U.S. Department of Health and Human

Services

National Institutes of Health

National Heart, Lung, and Blood Institute

ALLHAT

Major Outcomes in Moderately

Hypercholesterolemic,Hypertensive Patients

Randomized toPravastatin vs Usual Care*

The ALLHAT Collaborative Research Group

Sponsored by the National Heart, Lung, andBIood Institute (NHLBI)

*JAMA, December 18, 2002 – Vol. 288, No. 23, pp 2998 - 3007

Primary ObjectiveALLHAT - LLT

ALLHAT

To determine whether pravastatin* compared with usual care

reduces all-cause mortality inmoderately hypercholesterolemic,

hypertensive, older participants

with at least one additional CHD risk factor.

*40 mg/d

Randomized DesignHigh-risk hypertensive patients

Consent / Randomize(N = 42,418)

Amlodipine

Chlorthalidone

Doxazosin

Lisinopril

Eligible for lipid-lowering

Not eligible for lipid-lowering

Consent / Randomize (N = 10,355)

Pravastatin Usual care

Follow until death or end of study (max 7.8 yr, average 4.8 yr).

ALLHAT

Secondary Outcomes

•CHD•Cause-specific mortality•Total and site-specific cancers

ALLHAT

Major Subgroups (a priori)

ALLHAT

• Age 65+

• Women

• African-Americans

• Type 2 Diabetes

Major Subgroups(post hoc)

• CHD at Baseline

• No CHD and

LDL-C ≥ 130 mg/dL

• No CHD and

LDL-C < 130 mg/dL

ALLHAT

Eligibility Criteria

ALLHAT

Eligible for and enrolled inantihypertensive trial

Triglyceride level<350 mg/dL

Eligibility CriteriaALLHAT

Moderate hypercholesterolemia

• LDL 120-189 mg/dLwithout CHD

• LDL 100-129 mg/dL with known CHD

Exclusion Criteria

• Continuing use of prescribed lipid-lowering agents

• Contraindications to statins

• Secondary cause of elevated serum cholesterol

• ALT > 2 times ULN

ALLHAT

Clinical Sites in LLT

• 513 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

Sample Size Assumptions & Statistical Methods

• 84% power to detect 20% reduction in risk for primary outcome

• 2-sided α = 0.05• 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

Vital Statusat Closeout

8776 (84.8%) known alive

1272 (12.3%) confirmed deaths

55 ( 0.5%) confirmation of death pending

206 ( 2.0%) lost

46 ( 0.4%) refused

ALLHAT

Observed/expected person-years: 99%

Pravastatin and usual care groups similar with respect to vital status at closeout.

Pravastatin

(5170)

Usual Care

(5185)

Mean BL* LDL, mg/dL

Mean BL TC, mg/dL

146

224

146

224

Mean age, years

Black, %

Women, %

66 66

39 37

49 49

History of CHD, %

Type 2 diabetes, %

Current smoking, %

13 15

36 34

23 23

Baseline Characteristics

*BL = baseline

0.0

20.0

40.0

60.0

80.0

100.0

%

Pravastatin, N*Usual Care, N

2 Years 4 Years 6 Years

88% 84% 83%

* N gives the total number of participants at the visit.

8% 17%26%

Percent on StatinALLHAT

82429964295

84830634353

Pravastatin Mean (N)

Usual Care Mean (N)

Mean BL* LDL, mg/dL 146 (5129) 146 (5131)

Mean LDL at 4 yrs, mg/dL 104 ( 572) 129 ( 330)

% decrease LDL BL to 4 yrs 28 ( 567) 11 ( 326)

Mean BL TC, mg/dL 224 (5134) 224 (5139)

Mean TC at 4 yrs, mg/dL 184 (2998) 206 (2781)

% decrease TC BL to 4 yrs 17 (2977) 8 (2756)

Mean BL HDL, mg/dL 48 (5134) 47 (5137)

Mean HDL at 4 yrs, mg/dL 49 ( 593) 46 ( 348)

% increase HDL BL to 4yrs 3 ( 589) 2 ( 344)

Lipid ResultsALLHAT

*BL = baseline

Total Cholesterol T

ota

l C

ho

lest

ero

l in

mg

/dL

Year of Blood Draw

0 2 4 6

170

180

190

200

210

220

230

Pravastatin

Usual Care4% *

8%

11%

15%

17%

20%

* Percent decrease from baseline.

No. of Participants

854278137635139Usual Care

912299841025134Pravastatin

LDL-CL

DL

-C in

mg

/dL

0 2 4 6

100

110

120

130

140

150

Usual Care

Pravastatin

7% *

11%

16%

23%

28% 30%

Year of Blood Draw

* Percent decrease from baseline.

No. of Participants

Pravastatin 5129 850 572 157

Usual Care 5131 508 330 75

ALLHAT

Cause-Specific MortalityNumber of Deaths

(6-Year Rate per 100 Participants)

Cause of Death

Pravastatin

N = 5170

Usual Care

N = 5185

All-cause 631 (14.9) 641 (15.3)

CVD 295 (6.9) 300 (7.1)

Non-CVD 302 (7.7) 302 (7.8)

Cause unknown 34 (1.0) 39 (1.1)

Cu

mu

lati

ve M

ort

alit

y R

ate

, %

RR = 0.9995% CI = (0.89, 1.11) p = 0.88

Pravastatin/Usual Care

Time to Death, years0 1 2 3 4 5 6

0

3

6

9

12

15

Usual Care

Pravastatin

All-Cause Mortality

No. at Risk

Pravastatin 5170 5088 4956 4809 3819 2173 1132

Usual Care 5185 5104 4994 4845 3832 2179 1138

All-Cause MortalityPravastatin/Usual Care

Relative Risk and 95% Confidence Intervals

Favors Pravastatin Favors Usual Care0.50 1 2

ALLHAT

0.96 (0.84, 1.11)No Diabetes

1.03 (0.86, 1.22)Type 2 Diabetes

0.98 (0.85, 1.13)Non-Black

1.01 (0.85, 1.19)Black

0.98 (0.83, 1.17)Women

0.99 (0.86, 1.14)Men

1.01 (0.89, 1.15)Age ≥ 65 y

0.93 (0.74, 1.16)Age 55-64 y

0.99 (0.89, 1.11)Total

ALLHAT All-Cause MortalityPravastatin/Usual Care

Relative Risk and 95% Confidence Intervals

No CHD & LDL-C < 130 mg/dL

No CHD & LDL-C ≥ 130 mg/dL

Favors Pravastatin Favors Usual Care

0.50 1 2

1.18 (0.90, 1.56)

0.96 (0.84, 1.11)

CHD at baseline 0.95 (0.74, 1.23)

CHD (Nonfatal MI + CHD Death) C

um

ula

tive

CH

D E

ven

t R

ate

, %

RR = 0.9195% CI = (0.79, 1.04) p = 0.16

Pravastatin/Usual Care

Time to CHD Event, years0 1 2 3 4 5 6

0

3

6

9

12

15

Usual Care

Pravastatin

988196035234558478249715185Usual Care

992196635464543476149625170Pravastatin

No. at Risk

0.91 (0.79, 1.04)Total

Relative Risk and 95% Confidence Intervals

Favors Pravastatin Favors Usual Care*There is a Black/Non-Black by Treatment interaction (p = 0.025).

0.50 1 2

CHD (Nonfatal MI + CHD Death)Pravastatin/Usual Care

0.92 (0.76, 1.10)No Diabetes

0.89 (0.71, 1.10)Type 2 Diabetes

1.02 (0.86, 1.21)Non-Black*

0.73 (0.58, 0.92)Black*

1.02 (0.81, 1.28)Women

0.84 (0.71, 1.00)Men

0.94 (0.80, 1.12)Age ≥ 65 y

0.83 (0.65, 1.06)Age 55-64 y

CHD (Nonfatal MI + CHD Death)Pravastatin/Usual Care

Relative Risk and 95% Confidence Intervals

Favors Pravastatin Favors Usual Care

0.50 1 2

CHD at baseline 1.03 (0.77, 1.38)

No CHD &LDL-C ≥ 130 mg/dL

0.92 (0.77, 1.09)

No CHD & LDL-C < 130 mg/dL

0.73 (0.49, 1.07)

ALLHAT Cancer Incidence

Site

Pravastatin

N = 5170

Usual Care

N = 5185

Total

Prostate

Lung

Colon

Breast

Other/Unknown

378*

86

63

46

34

162

369

79

78

38

37

140

*The numbers don’t add to the total because some participants have more than one type of cancer.

0.95 (0.75, 1.21)Lisinopril

1.06 (0.84, 1.35)Amlodipine

1.03 (0.86, 1.23)Chlorthalidone

0.91 (0.71, 1.16)Doxazosin

0.99 (0.89, 1.11)Total

All-Cause MortalityPravastatin/Usual Care

Relative Risk and 95% Confidence Intervals

Favors Pravastatin Favors Usual Care

0.50 1 2

ALLHAT

Meta-Analysis of Large Long-Term Statin Trials

and Impact of ALLHAT - LLT

Trial N %∆TC†Odds Ratio (95% CI)

Mortality CHD

8 Statin

Trials*54,381 20.2%

0.83

(0.78, 0.88)

0.70

(0.67, 0.74)

ALLHAT-LLT

10,355 9.6%0.99

(0.89, 1.11)

0.91

(0.79, 1.04)

Total64,736 18.5%

0.86

(0.82, 0.90)

0.73

(0.69, 0.77)

*4S, WOSCOPS, CARE, LIPID, AFCAPS/TexCAPS, Post-CABG, HPS, LIPS†Percent change in total cholesterol

Relation of total cholesterol (TC) differential in active treatment (TRT) versus control group (CTL) to log odds ratio for mortality.

-0.8

-0.6

-0.4

-0.2

-0

0.2

0.4

0.6

0 5 10 15 20 25 30

ALLHAT-LLT

HPS

Post-CABG AFCAPS

CARE

LIPID

WOSCOPS

LIPS

4S

% ΔTC (CTL-TRT)

lnO

R (

TR

T/C

TL

)Meta-Regression Analysis

All-Cause Mortality

Meta-Regression AnalysisCHD (Nonfatal MI + CHD Death)

Relation of total cholesterol (TC) differential in active treatment (TRT) versuscontrol group (CTL) to log odds ratio for CHD events.

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0 5 10 15 20 25 30

ALLHAT-LLT

HPS

Post-CABG

AFCAPS

CARELIPID

WOSCOPS

LIPS

4S

% ΔTC (CTL-TRT)

lnO

R (

TR

T/C

TL

)

ConclusionsALLHAT - LLT

ALLHAT

ALLHAT pravastatin and usual care groups both attained substantial cholesterol reductions, resulting in a relatively modest cholesterol difference between them.

Accordingly, ALLHAT found only a small decrease in CVD event rates (non-significant) for pravastatin compared with usual care and no difference in mortality.

ConclusionsALLHAT - LLT

ALLHAT

ConclusionsALLHAT - LLT

ALLHAT

The study results do not alter current cholesterol treatment guidelines, which are based on a series of clinical trials with larger cholesterol reductions than those observed in ALLHAT. Thus, cholesterol lowering by lifestyle changesand drug treatment is recommended toreduce CVD morbidity and mortality.