chlorthalidone than lisinopril group.

ALLHAT

41

Other Conclusions

• Among nondiabetic participants, incidence of fasting glucose 126 mg/dL at 4 years was 1.8% higher in chlorthalidone vs amlodipine, and 3.5% higher in chlorthalidone vs lisinopril.

• Estimated GFR decreased by 7-8 units at 4 years in chlorthalidone and lisinopril arms, but decreased only by about 3 units in the amlodipine arm.

• Overall, metabolic differences did not translate into more adverse cardiovascular events, or into higher all-cause mortality, with chlorthalidone.

ALLHAT

42

Further Conclusions: Amlodipine versus

Chlorthalidone

Drug tolerance and blood pressure control were similar (and high):

• The percent of participants who remained on the assigned drug or another of the same class was essentially identical (80% of those attending the 5-year visit)

• Mean SBP averaged about 1 mm Hg higher, and mean DBP about 1 mm Hg lower, in the amlodipine group

• BP control averaged about 2% better in the chlorthalidone group, reaching 68% after 5 years

ALLHAT

43

Further Conclusions: Amlodipine versus Chlorthalidone

There were no differences for other secondary outcomes:

– Cardiovascular—stroke, angina, coronary revascularization, peripheral arterial disease

– End stage renal disease

– Cancer incidence and mortality

– Hospitalization for gastrointestinal bleeding (in a subset of the cohort)

– All-cause mortality

ALLHAT

44

Further Conclusions: Amlodipine versus Chlorthalidone

Results for all cited outcomes were consistent for major (pre-specified) subgroups:

– Men and women

– Black and nonblack participants

– Older and younger participants (<65 and 65+)

– Diabetic and non-diabetic participants

ALLHAT

45

Further Conclusions: Lisinopril versus Chlorthalidone

Drug tolerance and blood pressure control were better with chlorthalidone, especially for black patients:

• The percent of participants remaining on lisinopril or another ACEI averaged about 5-6% less than participants assigned to the diuretic

• About 6-8% more of the participants in the lisinopril group than those in the chlorthalidone group required additional antihypertensive drugs

ALLHAT

46

Further Conclusions: Lisinopril versus Chlorthalidone

• Mean SBP averaged about 2 mm Hg higher in the lisinopril than the chlorthalidone group (4 mm Hg for blacks); mean DBPs were equivalent

• BP control averaged about 4-7% better in the chlorthalidone group

• Of patients in the lisinopril group who remained on an ACEI, 19% were also on a diuretic at 5 years

ALLHAT

47

Further Conclusions: Lisinopril versus Chlorthalidone

There were no differences for other secondary outcomes

– peripheral arterial disease

– end stage renal disease

– cancer incidence and mortality

– all-cause mortality

ALLHAT

48

Further Conclusions: Lisinopril versus Chlorthalidone

• Results were consistent for all outcomes by age, gender, race, and diabetic status, except for stroke and CVD, where there was significant heterogeneity by race (p=.01 and p=.04, respectively)

– Among black participants assigned to lisinopril, the stroke rate was increased 40% compared to the chlorthalidone group. (No difference among non-black participants.)

– The combined CVD rate was increased 19% in blacks and by 6% in whites.

• Angiodema, a rare adverse effect, was more frequent with lisinopril, especially in blacks

ALLHAT

49

Antihypertensive Trial:Implications

• Diuretics should be the drug of choice for first step therapy of hypertension

• For the patient who cannot take a diuretic (which should be an unusual circumstance), CCB’s and ACEI’s may be considered.

• Most hypertensive patients require more than one drug. Diuretics should generally be part of the antihypertensive regimen. Lifestyle advice should also be provided.

ALLHAT

50

Angioedema

Total BlacksNon-

blacks

Chlorthalidone 8 / 15,255

0.1%

2 / 5,369

<0.1%

6 / 9,886

0.1%

Lisinopril 38 / 9,054

0.4%

23 / 3,210

0.7%

15 / 5,844

0.3%p<.001 p<.001 p=.002

There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to chlorthalidone not significant).

ALLHAT