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)

doi:10.1001/JAMA.288.23.2981

JAMA-EXPRESSORIGINAL CONTRIBUTION

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 Officers and

Coordinators for the ALLHAT

Collaborative Research Group

T

REATMENT AND COMPLICA-

tions among the 50 to 60 mil-

lion people in the United States

with hypertension are esti-

mated to cost $37 billion annually, with

antihypertensive drug costs alone ac-

counting for an estimated $15.5 bil-

lion per year.

1

Antihypertensive drug

therapy substantially reduces the risk

of hypertension-related morbidity and

mortality.

2-6

However, the optimal

choice for initial pharmacotherapy of

hypertension is uncertain.

7

Earlier clinical trials documented the

benefit of lowering blood pressure (BP)

using primarily thiazide diuretics or

␤-blockers.

2,3,8

After these studies, sev-

eral newer classes of antihypertensive

agents (ie, angiotensin-converting en-

zyme [ACE] inhibitors, calcium chan-

nel blockers [CCBs], ␣-adrenergic

blockers, and more recently angioten-

sin-receptor blockers) became avail-

able. Over the past decade, major pla-

cebo-controlled trials have documented

that ACE inhibitors and CCBs reduce

cardiovascular events in individuals

with hypertension.

9-11

However, their

relative value compared with older, less

expensive agents remains unclear.

There has been considerable uncer-

tainty regarding effects of some classes

of antihypertensive drugs on risk of

Author Affiliations: ALLHAT Authors, Their Finan-

cial Disclosures, and Group Members are listed at the

end of this article.

Corresponding Authors and Reprints: Jackson T.

Wright, Jr, MD, PhD, Case Western Reserve Univer-

sity, General Clinical Research Center, Suite 7311,

Horvitz Tower, 11000 Euclid Ave, Cleveland, OH

44106-5041 (e-mail: jxw20@po.cwru.edu); Barry R.

Davis, MD, PhD, University of Texas-Houston Health

Science Center, School of Public Health, 1200 Her-

man Pressler St, Suite E801, Houston, TX 77030

(e-mail: bdavis@sph.uth.tmc.edu).

Context Antihypertensive therapy is well established to reduce hypertension-

related morbidity and mortality, but the optimal first-step therapy is unknown.

Objective To determine whether treatment with a calcium channel blocker or an

angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart dis-

ease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic.

Design The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart At-

tack Trial (ALLHAT), a randomized, double-blind, active-controlled clinical trial con-

ducted from February 1994 through March 2002.

Setting and Participants A total of 33357 participants aged 55 years or older with

hypertension and at least 1 other CHD risk factor from 623 North American centers.

Interventions Participants were randomly assigned to receive chlorthalidone, 12.5

to 25 mg/d (n=15255); amlodipine, 2.5 to 10 mg/d (n=9048); or lisinopril, 10 to 40

mg/d (n=9054) for planned follow-up of approximately 4 to 8 years.

Main Outcome Measures The primary outcome was combined fatal CHD or non-

fatal myocardial infarction, analyzed by intent-to-treat. Secondary outcomes were all-

cause mortality, stroke, combined CHD (primary outcome, coronary revascularization,

or angina with hospitalization), and combined CVD (combined CHD, stroke, treated an-

gina without hospitalization, heart failure [HF], and peripheral arterial disease).

Results Mean follow-up was 4.9 years. The primary outcome occurred in 2956 par-

ticipants, with no difference between treatments. Compared with chlorthalidone (6-

year rate, 11.5%), the relative risks (RRs) were 0.98 (95% CI, 0.90-1.07) for amlo-

dipine (6-year rate, 11.3%) and 0.99 (95% CI, 0.91-1.08) for lisinopril (6-year rate,

11.4%). Likewise, all-cause mortality did not differ between groups. Five-year sys-

tolic blood pressures were significantly higher in the amlodipine (0.8 mm Hg, P=.03)

and lisinopril (2 mm Hg, P⬍.001) groups compared with chlorthalidone, and 5-year

diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, P⬍.001).

For amlodipine vs chlorthalidone, secondary outcomes were similar except for a higher

6-year rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52).

For lisinopril vs chlorthalidone, lisinopril had higher 6-year rates of combined CVD (33.3%

vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% CI,

1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31).

Conclusion Thiazide-type diuretics are superior in preventing 1 or more major forms

of CVD and are less expensive. They should be preferred for first-step antihyperten-

sive therapy.

JAMA. 2002;288:2981-2997 www.jama.com

See also pp 2998 and 3039.

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coronary heart disease (CHD).

6,12-16

The

relative benefit of various agents in

high-risk hypertensive subgroups such

as older patients, black patients, and pa-

tients with diabetes also needed to be

established.

17

The Antihypertensive and Lipid-

Lowering Treatment to Prevent Heart

Attack Trial (ALLHAT), a random-

ized, double-blind, multicenter clini-

cal trial sponsored by the National

Heart, Lung, and Blood Institute, was

designed to determine whether the oc-

currence of fatal CHD or nonfatal myo-

cardial infarction is lower for high-

risk patients with hypertension treated

with a CCB (represented by amlo-

dipine), an ACE inhibitor (repre-

sented by lisinopril), or an ␣-blocker

(represented by doxazosin), each com-

pared with diuretic treatment (repre-

sented by chlorthalidone).

18

Chlortha-

lidone was found to be superior to

doxazosin and was previously re-

ported after early termination of the

doxazosin arm of the trial.

19,20

Second-

ary outcomes included all-cause mor-

tality, stroke, and other cardiovascu-

lar disease (CVD) events. A lipid-

lowering subtrial was designed to

determine whether lowering choles-

terol with 3-hydroxy-3-methylglu-

taryl coenzyme A reductase inhibitor

(pravastatin) compared with usual care

reduced all-cause mortality in a mod-

erately hypercholesterolemic subset of

ALLHAT participants.

18,21

To evaluate

differences in CVD effects of the vari-

ous first-step drugs, ALLHAT was de-

signed with a large sample size (9000-

15000 participants/intervention arm)

and long follow-up (4-8 years). This

study presents results of the amlo-

dipine and lisinopril vs chlorthali-

done comparisons on major CVD out-

comes.

METHODS

Study Design

The rationale and design of ALLHAT

have been presented elsewhere.

18

Par-

ticipants were men and women aged 55

years or older who had stage 1 or stage

2 hypertension with at least 1 addi-

tional risk factor for CHD events.

18,22

The risk factors included previous (⬎6

months) myocardial infarction or

stroke, left ventricular hypertrophy

demonstrated by electrocardiography

or echocardiography, history of type 2

diabetes, current cigarette smoking,

high-density lipoprotein cholesterol of

less than 35 mg/dL (⬍0.91 mmol/L),

or documentation of other atheroscle-

rotic CVD. Individuals with a history

of hospitalized or treated symptom-

atic heart failure (HF) and/or known left

ventricular ejection fraction of less than

35% were excluded.

Unless the drug regimen had to be

tapered for safety reasons, individuals

continued any prior antihypertensive

medications until they received ran-

domized study drug, at which point

they stopped taking all previous medi-

cations. Treatment with the study drug

was initiated the day after randomiza-

tion. By telephone, participants were

randomly assigned to chlorthalidone,

amlodipine, or lisinopril in a ratio of 1.7:

1:1. The concealed randomization

scheme was generated by computer,

implemented at the clinical trials cen-

ter, stratified by center and blocked in

random block sizes of 5 or 9 to main-

tain balance. Participants (n=33357)

were recruited at 623 centers in the

United States, Canada, Puerto Rico, and

the US Virgin Islands between Febru-

ary 1994 and January 1998. (The origi-

nal reported number of 625 sites

changed because 2 sites and their pa-

tients with poor documentation of in-

formed consent were excluded.

20

) All

participants gave written informed con-

sent, and all centers obtained institu-

tional review board approval. Fol-

low-up visits were at 1 month; 3, 6, 9,

and 12 months; and every 4 months

thereafter. The range of possible fol-

low-up was 3 years 8 months to 8 years

1 month. The closeout phase began on

October 1, 2001, and ended on March

31, 2002.

Treatment

Trained observers using standardized

techniques measured BPs during the

trial.

20

Visit BP was the average of 2

seated measurements. Goal BP in each

randomized group was less than 140/90

mm Hg achieved by titrating the as-

signed study drug (step 1) and adding

open-label agents (step 2 or 3) when nec-

essary. The choice of step 2 drugs (aten-

olol, clonidine, or reserpine) was at the

physician’s discretion. Nonpharmaco-

logic approaches to treatment of hyper-

tension were recommended according

to national guidelines.

4,23

Step 1 drugs

were encapsulated and identical in ap-

pearance so that the identity of each

agent was double-masked at each dos-

age level. Dosages were 12.5, 12.5 (sham

titration), and 25 mg/d for chlorthali-

done; 2.5, 5, and 10 mg/d for amlo-

dipine; and 10, 20, and 40 mg/d for li-

sinopril. Doses of study-supplied open-

label step 2 drugs were 25 to 100 mg/d

of atenolol; 0.05 to 0.2 mg/d of reser-

pine; or 0.1 to 0.3 mg twice a day of

clonidine; step 3 was 25 to 100 mg twice

a day of hydralazine. Other drugs, in-

cluding low doses of open-label step 1

drug classes, were permitted if clini-

cally indicated.

18,20

Outcomes

The primary outcome was fatal CHD or

nonfatal myocardial infarction com-

bined.

18

Four major prespecified sec-

ondary outcomes were all-cause

mortality, fatal and nonfatal stroke,

combined CHD (the primary out-

come, coronary revascularization, hos-

pitalized angina), and combined CVD

(combined CHD, stroke, other treated

angina, HF [fatal, hospitalized, or

treated nonhospitalized], and periph-

eral arterial disease). Coronary revas-

cularization included coronary artery

bypass graft, percutaneous angio-

plasty, insertion of stents, and ather-

ectomy. Individual components of the

combined outcomes were prespeci-

fied and examined, as were other sec-

ondary outcomes including cancer,

incident electrocardiographic left ven-

tricular hypertrophy, end-stage renal

disease (ESRD) (dialysis, renal trans-

plant, or death), and slope of the

reciprocal of longitudinal serum cre-

atinine measurements. Change in es-

timated glomerular filtration rate

24,25

was examined post hoc.

ANTIHYPERTENSIVE TREATMENT IN ALLHAT

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Study outcomes were assessed at fol-

low-up visits and reported to the clini-

cal trials center.

18

Hospitalized out-

comes were primarily based on clinic

investigator reports, and copies of death

certificates and hospital discharge sum-

maries were requested. Among all com-

bined CVD events that resulted in

deaths, hospitalizations, or both, the

proportion with documentation (ie, a

death certificate or a hospital dis-

charge summary) was 99% in all 3 treat-

ment groups. In addition, searches for

outcomes were accomplished through

the Center for Medicare and Medicaid

Services, the Department of Veterans

Affairs, the National Death Index, and

the Social Security Administration da-

tabases. A death was ascertained by

clinic report or by match with the afore-

mentioned databases plus a confirma-

tory death certificate. A death pend-

ing confirmation is one found using

databases but for which a confirma-

tory death certificate has not yet been

obtained. Medical reviewers from the

clinical trials center verified the phy-

sician-assigned diagnoses of out-

comes using death certificates and hos-

pital discharge summaries. More

detailed information was collected on

a random (10%) subset of CHD and

stroke events to validate the proce-

dure of using physician diagnoses.

18

When a large excess of HF became evi-

dent in the doxazosin arm, a 1-time

sample of HF hospitalizations was re-

viewed by the ALLHAT Endpoints Sub-

committee. Agreement rates between

the subcommittee and clinic investiga-

tors were 90% (155/172) for the pri-

mary outcome, 85% (33/39) for HF hos-

pitalizations,

26

and 84% (129/153) for

stroke, and were similar in all treat-

ment groups.

Two major safety outcomes, angio-

edema and hospitalization for gastro-

intestinal bleeding, were prespecified.

Occurrence of gastrointestinal bleed-

ing was ascertained from Center for

Medicare and Medicaid Services and

Department of Veterans Affairs hospi-

talization databases, representing 74%

of ALLHAT participants (persons ⱖ65

years, Department of Veterans Affairs

participants, or both).

27

Angioedema

was ascertained using a solicited event

question on a serious adverse event

form.

Statistical Methods

To maximize statistical power, 1.7 times

as many participants were assigned to

the diuretic group as to each of the other

3 groups.

18

Given the achieved sample

size and expected event rate, treat-

ment crossovers, and losses to follow-

up, ALLHAT had 83% power to detect

a 16% reduction in risk of the primary

outcome between chlorthalidone and

each other group at a 2-sided ␣ =.0178

(z = 2.37) to account for the 3 original

comparisons.

28

Data were analyzed

according to participants’ randomized

treatment assignments regardless of

their subsequent medications (intent-

to-treat analysis). Cumulative event

rates were calculated using the Kaplan-

Meier method. Although rates are pre-

sented only through 6 years, both the

log-rank test and Cox proportional haz-

ards regression model incorporated the

participant’s entire trial experience to

evaluate differences between cumula-

tive event curves and to obtain 2-sided

P values. Only the Cox proportional

hazard regression results are pre-

sented, because P values were essen-

tially identical. Hazard ratios (relative

risks [RRs]) and 95% confidence inter-

vals (CIs) were obtained from the Cox

proportional hazards regression

model.

29

For consistency with ␣=.0178,

95% CIs may be converted to 98.2% lim-

its by multiplying the upper limit and

dividing the lower limit by RR

(0.41/Z)

,

where Z is the value of the test statistic

for the RR estimate. The Cox propor-

tional hazards regression model

assumption was examined by using log-

log plots and testing a treatment ⫻ time

(time-dependent) interaction term; if it

was violated, the RR estimate from a

2-by-2 table was used.

29

Heterogeneity

of effects in prespecified subgroups, (1)

men and women, (2) participants less

than 65 and 65 years or older, (3) black

and nonblack participants, and (4) dia-

betic and nondiabetic participants, and

the post hoc subgroups presence or

absence of CHD at baseline, was exam-

ined by testing for treatment-covariate

interaction with the Cox proportional

hazards regression model by using

P⬍.05. SAS version 8.0 (SAS Institute,

Cary, NC) and STATA version 7 (Stata

Corp, College Station, Tex) were used

for statistical analyses.

A National Heart, Lung, and Blood

Institute–appointed data and safety

monitoring board met at least annu-

ally to review the accumulating data and

to monitor for safety and efficacy. The

Lan-DeMets version of the O’Brien-

Fleming group sequential boundaries

was used to assess treatment group dif-

ferences, and conditional power was

used to assess futility.

30,31

RESULTS

Patient Characteristics

TABLE 1 presents baseline characteris-

tics for the 33357 participants in the

chlorthalidone, amlodipine, and lisin-

opril treatment groups. The mean age

was 67 years; 47% were women, 35%

were black, 19% were Hispanic, and

36% were diabetic. There were nearly

identical distributions of baseline fac-

tors in the 3 treatment groups.

22

Visit and Medication Adherence

FIGURE 1 shows the number of partici-

pants randomized and followed up to the

time of closeout. In all 3 treatment

groups, the mean (SD) length of fol-

low-up was 4.9 years (1.4 years), and

99% of expected person-years were ob-

served. The maximum range of fol-

low-up was 8.0, 7.9, and 8.1 years in the

chlorthalidone, amlodipine, and lisin-

opril groups, respectively. At trial close-

out, 419 (2.7%) of the chlorthalidone

group, 258 (2.8%) of the amlodipine

group, and 276 (3.0%) of the lisinopril

group had unknown vital status. Among

participants with unknown vital sta-

tus, the distributions of most baseline

factors were similar among the 3 treat-

ment groups, but participants assigned

to lisinopril were less likely to be black

and more likely to be women, have un-

treated hypertension, evidence of CHD

or atherosclerotic CVD, and a lower

mean serum glucose.

ANTIHYPERTENSIVE TREATMENT IN ALLHAT

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Visit adherence decreased over time

from about 92% at 1 year to 84% to 87%

at 5 years in all 3 treatment groups

(T

ABLE 2). Among participants in the

chlorthalidone group who were con-

tacted in the clinic or by telephone

within 12 months of annual sched-

uled visits, 87.1% were taking chlortha-

lidone or another diuretic at 1 year, de-

creasing to 80.5% at 5 years; 67.5%

(n= 4387) were taking a diuretic with-

out a CCB or an ACE inhibitor; and

13.2% were taking a diuretic with a CCB

(5.8% [n=399]) or an ACE inhibitor

(9.3% [n= 641]). Only 9.0% were tak-

ing either a CCB (5.8% [n=399]) or an

ACE inhibitor (5.6% [n=385]) with-

out a diuretic at 5 years.

Among participants in the amlo-

dipine group, 87.6% were taking amlo-

dipine or another CCB at 1 year, decreas-

ing to 80.4% at 5 years; and 63.8%

(n= 2502) were taking a CCB alone with-

out a diuretic. Another 16.6% were tak-

ing a CCB with a diuretic, and only 6.9%

were taking a diuretic without a CCB.

Among participants in the lisinopril

group, 82.4% were taking lisinopril or

another ACE inhibitor at 1 year, decreas-

ing to 72.6% at 5 years; 56.9% (n=2143)

were taking an ACE inhibitor alone with-

out a diuretic; and 15.7% were taking an

ACE inhibitor with a diuretic at 5 years.

About 8.5% were taking a diuretic with-

out an ACE inhibitor.

The most common reasons for not

taking step 1 medication at 5 years in the

chlorthalidone, amlodipine, and lisin-

opril groups were unspecified refusals

(41.4% [n=775], 40.5% [n=443], and

37.9% [n=552], respectively) and symp-

tomatic adverse effects (15.0% [n =282],

16.4% [n=180], and 18.1% [n=264],

respectively). Elevated BP (4.5% [n=84],

3.5% [n=38], and 9.0% [n=131]) or

other adverse effects such as abnormal

laboratory values (3.8% [n=71], 1.6%

[n= 17], and 2.3% [n=34]) were other

reasons given for discontinuation of step

1 medications. Among participants with

available medication information at 1

year, 26.7%, 25.9%, and 32.6% of those

assigned to chlorthalidone, amlo-

dipine, and lisinopril, respectively, were

taking a step 2 or step 3 drug. At 5 years,

the corresponding percentages were

40.7%, 39.5%, and 43.0%, respec-

tively. Usage patterns of specific step 2

drugs were similar among groups.

Participants could be taking more than

1 step-up drug. At 1 year, 40.0%

(n= 4645), 44.0% (n=3017), and 43.8%

(n= 2764) of participants assigned to

chlorthalidone, amlodipine, and lisin-

opril, respectively, still taking their

Table 1. Baseline Characteristics of the ALLHAT Participants

*

Characteristic

No. of Participants (%)

Chlorthalidone

(n = 15 255)

Amlodipine

(n = 9048)

Lisinopril

(n = 9054)

Age, mean (SD), y 66.9 (7.7) 66.9 (7.7) 66.9 (7.7)

Age range, y

55-64 6471 (42.4) 3844 (42.5) 3869 (42.7)

ⱖ65 8784 (57.6) 5204 (57.5) 5185 (57.3)

Ethnicity

White, non-Hispanic 7202 (47.2) 4305 (47.6) 4262 (47.1)

Black, non-Hispanic 4871 (31.9) 2911 (32.2) 2920 (32.3)

White Hispanic 1912 (12.5) 1108 (12.2) 1136 (12.5)

Black Hispanic 498 (3.3) 302 (3.3) 290 (3.2)

Other 772 (5.1) 422 (4.7) 446 (4.9)

Women 7171 (47.0) 4280 (47.3) 4187 (46.2)

Education, mean (SD), y 11.0 (4.0) 11.0 (3.9) 11.0 (4.1)

Receiving antihypertensive

treatment

13 754 (90.2) 8171 (90.3) 8164 (90.2)

Blood pressure, mean (SD), mm Hg 146 (16)/84 (10) 146 (16)/84 (10) 146 (16)/84 (10)

Treated at baseline 145 (16)/83 (10) 145 (16)/83 (10) 145 (16)/84 (10)

Untreated at baseline 156 (12)/89 (9) 157 (12)/90 (9) 156 (12)/89 (9)

Eligibility risk factors†

Cigarette smoker 3342 (21.9) 1980 (21.9) 1981 (21.9)

Atherosclerotic CVD‡ 7900 (51.8) 4614 (51.0) 4684 (51.7)

History of MI or stroke 3581 (23.5) 2098 (23.2) 2058 (22.7)

History of coronary

revascularization

1986 (13.0) 1106 (12.2) 1218 (13.5)

Other atherosclerotic CVD 3604 (23.6) 2145 (23.7) 2152 (23.8)

Major ST depression or

T-wave inversion

1572 (10.4) 908 (10.1) 940 (10.5)

Type 2 diabetes 5528 (36.2) 3323 (36.7) 3212 (35.5)

HDL-C ⬍35 mg/dL 1798 (11.8) 1018 (11.3) 1061 (11.7)

LVH by electrocardiogram 2467 (16.2) 1533 (16.9) 1474 (16.3)

LVH by echocardiogram 695 (4.6) 411 (4.6) 402 (4.5)

History of CHD at baseline§ 3943 (26.0) 2202 (24.5) 2270 (25.3)

Body mass index, mean (SD) 29.7 (6.2) 29.8 (6.3) 29.8 (6.2)

Current medication use

Aspirin 5426 (35.6) 3268 (36.1) 3258 (36.0)

Estrogen supplementation

(women only)

1273 (17.8) 752 (17.6) 727 (17.4)

Lipid trial participants 3755 (24.6) 2240 (24.8) 2167 (23.9)

*

ALLHAT indicates Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CVD, cardiovascular

disease; MI, myocardial infarction; HDL-C, high-density lipoprotein cholesterol; LVH, left ventricular hypertrophy; and

CHD, coronary heart disease. Body mass index was calculated as weight in kilograms divided by the square of height

in meters. To convert HDL-C to mmol/L, multiply by 0.0259.

†For trial eligibility, participants had to have at least 1 other risk factor in addition to hypertension. Thus, the indicated

risk factors are not mutually exclusive or exhaustive and may not represent prevalence.

‡History of MI or stroke, history of coronary revascularization, major ST segment depression or T-wave inversion on

any electrocardiogram in the past 2 years, other atherosclerotic CVD (history of angina pectoris; history of intermit-

tent claudication, gangrene, or ischemic ulcers; history of transient ischemic attack; coronary, peripheral vascular, or

carotid stenosis ⱖ50% documented by angiography or Doppler studies; ischemic heart disease documented by

reversible or fixed ischemia on stress thalium or dipyridamole thalium, ST depression ⱖ1mmforⱖ1 minute on ex-

ercise testing or Holter monitoring; reversible wall motion abnormality on stress echocardiogram; ankle-arm index

⬍0.9; abdominal aortic aneurysm detected by ultrasonography, computed tomography scan, or radiograph; carotid

or femoral bruits).

§P = .03 for comparison of groups.

ANTIHYPERTENSIVE TREATMENT IN ALLHAT

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blinded medication were receiving the

maximal study dose. At 5 years, the per-

centages were 56.9% (n=2629), 65.7%

(n= 1856), and 60.3% (n=1391), re-

spectively.

Intermediate Outcomes

Given the large sample size in ALLHAT,

almost all differences in follow-up BP

and biochemical measurements were

statistically significant (T

ABLE 3 and

T

ABLE 4). Mean seated BP at random-

ization was about 146/84 mm Hg in all

3 groups, with 90% of participants re-

porting current antihypertensive drug

treatment (Table 1). Follow-up BPs in

all 3 groups are shown in Table 3 and

F

IGURE 2.

Mean total serum cholesterol levels

at baseline and 4 years follow-up are

shown in Table 4. At 4 years, about 35%

to 36% of participants in all 3 groups

reported taking lipid-lowering drugs,

largely statins, some as a result of par-

ticipation in the ALLHAT lipid trial.

Mean serum potassium levels at base-

line and follow-up are also shown;

about 8% of the chlorthalidone group

were receiving potassium supplemen-

tation at 5 years compared with 4% in

the amlodipine group and 2% in the li-

sinopril group. Among individuals clas-

sified as nondiabetic at baseline, with

baseline fasting serum glucose less than

126 mg/dL (7.0 mmol/L), incidence of

diabetes (fasting serum glucose, ⱖ126

mg/dL [7.0 mmol/L]) at 4 years was

11.6%, 9.8%, and 8.1%, respectively.

Mean estimated glomerular filtra-

tion rate at baseline was about 78 mL /

min per 1.73 m

2

in all groups. At 4

years, it was 70.0, 75.1, and 70.7 mL/

min per 1.73 m

2

in the chlorthali-

done, amlodipine, and lisinopril groups,

respectively. The slopes of the recip-

rocal of serum creatinine over time were

virtually identical in the chlorthali-

done and lisinopril groups (–0.018 and

–0.019 dL/mg per year), whereas the

decline in the amlodipine slope (–0.012

dL/mg per year) was less than that of

the chlorthalidone slope (P⬍.001).

Primary and Secondary Outcomes

Amlodipine vs Chlorthalidone. No sig-

nificant difference was observed be-

tween amlodipine and chlorthalidone

for the primary outcome (RR, 0.98; 95%

CI, 0.90-1.07) or for the secondary out-

comes of all-cause mortality, com-

bined CHD, stroke, combined CVD,

angina, coronary revascularization,

peripheral arterial disease, cancer,

or ESRD (T

ABLE 5, FIGURE 3, and

F

IGURE 4). The amlodipine group had

a 38% higher risk of HF (P⬍.001) with

Figure 1. Randomization and Follow-up of Participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

7479 Known Alive

1256 Confirmed Dead

55 Deaths Pending Confirmation

200 Lost to Follow-up

58 Refused Follow-up

Status at Study Closeout

7412 Known Alive

1314 Confirmed Dead

52 Deaths Pending Confirmation

218 Lost to Follow-up

58 Refused Follow-up

Status at Study Closeout

769 Confirmed Dead

361 Vital Status Unknown

Status as of February 15, 2000

12

530 Known Alive

2203 Confirmed Dead

103 Deaths Pending Confirmation

339 Lost to Follow-up

80 Refused Follow-up

Status at Study Closeout

Year 1

13

854 Completed Visit

2235 Discontinued Study Drug

6210 Completed Visit

1873 Discontinued Study Drug

775 Unspecified Refusal

282 Symptomatic Adverse Event

84 Blood Pressure Elevation

91 Blood Pressure Too Low

73 Morbid Event

71 Other Adverse Effects

125 Other Nonmedical Reasons

638 Other

Year 5

Year 1

8215 Completed Visit

1357 Discontinued Study Drug

3769 Completed Visit

1052 Discontinued Study Drug

443 Unspecified Refusal

180 Symptomatic Adverse Event

38 Blood Pressure Elevation

51 Blood Pressure Too Low

45 Morbid Event

17 Other Adverse Effects

83 Other Nonmedical Reasons

387 Other

Year 5

Year 1

8158 Completed Visit

1842 Discontinued Study Drug

3605 Completed Visit

1399 Discontinued Study Drug

552 Unspecified Refusal

264 Symptomatic Adverse Event

131 Blood Pressure Elevation

76 Blood Pressure Too Low

49 Morbid Event

34 Other Adverse Effects

94 Other Nonmedical Reasons

484 Other

Year 5

Year 1

7217 Completed Visit

1402 Discontinued Study Drug

Year 5

NA

42

418 Patients Randomized

15

255 Assigned to Receive

Chlorthalidone

9048 Assigned to Receive

Amlodipine

9054 Assigned to Receive

Lisinopril

9061 Assigned to Receive

Doxazosin

15

255 Included in Analysis 9048 Included in Analysis 9054 Included in Analysis

NA indicates not applicable. Eligibility data were not collected for nonrandomized screenees. All randomized participants were included in the analyses. A patient may

have more than 1 reason for discontinuing study drug; therefore, numbers do not sum to total. On January 24, 2000, the National Heart, Lung, and Blood Institute

decided to discontinue the doxazosin group and report results.

18

Study closeout for chlorthalidone, amlodipine, and lisinopril groups was from October 1, 2001, through

March 31, 2002. Collection of last events for the doxazosin group had a closeout interval from October 15, 1999, through February 15, 2000, which captures more

information than that reported previously.

24

ANTIHYPERTENSIVE TREATMENT IN ALLHAT

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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)

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