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. 2002;288(23):2981-2997 (doi:10.1001/jama.288.23.2981)JAMAResearch GroupThe ALLHAT Officers and Coordinators for the ALLHAT CollaborativePrevent Heart Attack Trial (ALLHAT)Antihypertensive and Lipid-Lowering Treatment toInhibitor or Calcium Channel Blocker vs Diuretic: TheRandomized to Angiotensin-Converting EnzymeMajor Outcomes in High-Risk Hypertensive Patients

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Randomized Controlled Trial; Hypertension

the same issueRelated Articles published in

. 2002;288(23):3039.JAMALawrence J. Appel.HypertensionThe Verdict From ALLHATThiazide Diuretics Are the Preferred Initial Therapy for

. 2002;288(23):2998.JAMAThe ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)Randomized to Pravastatin vs Usual Care: The Antihypertensive andMajor Outcomes in Moderately Hypercholesterolemic, Hypertensive Patients

Related Letters

. 2005;165(11):1312.JAMA

Peter W. de Leeuw et al.

In Reply:

. 2004;292(20):2467.JAMAKatherine Esposito et al.In Reply:

. 2004;292(15):1817.JAMABruce M. Psaty et al.In Reply:

. 2004;292(15):1816.JAMAKenneth L. Choi et al.Chlorthalidone vs Other Low-Dose Diuretics

. 2003;290(23):3066.JAMAThomas Kaiser et al.Acarbose for Patients With Hypertension and Impaired Glucose Tolerance

. 2003;290(10):1314.JAMAAram V. Chobanian et al.In Reply:

. 2003;290(10):1312.JAMAHean Teik Ong.

The JNC 7 Hypertension Guidelines

. 2003;289(16):2069.JAMAJackson T. Wright, Jr et al.In Reply:

. 2003;289(16):2068.JAMASteven A. Yarows.. 2003;289(16):2068.JAMAH. T. Ong.

. 2003;289(16):2068.JAMAWilliam Rifkin.. 2003;289(16):2067.JAMAFranz H. Messerli et al.

. 2003;289(16):2066.JAMAChristopher R. Palmer et al.. 2003;289(16):2066.JAMAJan Laws Houghton.

. 2003;289(16):2066.JAMATaishiro Chikamori.Blockers vs Angiotensin-Converting Enzyme InhibitorsLong-term Cardiovascular Consequences of Diuretics vs Calcium Channel

. 2003;289(15):1929.JAMASharon E. Straus et al.In Reply:

. 2003;289(6):701.JAMASverre E. Kjeldsen.Losartan vs Atenolol in Prevention of Stroke and Cardiovascular Disease

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JAMA-EXPRESSORIGINAL CONTRIBUTION

Major Outcomes in High-RiskHypertensive Patients Randomized to

Angiotensin-Converting Enzyme Inhibitoror Calcium Channel Blocker vs DiureticThe Antihypertensive and Lipid-Lowering Treatmentto Prevent Heart Attack Trial (ALLHAT)The ALLHAT Officers andCoordinators for the ALLHATCollaborative Research Group

TREATMENT AND COMPLICA-tions among the 50 to 60 mil-lion peoplein the United Stateswith hypertension are esti-

mated to cost $37 billion annually,withantihypertensive drug costs alone ac-counting for an estimated $15.5 bil-lion per year.1 Antihypertensive drugtherapy substantially reduces the riskof hypertension-related morbidity andmortality. 2-6 However, the optimalchoice for initial pharmacotherapy ofhypertension 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 antihypertensiveagents (ie, angiotensin-converting en-zyme [ACE] inhibitors, calcium chan-nel blockers [CCBs], -adrenergicblockers, and more recently angioten-sin-receptor blockers) became avail-able. Over the past decade, major pla-cebo-controlledtrials have documentedthat ACE inhibitors and CCBs reducecardiovascular events in individuals

with hypertension.9-11 However, theirrelative value compared with older, lessexpensive agents remains unclear.There has been considerable uncer-tainty regarding effects of some classesof antihypertensive drugs on risk of

Author Affiliations: ALLHAT Authors, Their Finan-cialDisclosures, and Group Members arelistedat theend 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, OH44106-5041 (e-mail: [email protected]); Barry R.Davis, MD, PhD, University of Texas-HoustonHealthScience Center, School of Public Health, 1200 Her-man Pressler St, Suite E801, Houston, TX 77030(e-mail: [email protected]).

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 anangiotensin-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 withhypertension and at least 1 other CHD risk factor from 623 North American centers.

Interventions Participants were randomly assigned to receive chlorthalidone, 12.5to 25 mg/d (n =15 255); amlodipine, 2.5 to 10 mg/d (n= 9048); or lisinopril, 10 to 40mg/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-yeardiastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, P.001).For amlodipine vs chlorthalidone, secondary outcomes were similar except for a higher6-year rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52).Forlisinopril vs chlorthalidone, lisinopril hadhigher 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 formsof 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.

2002 American Medical Association. All rights reserved. (Reprinted) JAMA, December 18, 2002Vol 288, No. 23 2981

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coronary heart disease (CHD).6,12-16 Therelative benefit of various agents inhigh-risk hypertensive subgroups suchas older patients, blackpatients, andpa-tients with diabetes also needed to beestablished.17

The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT), a random-ized, double-blind, multicenter clini-cal trial sponsored by the NationalHeart, Lung, and Blood Institute, wasdesigned to determine whether the oc-currenceof fatalCHD or nonfatal myo-cardial infarction is lower for high-risk patients with hypertension treatedwith 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 todoxazosin and was previously re-ported after early termination of thedoxazosin 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 todetermine whether lowering choles-terol with 3-hydroxy-3-methylglu-taryl coenzyme A reductase inhibitor

(pravastatin) compared with usual carereduced all-cause mortality in a mod-erately hypercholesterolemic subset ofALLHAT participants.18,21 To evaluatedifferences 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). Thisstudy presents results of the amlo-dipine and lisinopril vs chlorthali-done comparisons on major CVD out-comes.

METHODSStudy Design

The rationale and design of ALLHAThave been presented elsewhere.18 Par-ticipants were men andwomenaged 55years or older who had stage 1 or stage2 hypertension with at least 1 addi-tional risk factor for CHD events.18,22

The risk factors included previous (6months) myocardial infarction orstroke, left ventricular hypertrophydemonstrated by electrocardiographyor echocardiography, history of type 2diabetes, current cigarette smoking,

high-density lipoprotein cholesterol ofless than 35 mg/dL (0.91 mmol/L),or documentation of other atheroscle-rotic CVD. Individuals with a historyof hospitalized or treated symptom-atic heart failure(HF) and/or known leftventricular ejection fraction of less than35% were excluded.

Unless the drug regimen had to betapered for safety reasons, individualscontinued any prior antihypertensivemedications until they received ran-domized study drug, at which pointthey stopped taking all previous medi-

cations. Treatment with the study drugwas initiated the day after randomiza-tion. By telephone, participants wererandomly assigned to chlorthalidone,amlodipine, or lisinoprilin a ratio of 1.7:1:1. The concealed randomizationscheme was generated by computer,implemented at the clinical trials cen-ter, stratified by center and blocked inrandom block sizes of 5 or 9 to main-tain balance. Participants (n= 33357)were recruited at 623 centers in theUnitedStates, Canada, Puerto Rico, and

the US Virgin Islands between Febru-ary 1994 and January 1998. (The origi-nal reported number of 625 siteschanged because 2 sites and their pa-tients with poor documentation of in-formed consent were excluded.20) Allparticipants gavewritten informedcon-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 monthsthereafter. The range of possible fol-low-up was 3 years 8 months to 8 years

1 month. The closeout phase began onOctober 1, 2001, and ended on March31, 2002.

Treatment

Trained observers using standardizedtechniques measured BPs during thetrial.20 Visit BP was the average of 2seated measurements. Goal BP in each

randomized group was lessthan 140/90mm Hg achieved by titrating the as-signed study drug (step 1) and addingopen-label agents(step2 or 3)when nec-essary. Thechoiceof step 2 drugs (aten-olol, clonidine, or reserpine) was at the

physicians discretion. Nonpharmaco-logic approaches to treatment of hyper-tension were recommended accordingto national guidelines.4,23 Step 1 drugswere encapsulated and identical in ap-pearance so that the identity of eachagent was double-masked at each dos-agelevel.Dosages were 12.5, 12.5 (shamtitration), 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. Dosesof study-supplied open-label step 2 drugs were 25 to 100 mg/dof atenolol; 0.05 to 0.2 mg/d of reser-

pine; or 0.1 to 0.3 mg twice a day ofclonidine; step 3 was 25 to 100 mg twicea day of hydralazine. Other drugs, in-cluding low doses of open-label step 1drug classes, were permitted if clini-cally indicated.18,20

Outcomes

The primary outcome wasfatal CHD ornonfatal myocardial infarction com-bined.18 Four major prespecified sec-ondary outcomes were all-causemortality, fatal and nonfatal stroke,

combined CHD (the primary out-come, coronary revascularization, hos-pitalized angina), and combined CVD(combined CHD, stroke, other treatedangina, HF [fatal, hospitalized, ortreated nonhospitalized], and periph-eral arterial disease). Coronary revas-cularization included coronary arterybypass graft, percutaneous angio-plasty, insertion of stents, and ather-ectomy. Individual components of thecombined outcomes were prespeci-fied and examined, as were other sec-

ondary outcomes including cancer,incident electrocardiographic left ven-tricular hypertrophy, end-stage renaldisease (ESRD) (dialysis, renal trans-plant, or death), and slope of thereciprocal of longitudinal serum cre-atinine measurements. Change in es-timated glomerular filtration rate24,25

was examined post hoc.

ANTIHYPERTENSIVE TREATMENT IN ALLHAT

2982 JAMA,December 18, 2002Vol 288, No. 23(Reprinted) 2002 American Medical Association. All rights reserved.



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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 clinicinvestigator reports, and copies of deathcertificates and hospital discharge sum-

marieswere requested. Among allcom-bined CVD events that resulted indeaths, hospitalizations, or both, theproportion with documentation (ie, adeath certificate or a hospital dis-chargesummary) was 99% in all 3 treat-ment groups. In addition, searches foroutcomes were accomplished throughthe Center for Medicare and MedicaidServices, the Department of VeteransAffairs, the National Death Index, andthe Social Security Administration da-tabases. A death was ascertained byclinicreportor by match with theafore-

mentioned databases plus a confirma-tory death certificate. A death pend-ing confirmation is one found usingdatabases but for which a confirma-tory death certificate has not yet beenobtained. Medical reviewers from theclinical trials center verified the phy-sician-assigned diagnoses of out-comes using death certificates and hos-pital discharge summaries. Moredetailed information was collected ona random (10%) subset of CHD andstroke 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-timesample of HF hospitalizations was re-viewedby the ALLHAT Endpoints Sub-committee. Agreement rates betweenthe 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) forstroke, 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 forMedicare and Medicaid Services andDepartment of Veterans Affairs hospi-talization databases, representing 74%of ALLHAT participants (persons65years, Department of Veterans Affairs

participants, or both).27 Angioedemawas ascertained using a solicited eventquestion on a serious adverse eventform.

Statistical Methods

To maximize statisticalpower,1.7timesas many participants were assigned tothediureticgroup asto each of theother3 groups.18 Given the achieved samplesize and expected event rate, treat-ment crossovers, and losses to follow-up, ALLHAT had 83% power to detecta 16% reduction in risk of the primaryoutcome between chlorthalidone andeach other group at a 2-sided=.0178(z=2.37) to account for the 3 originalcomparisons.28 Data were analyzedaccording to participantsrandomizedtreatment assignments regardless of

their subsequent medications (intent-to-treat analysis). Cumulative eventrates werecalculatedusing the Kaplan-Meier method. Although rates are pre-sented only through 6 years, both thelog-ranktestand Coxproportional haz-ards regressionmodel incorporated theparticipants entire trial experience toevaluate differences between cumula-tive event curves and to obtain 2-sidedPvalues. Only the Cox proportionalhazard regression results are pre-sented, because P values were essen-

tially identical. Hazard ratios (relativerisks [RRs]) and 95% confidence inter-vals (CIs) were obtained from the Coxproportional hazards regressionmodel.29 For consistencywith=.0178,95% CIs may beconvertedto 98.2%lim-its by multiplying the upper limit anddividing the lower limit by RR(0.41/Z),where Z is the value of thetest statisticfor the RR estimate. The Cox propor-tional hazards regression modelassumption wasexaminedby using log-logplotsand testing a treatment time

(time-dependent) interaction term; if itwas violated, the RR estimate from a2-by-2 table was used.29 Heterogeneityof effects in prespecifiedsubgroups, (1)men and women, (2) participants lessthan 65 and65 yearsor older, (3) blackandnonblack participants, and(4) dia-betic and nondiabeticparticipants, andthe post hoc subgroups presence or

absence of CHD at baseline, was exam-ined by testing for treatment-covariateinteraction with the Cox proportionalhazards regression model by usingP.05. SAS version 8.0 (SAS Institute,Cary, NC)and STATA version 7 (Stata

Corp, College Station, Tex) were usedfor statistical analyses.A National Heart, Lung, and Blood

Instituteappointed data and safetymonitoring board met at least annu-ally to review the accumulating dataandto monitor for safety and efficacy. TheLan-DeMets version of the OBrien-Fleming group sequential boundarieswas used to assess treatment group dif-ferences, and conditional power wasused to assess futility.30,31

RESULTS

Patient CharacteristicsTABLE1presents baseline characteris-tics for the 33357 participants in thechlorthalidone, amlodipine, and lisin-opril treatment groups. The mean agewas 67 years; 47% were women, 35%were black, 19% were Hispanic, and36% were diabetic. There were nearlyidentical distributions of baseline fac-tors in the 3 treatment groups.22

Visit and Medication Adherence

FIGURE1shows the number of partici-

pants randomizedandfollowedupto thetime of closeout. In all 3 treatmentgroups, the mean (SD) length of fol-low-up was 4.9 years (1.4 years), and99% of expected person-years were ob-served. The maximum range of fol-low-up was 8.0, 7.9, and 8.1 years in thechlorthalidone, amlodipine, and lisin-opril groups, respectively.At trial close-out, 419 (2.7%) of the chlorthalidonegroup, 258 (2.8%) of the amlodipinegroup, and 276 (3.0%) of the lisinoprilgroup hadunknown vital status. Among

participants with unknown vital sta-tus, the distributions of most baselinefactors were similar among the 3 treat-ment groups, but participants assignedto lisinopril were less likely to be blackand more likely to be women, have un-treated hypertension, evidence of CHDor atherosclerotic CVD, and a lowermean serum glucose.





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Visit adherence decreased over timefromabout 92% at1 yearto 84% to87%at 5 years in all 3 treatment groups(TABLE2). Among participants in thechlorthalidone group who were con-

tacted in the clinic or by telephonewithin 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; and13.2% were taking a diureticwitha 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-dipineor another CCBat 1 year, decreas-ing to 80.4% at 5 years; and 63.8%(n=2502)weretakingaCCBalonewith-outa diuretic. Another16.6% were tak-inga CCB with a diuretic,and only 6.9%were taking a diuretic without a CCB.Among participants in the lisinoprilgroup, 82.4% were taking lisinopril oranother ACEinhibitor at 1 year, decreas-ing to 72.6%at 5 years; 56.9% (n= 2143)

were takingan ACEinhibitoralonewith-outa diuretic;and 15.7%weretakinganACEinhibitor with a diuretic at 5 years.About 8.5% were takinga diuretic with-out an ACE inhibitor.

The most common reasons for nottaking step 1 medicationat 5 yearsin thechlorthalidone, amlodipine, and lisin-opril groups were unspecified refusals(41.4% [n=775], 40.5% [n=443], and37.9% [n= 552], respectively)andsymp-tomatic adverseeffects (15.0%[n= 282],16.4% [n=180], and 18.1% [n=264],

respectively). ElevatedBP (4.5% [n= 84],3.5% [n=38], and 9.0% [n=131]) orother adverse effects such as abnormallaboratory values (3.8% [n=71], 1.6%[n=17], and 2.3% [n=34]) were otherreasons given for discontinuation of step1 medications. Among participants withavailable medication information at 1year, 26.7%, 25.9%, and 32.6% of thoseassigned to chlorthalidone, amlo-dipine,and lisinopril, respectively, weretaking a step 2 orstep3 drug. At 5 years,the corresponding percentages were

40.7%, 39.5%, and 43.0%, respec-tively. Usage patterns of specific step 2drugs were similar among groups.Participants could be taking more than1 step-up drug. At 1 year, 40.0%(n= 4645), 44.0% (n= 3017), and43.8%(n=2764) of participants assigned tochlorthalidone, 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, y55-64 6471 (42.4) 3844 (42.5) 3869 (42.7)

65 8784 (57.6) 5204 (57.5) 5185 (57.3)

EthnicityWhite, 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 antihypertensivetreatment

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)

Untr eated at basel ine 156 (12)/89 (9) 157 (12) /90 (9) 156 (12) /89 (9)

Eligibility risk factorsCigarette 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 coronaryrevascularization

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

Other at heroscleroti c CVD 3604 (23.6) 2145 (23.7) 2152 (23.8)

Major ST depression orT-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 useAspirin 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, cardiovasculardisease; MI, myocardialinfarction; HDL-C, high-density lipoproteincholesterol; LVH,left ventricular hypertrophy; and

CHD, coronary heart disease. Body mass indexwas calculated as weightin kilograms divided bythe squareof heightin 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, peripheralvascular,orcarotid stenosis 50% documented by angiography or Doppler studies; ischemic heart disease documented byreversible or fixed ischemia on stress thalium or dipyridamole thalium, ST depression 1 mm for 1 minute on ex-ercise testing or Holter monitoring; reversible wall motion abnormality on stress echocardiogram; ankle-arm index0.9; abdominalaortic aneurysm detected by ultrasonography,computedtomography scan,or radiograph; carotidor femoral bruits).

P= .03 for comparison of groups.





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blinded medication were receiving themaximalstudy dose.At 5 years, theper-centages were 56.9% (n= 2629), 65.7%(n=1856), and 60.3% (n=1391), re-spectively.

Intermediate Outcomes

Given thelargesample size in ALLHAT,almost all differences in follow-up BPand biochemical measurements werestatistically significant (TABLE 3 andTABLE4). Mean seated BP at random-ization was about 146/84 mmHg in all3 groups, with 90% of participants re-porting current antihypertensive drugtreatment (Table 1). Follow-up BPs inall 3 groups are shown in Table 3 andFIGURE2.

Mean total serum cholesterol levelsat 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% inthe amlodipine group and 2% in the li-sinopril group. Among individuals clas-sified as nondiabetic at baseline, withbaselinefasting serum glucose less than126 mg/dL (7.0 mmol/L), incidence ofdiabetes (fasting serum glucose,126mg/dL [7.0 mmol/L]) at 4 years was11.6%, 9.8%, and 8.1%, respectively.

Mean estimated glomerular filtra-tion rate at baseline was about 78 mL/min per 1.73 m2 in all groups. At 4years, it was 70.0, 75.1, and 70.7 mL/

min per 1.73 m2 in the chlorthali-done,amlodipine,and lisinopril groups,

respectively. The slopes of the recip-rocalof serum creatinine over time werevirtually identical in the chlorthali-done and lisinopril groups (0.018 and0.019 dL/mg per year), whereas thedecline in theamlodipine slope (0.012

dL/mg per year) was less than that ofthe chlorthalidone slope (P.001).

Primary and Secondary Outcomes

Amlodipine vs Chlorthalidone. No sig-nificant difference was observed be-tween amlodipine and chlorthalidonefor theprimaryoutcome (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 (TABLE 5, FIGURE 3, and

FIGURE4). The amlodipine group hada 38% higherrisk ofHF (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-up58 Refused Follow-up

Status at Study Closeout

7412 Known Alive

1314 Confirmed Dead




769 Confirmed Dead

361 Vital Status Unknown

Status as of February 15, 2000

12530 Known Alive

2203 Confirmed Dead




Year 1

13

854 Completed Visit2235 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








45 Morbid Event



387 Other

Year 5

Year 1








49 Morbid Event



484 Other

Year 5

Year 1


Year 5

NA

42418 Patients Randomized

15255 Assigned to ReceiveChlorthalidone

9048 Assigned to ReceiveAmlodipine

9054 Assigned to ReceiveLisinopril

9061 Assigned to ReceiveDoxazosin

15255 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 mayhave 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 Institutedecided to discontinuethe doxazosingroup and report results.18 Studycloseout for chlorthalidone, amlodipine, and lisinopril groups was from October 1, 2001, throughMarch 31, 2002. Collection of last events for the doxazosin group had a closeout interval from October 15, 1999, through February 15, 2000, which captures moreinformation than that reported previously.24





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a 6-year absolute risk difference of 2.5%and a 35% higher risk of hospitalized/fatal HF (P.001). The treatment ef-fects for all outcomes were consistentacross the predefined subgroups(FIGURE 5) and by absence or pres-

ence of CHD at baseline. Cause-specific mortality rates (except forunintentional injuries/suicides/ homicides in amlodipine comparedwith chlorthalidone, not a prespeci-fied hypothesis) were similar for the 2groups (TABLE6).

Lisinopril vs Chlorthalidone.No sig-nificant difference was observed be-tween lisinopril and chlorthalidone forthe primary outcome (RR, 0.99; 95%CI,

0.91-1.08) or for the secondary out-comes of all-cause mortality, combinedCHD, peripheral arterial disease, can-cer, or ESRD (Table 5, Figures 3 and 4).Cause-specific mortality rates were alsosimilar in the 2 groups (Table 6). The li-

sinoprilgrouphada 15% higher risk forstroke(P=.02) and a 10% higher risk ofcombined CVD (P.001), with a 6-yearabsolute risk difference for combinedCVD of 2.4%. Included in this analysiswas a 19% higher risk of HF (P.001),a 10%higher riskof hospitalized/fatal HF(P=.11), an 11% higher risk of hospital-ized/treated angina (P=.01), and a 10%higher risk of coronary revasculariza-tion (P=.05). The treatment effects for

alloutcomes were consistentacrosssub-groupsby sex, diabeticstatus (FIGURE 6),and baseline CHD status. For com-bined CHD, there was a significantdifferential effect by age (P=.01 for in-teraction) with RRs (lisinopril vs

chlorthalidone) of 0.94 for those lessthan 65 years vs 1.11 in those 65 yearsor older. However, when age was mod-eled as a continuous variable, there wasno significant interaction. For stroke andcombined CVD, there was a significantdifferential effect by race (P=.01 andP=.04 for interaction, respectively). TheRRs (lisinopril vs chlorthalidone) were1.40 (95% CI, 1.17-1.68) and 1.00 (95%CI, 0.85-1.17) for strokeand 1.19 (95%

Table 2.Visits Expected and Completed and Antihypertensive Medication Use at Annual Visits

Years, No. (%)

1 2 3 4 5

ChlorthalidoneExpected visits 15 067 (98.8) 14 711 (96.4) 14 272 (93.6) 12 380 (81.2) 7243 (47.5)

Completed visits 13 854 (91.9) 12 988 (88.3) 12 335 (86.4) 10 618 (85.8) 6210 (85.7)

Receiving blinded study drug 11 618 (83.9) 10 367 (79.8) 9372 (76.0) 8149 (72.9) 4623 (71.2)

Receiving bl inded study dr ug or same class 12 0 63 (87.1) 11 0 01 (84.7) 10 2 02 (82.7) 9034 ( 80.8) 5247 ( 80.5)

Full crossovers* 707 (5.1) 865 (6.7) 944 (7.7) 921 (8.2) 583 (9.0)

Partial crossovers 469 (3.4) 770 (5.9) 1054 (8.5) 1223 (10.9) 860 (13.2)

Receiving step 2 or 3 3703 (26.7) 4185 (32.2) 4395 (35.6) 4244 (38.0) 2642 (40.7)

Other antihypertensive medication 594 (4.3) 586 (4.5) 618 (5.0) 609 (5.5) 320 (4.9)

No. of antihypertensive medications, mean (SD) 1.4 (0.7) 1.5 (0.8) 1.6 (0.9) 1.7 (1.0) 1.8 (1.0)

AmlodipineExpected visits 8937 (98.8) 8733 (96.5) 8510 (94.0) 7411 (81.9) 4343 (48.0)

Completed visits 8215 (91.9) 7672 (87.9) 7355 (86.4) 6341 (85.6) 3769 (86.8)

Receiving blinded study drug 6858 (83.5) 6106 (79.6) 5630 (76.6) 4886 (73.3) 2826 (72.1)

Receiving blinded study drug or same class 7192 (87.6) 6532 (85.2) 6116 (83.2) 5367 (80.5) 3151 (80.4)

Full crossovers* 232 (2.8) 342 (4.5) 369 (5.0) 401 (6.0) 270 (6.9)





LisinoprilExpected visits 8942 (98.8) 8725 (96.4) 8458 (93.4) 7356 (81.2) 4315 (47.7)

Completed visits 8158 (91.2) 7574 (86.8) 7185 (84.9) 6142 (83.5) 3605 (83.5)

Receiving blinded study drug 6316 (77.4) 5418 (71.5) 4897 (68.2) 4155 (64.4) 2307 (61.2)

Receiving blinded study drug or same class 6721 (82.4) 5944 (78.4) 5536 (77.1) 4824 (74.8) 2736 (72.6)

Full crossovers* 285 (3.5) 387 (5.1) 430 (6.0) 455 (7.0) 320 (8.5)





*Full crossovers: (1) assigned to chlorthalidone, not on step 1, no open-label diuretic, but on open-label calcium channel blocker (CCB) or angiotensin-converting enzyme (ACE)inhibitor; (2) assigned to lisinopril, not on step 1, no open-label ACE inhibitor, but on open-label diuretic; (3) assigned to amlodipine, not on step 1, no open-label CCB, but onopen-label diuretic.

Partial crossovers: (1) assigned to chlorthalidone, on step 1 or open-label diuretic and on open-label CCB or ACE inhibitor; (2) assigned to lisinopril, on step 1 or open-label ACEinhibitor and on open-label diuretic; (3) assigned to amlodipine, on step 1 or open-label CCB and on open-label diuretic.

Step 2: atenolol, clonidine, or reserpine; step 3: hydralazine.





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CI, 1.09-1.30) and 1.06 (95% CI, 1.00-1.13) for combined CVD in blacks andnonblacks, respectively.

The mean follow-up systolic BP forall participants was 2 mm Hg higher inthe lisinopril group than the chlortha-

lidone group, 4 mm Hg higher inblacks, and 3 mm Hg higher in those65 years or older. Adjustment for fol-low-up BP as time-dependent covari-ates in a Cox proportional hazards re-gression model slightlyreduced the RRsfor stroke (1.15 to 1.12) and HF (1.20to 1.17) overall and in the black sub-group (stroke, 1.40 to 1.35; and HF,1.32 to 1.26), but the results re-mained statistically significant.

Primary Safety Outcomes

Six-year rates of hospitalizationfor gas-

trointestinal bleeding, available only inMedicare and Department of VeteransAffairs participants, occurred in 8.8%,8.0%, and 9.6% participants in thechlorthalidone, amlodipine, and lisin-opril treatment groups, respectively,with no significant differences (Table5). Angioedema occurred in 8 of 15255(0.1%), 3 of 9048 (0.1%), and 38 of9054 (0.4%) persons in the chlortha-lidone, amlodipine, and lisinopril treat-ment groups, respectively. Significantdifferences were seen for the lisinopril

vs chlorthalidone comparison overall(P.001), in blacks(2 of5369 [0.1%]for chlorthalidone, 23 of 3210 [0.7%]for lisinopril; P.001), and in non-blacks (6 of 9886 [0.1%] for chlortha-lidone, 15 of 5844 for lisinopril [0.3%];P=.002). The only death from angio-edema was in the lisinopril group.

COMMENT

Neither amlodipine (representing CCBs,particularly dihydropyridine [DHP]CCBs) nor lisinopril (representing ACE

inhibitors) was superior to chlorthali-done (representing thiazide-type diuret-ics) in preventing major coronary eventsor in increasing survival. Chlorthali-done was superior to amlodipine (byabout 25%) in preventing HF, overall,and for hospitalized or fatal cases, al-though it did not differ from amlo-dipine in overall CVD prevention.

Chlorthalidone was superior to lisino-pril in lowering BP and in preventing ag-gregate cardiovascular events, princi-pally stroke, HF, angina, and coronaryrevascularization. ALLHAT previouslyreported that chlorthalidone was supe-

rior to doxazosin(representing-block-ers) in reducing BP and preventing car-diovascular events, particularly HF.19,20

It is not surprising that no signifi-cant differences in CHDandstroke rateswerefound betweenchlorthalidone and

Table 3.Number of Participants, Mean Blood Pressure, Achieved Blood Pressure Goal, andBlood Pressure Difference at Baseline and Annual Visits

Chlorthalidone Amlodipine Lisinopril

PValue

Amlodipine vsChlorthalidone

Lisinopril vsChlorthalidone

No. of Participants (%)

Baseline 15 2 55 ( 100) 9048 (100) 9054 ( 100)

1 Year 12 8 62 ( 84.3) 7609 (84. 1) 7521 ( 83.1)

2 Year s 11 7 40 ( 77.0) 6883 (76. 1) 6700 ( 74.0)

3 Year s 10 6 98 ( 70.1) 6381 (70. 5) 6076 ( 67.1)

4 Year s 9379 ( 61.5) 5637 (62. 3) 5325 ( 58.8)

5 Year s 5301 ( 34.7) 3195 (35. 3) 2963 ( 32.7)

Systolic Blood Pressure, Mean (SD), mm Hg

Baseline 146.2 (15.7) 146.2 (15.7) 146.4 (15.7) .98 .39

1 Year 136.9 (15.8) 138.5 (14.9) 140.0 (18.5) .001 .001

2 Years 135.9 (15.9) 137.1 (15.0) 138.4 (17.9) .001 .001

3 Years 134.8 (15.4) 135.6 (15.2) 136.7 (17.3) .001 .001

4 Years 133.9 (15.7) 134.8 (15.0) 135.5 (17.2) .002 .001

5 Years 133.9 (15.2) 134.7 (14.9) 135.9 (17.9) .03 .001

Diastolic Blood Pressure, Mean (SD), mm Hg

Baseline 84.0 (10.1) 83.9 (10.2) 84.1 (10.0) .52 .49

1 Year 79.3 (9.9) 78.7 (9.5) 79.9 (10.5) .001 .001

2 Years 78.3 (9.6) 77.7 (9.6) 78.6 (10.3) .001 .03

3 Years 77.2 (9.5) 76.4 (9.6) 77.3 (10.3) .001 .42

4 Years 76.5 (9.7) 75.7 (9.6) 76.6 (10.4) .001 .48

5 Years 75.4 (9.8) 74.6 (9.9) 75.4 (10.7) .001 .94

Achieved Blood Pressure Goal of 140/90 mm Hg, No. (%)

Baseline 4149 (27.2) 2497 (27.6) 2381 (26.3) .56 .12

1 Year 7434 (57.8) 4200 (55.2) 3806 (50.6) .001 .001

2 Year s 7161 ( 61.0) 3951 (57. 4) 3625 ( 54.1) .001 .001

3 Years 6836 (63.9) 4046 (63.4) 3597 (59.2) .54 .001

4 Years 6293 (67.1) 3709 (65.8) 3360 (63.1) .15 .001

5 Years 3615 (68.2) 2118 (66.3) 1813 (61.2) .09 .001

Systolic Blood Pressure, mm Hg*

Baseline 0 0.2

1 Year 1.6 3.1

2 Years 1.2 2.5

3 Years 0.8 1.9

4 Years 0.9 1.6

5 Years 0.8 2.0Diastolic Blood Pressure, mm Hg*

Baseline 0.1 0.1

1 Year 0.6 0.6

2 Years 0.6 0.3

3 Years 0.8 0.1

4 Years 0.8 0.1

5 Years 0.8 0

*Compared with chlorthalidone group.





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amlodipine-based therapy in ALLHAT.In the Systolic Hypertension in theElderly Program and the Systolic Hy-pertension in Europe trial, in which athiazide-like diuretic (chlorthali-done) or a DHP-CCB was compared

with a placebo, major CHDevents werereduced by 27% and 30%, and strokeby 37% and 42%, respectively.8,9 Moredirect evidence comes from 2 large ac-tive-controlled trials that comparedDHP-CCB and traditional first-stepdrugs. The Swedish Trial in Old Pa-tients with Hypertension-2 and the In-ternational Nifedipine GITS (long-acting gastrointestinal formulation)Study: Intervention as a Goal in Hy-pertension Treatment (INSIGHT),found no significant differences for ma-jor CHD or stroke rates between the

treatment groups.32,33 Some of these in-dividual trials have had limited powerto evaluate differences between treat-ments.34 In meta-analyses of 5 positive-controlled trials, which included bothDHP-CCB and nonDHP-CCB trials,there were trends that favored CCB-based therapy for stroke and tradi-tional treatment for CHD, with no dif-ference for all-cause mortality.13,14

However, ALLHAT observed approxi-mately the same number of strokes andnearly twice as many CHD events as all

5 trials combined, which suggests thattheaggregate of the evidence would in-dicate no difference between CCB-based treatment and diuretic-basedtreatment for these outcomes.

The amlodipine vs chlorthalidonefindings for HF reinforce previous trialresults. In the diuretic-based SystolicHy-pertension in the Elderly Program, ac-tive therapy reduced HF occurrence by49%compared with placebo (P.001),although in the DHP-CCBbased Sys-tolic Hypertensionin Europe trial, it was

reduced by 29% (not statistically sig-nificant).9,35 In the INSIGHT trial, HFwas approximately twice as frequent inthe CCB vs the diuretic arm.33 The pre-viously cited meta-analyses reported ahigher rate of HF with CCB-based treat-ment thantraditional regimens, withnodifference in RR for DHPs comparedwith nonDHPs.13,14

Table 4.Biochemical Changes by Treatment Group*


PValue



Cholesterol, mg/dL

No. of participants (%)

Baseline 14483 (94.9) 8586 (94.9) 8573 (94.7)

2 Years 10 2 06 (66.9) 6025 (66.6) 5739 (63.4)

4 Years 8495 (55.7) 5025 (55.5) 4711 (52.0)

Mean (SD)Baseline 216.1 (43.8) 216.5 (44.1) 215.6 (42.4) .47 .38

2 Years 205.3 (42.1) 202.5 (42.2) 202.0 (42.8) .001 .001

4 Years 197.2 (42.1) 195.6 (41.0) 195.0 (40.6) .009 .001

240 mg/dL, No. (%)Baseline 3838 (26.5) 2284 (26.6) 2178 (25.4) .89 .06

2 Years 1898 (18.6) 1018 (16.9) 976 (17.0) .005 .03

4 Years 1223 (14.4) 673 (13.4) 603 (12.8) .13 .005

Potassium, mEq/L

No. of participants (%)Baseline 14487 (95.0) 8586 (94.9) 8573 (94.7)

2 Years 9877 (64.7) 5794 (64.0) 5516 (60.9)

4 Years 8315 (54.5) 4919 (54.4) 4616 (51.0)

Mean (SD)Baseline 4.3 (0.7) 4.3 (0.7) 4.4 (0.7) .59 .001

2 Years 4.0 (0.7) 4.3 (0.7) 4.5 (0.7) .001 .001

4 Years 4.1 (0.7) 4.4 (0.7) 4.5 (0.7) .001 .001

3.5 mEq/L, No. (%)Baseline 493 (3.4) 292 (3.4) 223 (2.6) .99 .001

2 Years 1254 (12.7) 151 (2.6) 83 (1.5) .001 .001

4 Years 707 (8.5) 93 (1.9) 37 (0.8) .001 .001

Fasting Glucose, mg/dL


2 Years 5980 (39.2) 3506 (38.7) 3333 (36.8)4 Years 4972 (32.6) 2954 (32.6) 2731 (30.2)

Mean (SD)Baseline 123.5 (58.3) 123.1 (57.0) 122.9 (56.1) .71 .54

2 Years 127.6 (59.2) 122.4 (54.2) 120.8 (54.0) .001 .001

4 Years 126.3 (55.6) 123.7 (52.0) 121.5 (51.3) .20 .002

126 mg/dL, No. (%)Baseline 3258 (28.9) 1941 (29.2) 1985 (29.4) .68 .55

2 Years 1967 (32.9) 1048 (29.9) 947 (28.4) .001 .001

4 Years 1626 (32.7) 901 (30.5) 784 (28.7) .11 .001

Fasting Glucose Among Nondiabetics With Baseline Fasting Glucose 126 mg/dL

No. of participants (%)Baseline 6766 (100) 3954 (100) 4096 (100)

2 Years 3074 (45.4) 1787 (45.2) 1737 (42.4)

4 Years 2606 (40.3) 1567 (39.6) 1464 (35.7)

Mean (SD)Baseline 93.1 (11.7) 93.0 (11.4) 93.3 (11.8) .52 .45

2 Years 102.2 (27.1) 99.0 (22.5) 97.4 (20.0) .001 .001

4 Years 104.4 (28.5) 103.1 (27.7) 100.5 (19.5) .11 .001

126 mg/dL, No. (%)2 Years 295 (9.6) 132 (7.4) 101 (5.8) .006 .001

4 Years 302 (11.6) 154 (9.8) 119 (8.1) .04 .001

(continued)





11/21

A body of literature based on obser-vationalstudies andsecondaryCHD pre-vention trials of short-acting CCBs hassuggested that CCBs, especially DHP-CCBs, may increase the risk of cancer,gastrointestinal bleeding, and all-cause

mortality.

14,36,37

The results of ALLHATdo not support these findings. In fact,the mortality from noncardiovascularcauses was significantly lower in theCCB group (Table 6).

There were no significant differ-ences in the incidence of ESRD be-tween chlorthalidone and amlodipine,consistent with findings from theINSIGHT trial.33 Comparison of the re-ciprocal serum creatinine slopes sug-gested a slower decline in kidney func-tion in the amlodipine group.However,this finding requires cautious interpre-

tation becausestudiesassessing glomer-ular filtration rate more directly haveshown a hemodynamically mediatedacute increase in glomerular filtrationrate followed bya more rapid rate of de-cline with chronic therapy using amlo-dipine and other CCBs.38-40

Comparison of the lisinopril andchlorthalidone groups revealed betterdrug tolerance and BP control withchlorthalidone. Angioedema, a rare butpotentially seriousadverseeffect of ACEinhibitor use, occurred 4 times more

frequently in participants randomizedto lisinopril than in those randomizedto chlorthalidone. Cholesterol levels,the prevalence of hypokalemia (se-rum potassium3.5 mEq/L), and newdiabetes (fasting glucose 126 mg/dL[7.0 mmol/L]) were higher in thechlorthalidone than the other groupsfollowing 2 and 4 years of follow-up.Overall, thesemetabolicdifferences didnot translate into more cardiovascularevents or into higher all-cause mortal-ity in the chlorthalidone group com-

pared with the other 2 groups.The ALLHAT findings for some ma-jor outcomes are consistent with pre-dictions from placebo-controlled tri-als involving ACE inhibitors anddiuretics. Specifically, for ACE inhibi-tor and diuretic trials, respectively, thereductions in CHD rates were 20% and18%, and for all-cause mortality, 16%

and10%.13 The10% greater rate of com-bined CVD in the lisinopril than in thechlorthalidone group was due to in-creased occurrences of stroke, HF, an-gina, and coronary revascularization.Results for some of these outcomes may

seem surprising, because of reports ofbeneficial effects of ACE inhibitors onsurrogate markers of atherosclerosis andreductions in vascular and renal eventsin individuals with HF, diabetes, kid-ney disease, and cerebrovascular dis-ease in placebo-controlled trials.41-43

However, the finding in ALLHAT thatHF incidence was lower in the di-ureticvs theACEinhibitor group is alsoconsistent with previous reports. In theSystolic Hypertension in the ElderlyProgram trial (chlorthalidone vs pla-cebo), there was a 49% decrease in the

development of HF, whereas in theStudies of Left Ventricular Dysfunc-tion Prevention (enalapril vs placebo)and HeartOutcomes Prevention Evalu-ation trials (ramipril vs placebo), therewere only 20% and 23% reductions,

respectively.

8,10,44

In published meta-analyses of placebo-controlled trials,thereductions in rates for stroke with ACEinhibitor and diuretics were 30% and34%, translating into nearly equiva-lent results.3,13 The 15% relative in-crease in stroke incidence for lisino-pril compared with chlorthalidonetreatment in ALLHAT must be consid-ered in the context of heterogeneity ofthe results by race. The Swedish Trialin Old Patients with Hypertension-2trial, which compared ACE inhibitorswith conventional treatment (diuret-

Figure 2.Mean Systolic and Diastolic Blood Pressure by Year During Follow-up

150

135

140

145

1300 1 3 4 5 62

Follow-up, y

Mean Systolic Blood Pressure

mmH

g

90

75

80

85

700 1 3 4 5 62

Follow-up, y

Mean Diastolic Blood Pressure

mmH

g

Amlodipine

Lisinopril

Chlorthalidone

Number measured at baseline through 5 years is given in Table 3; numbers at 6 years for chlorthalidone, am-lodipine, and lisinopril are 2721, 1656, and 1551, respectively.

Table 4.Biochemical Changes by Treatment Group*(cont)


P Value



Estimated Glomerular Filtration Rate, mL/min per 1.73 m 2


2 Years 9877 (64.7) 5794 (64.0) 5516 (60.9)

4 Years 8316 (54.5) 4924 (54.4) 4621 (51.0)

Mean (SD)Baseline 77.6 (19.7) 78.0 (19.7) 77.7 (19.9) .08 .57

2 Years 73.3 (19.9) 78.0 (20.5) 74.0 (20.0) .001 .002

4 Years 70.0 (19.7) 75.1 (20.7) 70.7 (20.1) .001 .03

*To convert serum cholesterol to mmol/L, multiply by 0.0259; fasting glucose to mmol/L, multiply by 0.0555.Simplified 4-variable Modification of Diet in Renal Disease Study formula.24,25





12/21

ics and/or-blockers), showed no sig-nificantdifferences in CHD,stroke, HF,

or all-cause mortality.32

Although thesefindings are somewhat different fromthe experience in ALLHAT, consider-ation needs to be given to respectiveconfidence limits, population differ-ences (especially race), and study de-signs (open vs double-blind).

No substantial differences in inci-dence ofESRD, glomerular filtration rate,or reciprocalcreatinineslopeswere notedfor the lisinopril vs chlorthalidone com-parisons. The ALLHAT study popula-tion was selected for high CVD risk and

had a baseline mean creatinine of only1.0 mg/dL (88.4 mol/L). More de-tailed analyses of high renal risk sub-groups(ie, diabetic, renal-impaired, andblack patients)will be thesubject of sub-sequent reports.

Analyses of RRsfor stroke andHF ad-justedfor follow-up BP suggest that the2-mm Hg systolic BP difference over-

Figure 3.Cumulative Event Rates for the Primary Outcome (Fatal Coronary Heart Disease orNonfatal Myocardial Infarction) by Treatment Group

20

4

8

12

16

0

No. at Risk

1 3 4 5 6 72

15255Chlorthalidone 14477 13102 11362 6340 2956 20913820

9048Amlodipine 8576 7843 6824 3870 1878 2158218

9054Lisinopril 8535 7711 6662 3832 1770 1958123

Time to Event, y

CumulativeEventRate,

%

Chlorthalidone

Amlodipine

Lisinopril

No significant difference was observed for amlodipine (relative risk [RR], 0.98; 95% confidence interval [CI],0.90-1.07; P = .65) or lisinopril (RR, 0.99; 95% CI, 0.91-1.08;P = .81) vs chlorthalidone with a mean fol-low-up of 4.9 years.

Table 5.Clinical Outcomes by Antihypertensive Treatment Group*

Chlort halidone Amlodipine Lisinopril Amlodipine vsChlorthalidone Lisinopril vs Chlorthalidone

No. ofTotal

Events

6-Year Rateper 100

Persons (SE)

No. ofTotal

Events

6-Year Rateper 100

Persons (SE)

No. ofTotal

Events

6-Year Rateper 100

Persons (SE)RR

(95% CI)Z

ScoreP

ValueRR

(95% CI)Z

ScoreP

Value

Primary outcomeCHD 1 36 2 11 .5 ( 0.3 ) 7 98 1 1.3 (0 .4 ) 7 96 1 1.4 (0 .4 ) 0 .9 8 ( 0.90 -1 .0 7) 0.46 .65 0.99 (0.91-1.08) 0.24 .81

Secondary outcomesAll-cause mortality 2203 17.3 (0.4) 1256 16.8 (0.5) 1314 17.2 (0.5) 0.96 (0.89-1.02) 1.27 .20 1.00 (0.94-1.08) 0.12 .90

Combined CHD 2451 19.9 (0.4) 1466 19.9 (0.5) 1505 20.8 (0.5) 1.00 (0.94-1.07) 0.04 .97 1.05 (0.98-1.11) 1.35 .18

Stroke 675 5.6 (0.2) 377 5.4 (0.3) 457 6.3 (0.3) 0.93 (0.82-1.06) 1.09 .28 1.15 (1.02-1.30) 2.31 .02

Combined CVD 3941 30.9 (0.5) 2432 32.0 (0.6) 2514 33.3 (0.6) 1.04 (0.99-1.09) 1.55 .12 1.10 (1.05-1.16) 3.78 .001

End-stage renaldisease

19 3 1 .8 ( 0. 1) 1 29 2 .1 (0 .2 ) 1 26 2. 0 (0 .2 ) 1 .12 ( 0. 89 -1 .4 0) 0 .9 8 . 33 1 .11 ( 0. 88 -1 .3 8) 0. 87 .3 8

Cancer 1170 9.7 (0.3) 707 10.0 (0.4) 703 9.9 (0.4) 1.01 (0.92-1.11) 0.30 .77 1.02 (0.93-1.12) 0.42 .67

Hospitalized forgastrointestinalbleeding

817 8.8 (0.3) 449 8.0 (0.4) 526 9.6 (0.4) 0.92 (0.82-1.03) 1.44 .15 1.11 (0.99-1.24) 1.82 .07

Components of secondaryoutcomes

Heart failure 870 7.7 (0.3) 706 10.2 (0.4) 612 8.7 (0.4) 1.38 (1.25-1.52) 6 .29 .001 1.19 (1.07-1.31) 3.33 .001

Hospitalized/fatalheart failure

724 6.5 (0.3) 578 8.4 (0.4) 471 6.9 (0.4) 1.35 (1.21-1.50) 5.37 .001 1.10 (0.98-1.23) 1.59 .11

Angina (hospitalizedor treated)

1567 12.1 (0.3) 950 12.6 (0.4) 1019 13.6 (0.4) 1.02 (0.94-1.10) 0.42 .67 1.11 (1.03-1.20) 2.59 .01

Angina(hospitalized)

1078 8.6 (0.3) 630 8.4 (0.4) 693 9.6 (0.4) 0.98 (0.89-1.08) 0.41 .68 1.09 (0.99-1.20) 1.85 .06

Coronaryrevascularizations

1 11 3 9 .2 ( 0. 3) 7 25 10 .0 (0 .4 ) 7 18 1 0.2 (0 .4 ) 1 .0 9 (1 .00 -1 .2 0) 1 .8 8 .0 6 1 .1 0 ( 1.00 -1 .2 1) 1. 95 .0 5

Peripheral arterialdisease(hospitalized ortreated)

510 4.1 (0.2) 265 3.7 (0.2) 311 4.7 (0.4) 0.87 (0.75-1.01) 1.86 .06 1.04 (0.90-1.19) 0.48 .63

*RR indicates relative risk; CI, confidence interval; CHD, coronary heart disease; and CVD, cardiovascular disease. CHD includes nonfatal myocardial infarction (MI) and fatal CHD;end-stage renal disease: kidney disease death, kidney transplant, or start of chronic renal dialysis; and heart failure: fatal, nonfatal hospitalized, or treated.

Nonfatal MIs comprise 64% to 66% of the primary outcome.Combined CHD indicates CHD death, nonfatal MI, coronary revascularization procedures, and hospitalized angina. Combined CVD indicates CHD death, nonfatal MI, stroke, coro-

nary revascularization procedures, hospitalized or treated angina, treated or hospitalized heart failure, and peripheral arterial disease (hospitalized or outpatient revascularization).Denominators are 11 361 chlorthalidone, 6757 amlodipine, and 6665 lisinopril.Proportional hazards assumption violated; data are RRs from a 2 2 table.





13/21

all (4 mm Hg in black patients) be-tween the lisinopril and chlorthali-done groups only partially accounts for

the observed CVD event difference.However, such analyses are limited bythe infrequency and imprecision of BP

measurements for individual partici-pants and regression dilution, whichunderestimates CVD risk associated

Figure 4.Cumulative Event Rates for All-Cause Mortality, Stroke, Combined Coronary Heart Disease, Combined Cardiovascular Disease,Heart Failure, and Hospitalized Plus Fatal Heart Failure by Treatment Group

15

3

6

9

12

0

No. at Risk

Chlorthalidone

Amlodipine

15255

9048

9054Lisinopril

1

14528

8535

8496

3

13224

7801

7689

4

11511

6785

6698

5

6369

3775

3789

6

3016

1780

1837

7

384

210

313

2

13898

8185

8096

Time to Event, y

Heart Failure


%

15

3

6

9

12

0

15

255

9048

9054

1

14

556

8579

8538

3

13

312

7884

7780

4

11

606

6866

6768

5

6443

3833

3895

6

3130

1821

1894

7

396

216

322

2

13

962

8251

8169

Time to Event, y

Hospitalized Plus Fatal Heart Failure


%

No. at Risk

Chlorthalidone

Amlodipine

Lisinopril

50

10

20

30

40

0 1 3 4 5 6 72

Time to Event, y

Combined Cardiovascular Disease

CumulativeCombinedEventRate,

%

30

10

5

15

20

25

0

No. at Risk

Chlorthalidone

AmlodipineLisinopril

1 3 4 5 6 72

Time to Event, y

All-Cause Mortality


%

Chlorthalidone

Amlodipine

Lisinopril

15255

90489054

14515

86178543

13309

79497784

11570

69376765

6385

38453891

3217

18131828

567

506949

13934

82718172

10

2

4

6

8

0 1 3 4 5 6 72

Time to Event, y

Stroke


%

15255

9048

9054

14211

8428

8347

12415

7422

7264

10587

6357

6207

5804

3512

3461

2698

1672

1622

187

142

170

13320

7940

7789

30

10

20

0 1 3 4 5 6 72

Time to Event, y

Combined Coronary Heart Disease

CumulativeCombinedEventRate,

%

15255

90489054

14933

88478853

14077

83918318

12480

74427382

7185

43124304

3523

21012121

428

217144

14564

86548612

15255

9048

9054

13752

8118

7962

11517

6837

6631

9643

5724

5560

5167

3049

3011

2362

1411

1375

288

153

139

12594

7451

7259





14/21

with BP differences based on single-visit (or even visit-averaged) measure-ments.45 Such modeling is also unable

to account for differences among indi-viduals due to other unmeasured orpoorly represented risk factors; thus,

participants who lower their BP by agiven amount with one drug may notbe comparable to those who lower their

Figure 5.Relative Risks and 95% Confidence Intervals (CIs) for Amlodipine/Chlorthalidone Comparisons in Prespecified Subgroups

Total

Age


15/21

BP by the same magnitude with an-other drug.

Using an external standard of pooledresults of long-term hypertension treat-ment trials and observational studies(10-12 mm Hg systolic BP difference

associated with 38% stroke reduction),a 2-to 3-mmHg difference in BP mightaccount for a 6% to 12% difference instroke rates.45,46 This is consistent withthe observed 15% difference for strokeoverall but not with the difference seenin black patients (13%-16% expected,40% observed). For the HF outcome,trial results in isolated systolic hyper-tension suggest that a 3-mm Hg highersystolic BP could explain a 10% to 20%increase in risk.8,47 The forgoing ignoresthe absence of a diastolic BP differencein ALLHAT; however, the relationship

of diastolic pressure and CVD events inelderlypersonswhooftenhave increasedpulse pressure is not entirely clear.48

The primary and secondary out-come results for the amlodipine vschlorthalidone groupcomparisonswereconsistent for all subgroups of partici-pants: older and younger, men andwomen, black and nonblack, diabetic

and nondiabetic. For the lisinopril vschlorthalidone comparisons, resultswere generally consistent by age, sex,and diabetic status. Thus, for the im-portant diabetic population, lisinoprilappeared to have no special advantage(and amlodipine no particular detri-mental effect) for most CVD and renalo utco m es w hen co m par ed w i thchlorthalidone. In fact, chlorthali-done was superior to lisinopril for sev-eral CVDoutcomes andsuperior to am-lodipine for HF in both diabetic andnondiabetic participants. The consis-

tency of the ALLHAT findings acrossmultiple patient subgroups providesconfidence in the ability to generalize

the findings to most patients with hy-pertension.

In the lisinopril vs chlorthalidonecomparisons, there were 2 outcomeswith significant interactions. Thegreater differences observed in black vs

nonblack patients for combined CVDand stroke, along with a similar trendfor HF and lesser BP lowering with li-sinopril, are in accord with the mul-tiple reports of poorer BP response withACE inhibitor in black patients.49-51

They are also consistent with reportsof lesser effects of ACEinhibitors in sec-ondary prevention of HF in this popu-lation,52,53 although these findings havebeen recently questioned.54 The differ-ential responses for disease outcomesparallel thelesser response in the blacksubgroup for BP, although the differ-

ences in outcomes are not substan-tially reduced by statistically adjust-ing for systolic BP.

Figure 6.Relative Risks and 95% Confidence Intervals (CIs) for Lisinopril/Chlorthalidone Comparisons in Prespecified Subgroups

Nonfatal Myocardial Infarction

Plus Coronary Heart Disease Death

Total

Men

Black

Relative Risk(95% CI)

Relative Risk(95% CI)

0.99 (0.91-1.08)

0.95 (0.81-1.12)

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)

FavorsLisinopril

FavorsChlorthalidone

Combined Coronary Heart Disease

Total 1.05 (0.98-1.11)

0.94 (0.84-1.05)

1.11 (1.03-1.20)

Men 1.03 (0.95-1.12)1.05 (0.95-1.17)

Black 1.15 (1.02-1.30)

1.01 (0.93-1.09)

1.03 (0.93-1.14)

Age


16/21

Although subordinate to safety andefficacy, the cost of drugs and medicalcare for the individual and society is afactor that should be considered in theselection of antihypertensives. One ofthestated objectives of ALLHAT was to

answer the question, Are newer typesof antihypertensive agents, which arecurrently more costly, as good or bet-ter than diuretics in reducing CHD in-cidence and progression?18 Consider-ation of drug cost could have a majorimpact on the nations health care ex-penditures. Based on previous data thatshowed that diuretic use declined from56% to 27% of antihypertensive pre-scriptions between 1982 and 1992, thehealth care system would have saved$3.1 billion in estimated cost of anti-hypertensive drugs had the pattern of

prescriptions for treatment of hyper-tension remained at the 1982 level.55

Further economic analysesbased on theresults of ALLHAT are under way.

The strengths of ALLHAT include itsrandomized double-blind design, sta-tistical power to detect clinically mean-ingful differences in CVD outcomes ofinterest, diverse population with ad-equate representation from subgroupsof special interest in the treatment ofhypertension, and varied practice-based settings. In addition, the agents

that were directly compared represent3 of the most commonly used newerclasses of antihypertensives vs the beststudied of the older classes.

Some limitations are worth noting.After ALLHAT was designed, neweragents have been or may soon be re-leased (eg, angiotensin-receptor block-ers, selective aldosterone antago-nists), which were not evaluated.Although clinical centers were blindedto theregimen andurgedto achieve rec-ommended BP goals, equivalent BP re-

duction was not fully achieved in thetreatment groups. Furthermore, be-cause diuretics, ACE inhibitors, CCBs,and -blockers were evaluated in thetrial,the agents availablefor step-up ledto a somewhat artificial regimen (useof sympatholytics rather than diuret-ics and CCBs) of step-up drugs in theACE inhibitor group. This may have

contributed to the higher BPs in theACE inhibitor group, especially in theblack subgroup. However, mean fol-low-up BPs were well below 140/90mm Hg in all treatment groups. Al-though ALLHAT did not compare a

-blocker to chlorthalidone, previoustrials have suggested equivalence45 oreven inferiority3 for major CVD events.

The ALLHAT results apply directlyto chlorthalidone, amlodipine, and li-sinopril. Combined with evidence fromother trials, we infer that the findingsalso broadly apply to the drug classes(or subclass in the case of the dihy-dropyridine CCBs) that the study drugsrepresent. The evidence base for selec-tion of antihypertensiveagents has beenmarkedly strengthened by the addi-tion of ALLHAT.

In conclusion, the results of ALLHATindicate that thiazide-type diureticsshould be considered first for pharma-cologic therapy in patients with hyper-tension. They are unsurpassed in low-ering BP, reducing clinical events, andtolerability, andthey are less costly. Forpatients who cannot take a diuretic(which should be an unusual circum-stance), first-step therapy with CCBsand ACE inhibitors could be consid-ered with due regard for their higherrisk of 1 or more major manifestations

of CVD. Since a large proportion of par-ticipants required more than 1 drug tocontrol their BP, it is reasonable to in-fer that a diureticbe included in allmul-tidrug regimens, if possible. Althoughdiuretics already play a key role in mostantihypertensive treatment recommen-dations, the findings of ALLHAT shouldbe carefully evaluated by those respon-sible for clinical guidelines and bewidely applied in patient care.

ALLHAT Authors/Officers and Coordinators: Curt D.Furberg, MD, PhD; Jackson T. Wright, Jr, MD, PhD;

BarryR. Davis,MD, PhD; Jeffrey A. Cutler, MD,MPH;Michael Alderman, MD; Henry Black, MD; WilliamCushman, MD; Richard Grimm, MD, PhD; L. JulianHaywood, MD; Frans Leenen, MD; Suzanne Oparil,MD;JeffreyProbstfield, MD;Paul Whelton, MD,MSc;Chuke Nwachuku, MA, MPH; David Gordon, MD,PhD; MichaelProschan, PhD;Paula Einhorn,MD, MS;Charles E. Ford, PhD; Linda B. Piller, MD,MPH;J. KayDunn, PhD; David Goff, MD, PhD; Sara Pressel, MS;JudyBettencourt, MPH;Barbara deLeon, BA; LaraM.Simpson,MS; Joe Blanton, MS; Therese Geraci, MSN,RN, CS; Sandra M. Walsh, RN; Christine Nelson, RN,

BSN; Mahboob Rahman, MD; Anne Juratovac, RN;Robert Pospisil, RN; Lillian Carroll, RN; Sheila Sulli-van, BA; Jeanne Russo, BSN; Gail Barone, RN; RudyChristian, MPH; Sharon Feldman, MPH; Tracy Lu-cente,MPH; David Calhoun, MD;Kim Jenkins, MPH;Peggy McDowell, RN; Janice Johnson, BS;ConnieKin-gry, RN,BSN; Juan Alzate, MD;KarenL. Margolis,MD;Leslie Ann Holland-Klemme, BA; Brenda Jaeger; Jef-frey Williamson, MD, MHS; Gail Louis, RN; Pamela

Ragusa, RN, BSN; AngelaWilliard,RN, BSN; R. L. SueFerguson,RN; Joanna Tanner; JohnEckfeldt, MD, PhD;Richard Crow, MD; John Pelosi, RPh, MS.Financial Disclosures: The following listed authorshave served as consultantsfor, receivedpersonalcom-pensation from, weregrant recipients of, or ownstockin the following companies: Furberg: Merck, Pfizer,Pharmacia & Upjohn, Takeda, Wyeth-Ayerst; Wright:Aventis, Bayer, Bristol-Myers Squibb, Forrest Labs,King/Monarch, Merck, Novartis, Pfizer;Davis:Ab-bott, Bristol-Myers Squibb,Forrest Labs, Merck,Pfizer,Pharmacia& Upjohn, GlaxoSmithKline;Alderman: Bris-tol-Myers Squibb, Merck, Novartis, Pfizer, Glaxo-SmithKline; Black: Abbott, AstraZeneca, Bristol-MyersSquibb, Novartis, Pfizer, Pharmacia & Upjohn,GlaxoSmithKline,Solvay; Cushman: AstraZeneca, Bris-tol-Myers Squibb, Forrest Labs, Merck, Pfizer, Phar-macia & Upjohn, Sankyo, Searle, Solvay, Takeda;Grimm: AstraZeneca, Merck, Novartis, Pfizer, Roche,

Solvay; Haywood: Pharmacia & Upjohn; Leenen:AstraZeneca, Bayer, Bristol-Myers Squibb, Merck,Nu-Pharm, Pfizer, Pharmacia & Upjohn;Oparil: Ab-bott, AstraZeneca,Aventis,Bayer, Bristol-MyersSquibb,DuPont, Forrest Labs,King/Monarch, Merck, Novar-tis, Parke-Davis, Pfizer, Pharmacia & Upjohn, Roche,Sankyo, Schering-Plough, Searle, GlaxoSmithKline,Texas Biotechnology; Probstfield:AstraZeneca, King/Monarch, Pfizer; Whelton:Merck, Novartis, Pfizer,Pharmacia & Upjohn; Ford: Bristol-Myers Squibb; Rah-man: Abbott, Novartis,Pfizer, Searle; Lucente: Glaxo-SmithKline; Calhoun: AstraZeneca, Aventis, Merck,Novartis, GlaxoSmithKline; Solvay; McDowell:Am-gen, King/Monarch, Merck,Pfizer; Alzate: Pfizer; Tan-ner:SGP;Eckfeldt:Johnson & Johnson.Author Contributions: Dr Davis had full access to allthe data in the study and takes responsibility for theintegrityof thedataand theaccuracy ofthe data analy-ses in this article and its companion article on page

2998.Study concept and design: Furberg, Wright, Davis,Cutler, Alderman, Black, Cushman, Grimm, Oparil,Whelton, Proschan, Ford, Piller, Goff, Lucente,Margolis, Williamson, Ragusa.Acquisition of data:Wright, Davis, Alderman, Black,Cushman, Grimm, Haywood, Leenen, Oparil,Probstfield, Whelton, Einhorn, Ford, Piller, Pressel,deLeon, Simpson, Blanton, Geraci, Walsh, Nelson,Rahman, Juratovac, Pospisil, Carroll, Sullivan, Russo,Christian, Feldman, Lucente, Calhoun, Jenkins,McDowell, Johnson, Kingry,Alzate, Margolis, Holland,Jaeger, Williamson, Louis, Ragusa, Williard, Fergu-son, Tanner, Eckfeldt, Crow, Pelosi.Analysis and interpretation of data:Furberg, Wright,Davis, Cutler, Black, Cushman, Grimm, Haywood,Leenen, Oparil, Probstfield, Whelton, Nwachuku,Gordon, Proschan, Einhorn, Ford, Piller, Dunn, Goff,Pressel, Bettencourt, Simpson, Rahman, Barone,

Williamson.Drafting of the manuscript:Furberg, Wright, Davis,Cutler,Alderman, Black, Cushman, Grimm, Haywood,Leenan, Oparil, Probstfield, Whelton, Nwachuku,Gordon, Proschan, Einhorn, Ford, Piller, Dunn, Goff,Pressel, Bettencourt, Simpson, Rahman, Kingry,Margolis, Williamson.Critical revision of the manuscript for important in-tellectual content:Furberg, Wright, Davis, Cutler,Alderman, Black, Grimm, Haywood, Leenen, Oparil,Probstfield, Whelton, Nwachuku, Gordon, Proschan,Einhorn,Ford, Piller, Dunn, Goff,Pressel,Bettencourt,





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deLeon, Simpson, Geraci, Walsh, Rahman, Pospisil,Carroll, Sullivan, Russo, Barone, Christian, Feldman,Lucente, Calhoun, Jenkins, McDowell, Johnson, Kingry,Alzate,Margolis, Williamson, Louis,Williard, Ferguson,Tanner, Pelosi.Statistical expertise:Davis,Whelton, Proschan, Ford,Dunn, Pressel.Obtained funding:Davis, Cutler, Black, Einhorn,Ford,Goff, Sullivan.

Administrative,technical,or material support:Furberg,Wright, Davis, Cutler, Alderman, Black, Cushman,Grimm, Haywood, Oparil, Probstfield, Whelton,Nwachuku, Gordon, Einhorn, Ford, Piller, Pressel,Bettencourt,deLeon, Simpson, Blanton, Geraci,Walsh,Nelson, Rahman, Juratovac, Pospisil, Carroll, Russo,Barone, Christian, Feldman, Lucente, Jenkins,McDowell, Johnson, Kingry,Alzate, Margolis, Holland,Jaeger, Louis, Williard, Ferguson, Tanner, Eckfeldt,Pelosi.Study supervision: Furberg, Wright, Davis, Cutler,Black, Cushman, Grimm, Haywood, Leenen, Oparil,Probstfield, Ford, Pressel, Lucente, Alzate, Holland,Jaeger, Eckfeldt.Funding/Support: Thisstudywas supportedby con-tract NO1-HC-35130 with theNational Heart, Lung,andBlood Institute(NHLBI). ALLHAT investigatorsre-ceived contributions of study medications supplied byPfizer (amlodipine and doxazosin), AstraZeneca (aten-

olol and lisinopril), and Bristol-Myers Squibb (prava-statin), and financial support provided by Pfizer.Role of theSponsor: The NHLBIsponsored the studyand was involved in all aspects other than direct op-erations of the study centers. This included collec-tion, analysis, and interpretation of the data in addi-tion to the decision to submit the manuscript forpublication.Dedication: Special recognition is due to 3 ALLHATleaders who died in recent years after making verysignificant contributions to initiating the trial andover-seeingmost of itscourse: RichardCarleton,MD, Chair-manof theDataand SafetyMonitoring Board (1994-2000); H. Mitchell Perry, Jr, MD, member of theSteering Committee and Deputy Physician Coordina-torfor Region1 (1994-2001);and Peter Frommer, MD,National Heart, Lung, and Blood Institute DeputyDirector Emeritus, advisor to the Project Officers, andliaison to participating pharmaceutical companies

(1993-2002).Members of the ALLHAT Group: Steering Commit-tee:Furberg, Wright, Davis, Cutler, Alderman, Black,Cushman, Grimm,Haywood, Leenen, Oparil, Probst-field, Whelton; NHLBI Project Office:Cutler, Nwa-chuku, Gordon, Proschan, Einhorn;ALLHAT ClinicalTrials Center: Davis, Ford, Piller,Dunn,Pressel, Betten-court, deLeon, Simpson, Blanton; ALLHAT Regions:Veterans Administration, Memphis, Tenn: Cush-man,Geraci, Walsh, Nelson; Cleveland, Ohio:Wright,Rahman, Juratovac, Pospisil, Suhan; Bronx, NY: Al-derman, Carroll, Russo, Sullivan; Chicago, Ill:Black,Barone, Christian, Feldman, Lucente; Birmingham,Ala:Oparil, Calhoun, Jenkins, McDowell; Seattle, Wash:Probstfield; Alzate, Johnson, Kingry; Minneapolis,Minn: Grimm, Margolis, Holland, Jaeger; New Or-leans, La (formerlylocatedin Baltimore,Md):Whelton,Williamson,Louis, Ragusa, Williard, Adler; Ottawa, On-tario, Canada: Leenen, Ferguson, Tanner; ALLHAT

Central Laboratory:J. Eckfeldt, J. Bucksa, M. Now-icki; ALLHAT Drug Distribution Center:J. Pelosi;ALLHAT Electrocardiogram Reading Center:R. Crow,S. Thomas; ALLHAT Data and Safety MonitoringBoard:R. Califf, W. Applegate, J. Buring, E. Cooper,K. Ferdinand, M. Fisher, R. Gifford, S. Sheps.Investigatorsand Coordinators Participatingin the An-tihypertensive and Lipid Trials, United States: Ala-bama:L. Ada, D. Alexander, L. Black, C. Davis, W.Davis, S. Farooqui, H. Fritz, T. Kessler, S. Ledbetter,L. Means, J. Patterson, N. Qureshi, L. Redcross, R.Reeves, T.Tucker, N. Wettermark,A. Williams, W. Yar-

brough;Arizona:I. Cohen, W. Dachman, N. Estrada,J. Felicetta, D. Fowler, R. Fowler, S. Goldman, C. Lui,S. Morris, D. Morrison, J. Nelson, J. Ohm, D. Paull,G. Pulliam, D. Roberts, I. Ruiz, H. Thai; Arkansas:J.Acklin, M. Azhar, F. Berry, D. Burns, W. Carter, M.Dixon, S. Eldridge, A. Fendley, H. Fendley, M. Flow-ers,S. Goss,M. Guyer, G.Harris, M.Hawkins, D. Hop-son, P. Kern, R. King, M. Lynch, E. Maples, R.McCafferty, M. McGehee, J. Miller, D. Neil, M.

Oakum, N. Paslidis, K. Riordan, G. Robbins, D. Sim-mons, C. Vilayvanh, S. Whitmer; California:C. Al-varez, D. Anderson, M. Ariani, S. Barrett, J. Boggess,B. Brackeen, A. Bui, P. Callaham, M. Calong, J. Ca-macho, J. Cavendish, G. Chao, D. Cheung, B. Chris-tianson, W. Dempsey, G. Dennish, V. DeQuattro, R.Dharawat, D. Dizmang, N. Doherty, M. Donnell, S.Edmondson, D. Falcone, S. Franklin,J. Frazee, G. Friv-old, S. Ghattas, D. Goldfarb-Waysman, T. Haskett, L.Haywood, N. Horton, Y. Huang, K. Hui, N. Jacob, K.Jolley, B. Jurado, A. Karns, R. Karns, K. Karunaratne,A. Katchem, L. Katchem, J. Khoo, E. Kiger, L. Klein-man, J.

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