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
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 disease (CHD) or other cardiovascular disease (CVD) events vs treatment
with a diuretic.
Design The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT), a randomized, double-blind, active-controlled clinical
trial conducted from February 1994 through March 2002.
Setting and
Participants A total of 33 357
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 = 15 255); 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 nonfatal 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 angina
without hospitalization, heart failure [HF], and peripheral arterial disease).
Results Mean follow-up was 4.9 years. The primary outcome occurred in 2956
participants, 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 amlodipine (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 systolic 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
antihypertensive therapy.
JAMA. 2002;288:2981-2997
Treatment and complications among the 50 to 60
million people in the United States with hypertension are estimated to cost $37
billion annually, with antihypertensive drug costs alone accounting for an
estimated $15.5 billion 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,
several newer classes of antihypertensive agents (ie, angiotensin-converting
enzyme [ACE] inhibitors, calcium channel blockers [CCBs], -adrenergic blockers, and more recently
angiotensin-receptor blockers) became available. Over the past decade, major
placebo-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 uncertainty regarding effects of some classes of
antihypertensive drugs on risk of 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 patients with diabetes also needed to be
established.17
The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind,
multicenter clinical trial sponsored by the National Heart, Lung, and Blood
Institute, was designed to determine whether the occurrence of fatal CHD or
nonfatal myocardial infarction is lower for high-risk patients with
hypertension treated with a CCB (represented by amlodipine), an ACE inhibitor
(represented by lisinopril), or an -blocker (represented by doxazosin), each compared with diuretic
treatment (represented by chlorthalidone).18 Chlorthalidone was
found to be superior to doxazosin and was previously reported after early
termination of the doxazosin arm of the trial.19, 20 Secondary outcomes
included all-cause mortality, stroke, and other cardiovascular disease (CVD)
events. A lipid-lowering subtrial was designed to determine whether lowering
cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
(pravastatin) compared with usual care reduced all-cause mortality in a
moderately hypercholesterolemic subset of ALLHAT participants.18, 21 To evaluate
differences in CVD effects of the various first-step drugs, ALLHAT was designed
with a large sample size (9000-15 000 participants/intervention arm) and
long follow-up (4-8 years). This study presents results of the amlodipine and
lisinopril vs chlorthalidone comparisons on major CVD outcomes.
Study Design
The rationale and design of ALLHAT have been presented elsewhere.18 Participants were men
and women aged 55 years or older who had stage 1 or stage 2 hypertension with
at least 1 additional 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 atherosclerotic CVD. Individuals with a history of
hospitalized or treated symptomatic 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 randomized study drug, at which point they stopped taking
all previous medications. Treatment with the study drug was initiated the day
after randomization. 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 center, stratified by center and blocked in random block sizes of 5 or 9
to maintain balance. Participants (n = 33 357) were recruited at 623
centers in the United States, Canada, Puerto Rico, and the US Virgin Islands
between February 1994 and January 1998. (The original reported number of 625
sites changed because 2 sites and their patients with poor documentation of
informed consent were excluded.20) All participants
gave written informed consent, and all centers obtained institutional review
board approval. Follow-up visits were at 1 month; 3, 6, 9, and 12 months; and
every 4 months thereafter. The range of possible follow-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 assigned study drug (step 1) and
adding open-label agents (step 2 or 3) when necessary. The choice of step 2
drugs (atenolol, clonidine, or reserpine) was at the physician's discretion.
Nonpharmacologic approaches to treatment of hypertension were recommended
according to national guidelines.4, 23 Step 1 drugs were
encapsulated and identical in appearance so that the identity of each agent was
double-masked at each dosage level. Dosages were 12.5, 12.5 (sham titration),
and 25 mg/d for chlorthalidone; 2.5, 5, and 10 mg/d for amlodipine; and 10, 20,
and 40 mg/d for lisinopril. 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 reserpine; 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, including low doses of open-label step 1 drug classes,
were permitted if clinically indicated.18, 20
Outcomes
The primary outcome was fatal CHD or nonfatal myocardial infarction combined.18 Four major
prespecified secondary outcomes were all-cause mortality, fatal and nonfatal stroke,
combined CHD (the primary outcome, coronary revascularization, hospitalized
angina), and combined CVD (combined CHD, stroke, other treated angina, HF
[fatal, hospitalized, or treated nonhospitalized], and peripheral arterial
disease). Coronary revascularization included coronary artery bypass graft,
percutaneous angioplasty, insertion of stents, and atherectomy. Individual
components of the combined outcomes were prespecified and examined, as were
other secondary outcomes including cancer, incident electrocardiographic left
ventricular hypertrophy, end-stage renal disease (ESRD) (dialysis, renal
transplant, or death), and slope of the reciprocal of longitudinal serum
creatinine measurements. Change in estimated glomerular filtration rate24, 25 was examined post
hoc.
Study outcomes were assessed at follow-up visits
and reported to the clinical trials center.18 Hospitalized outcomes
were primarily based on clinic investigator reports, and copies of death
certificates and hospital discharge summaries were requested. Among all
combined CVD events that resulted in deaths, hospitalizations, or both, the
proportion with documentation (ie, a death certificate or a hospital discharge
summary) was 99% in all 3 treatment 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 databases. A death was ascertained by clinic report or
by match with the aforementioned databases plus a confirmatory death
certificate. A death pending confirmation is one found using databases but for
which a confirmatory death certificate has not yet been obtained. Medical
reviewers from the clinical trials center verified the physician-assigned
diagnoses of outcomes using death certificates and hospital discharge
summaries. More detailed information was collected on a random (10%) subset of
CHD and stroke events to validate the procedure of using physician diagnoses.18 When a large excess
of HF became evident in the doxazosin arm, a 1-time sample of HF
hospitalizations was reviewed by the ALLHAT Endpoints Subcommittee. Agreement
rates between the subcommittee and clinic investigators were 90% (155/172) for
the primary outcome, 85% (33/39) for HF hospitalizations,26 and 84% (129/153) for
stroke, and were similar in all treatment groups.
Two major safety outcomes, angioedema and hospitalization
for gastrointestinal bleeding, were prespecified. Occurrence of
gastrointestinal bleeding was ascertained from Center for Medicare and Medicaid
Services and Department of Veterans Affairs hospitalization databases,
representing 74% of ALLHAT participants (persons 65 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, treatment 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 presented only
through 6 years, both the log-rank test and Cox proportional hazards regression
model incorporated the participant's entire trial experience to evaluate
differences between cumulative event curves and to obtain 2-sided P values. Only the Cox proportional hazard
regression results are presented, because P
values were essentially identical. Hazard ratios (relative risks [RRs]) and 95%
confidence intervals (CIs) were obtained from the Cox proportional hazards
regression model.29 For consistency with = .0178, 95%
CIs may be converted to 98.2% limits 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 proportional 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)
diabetic and nondiabetic participants, and the post hoc subgroups presence or
absence of CHD at baseline, was examined 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 annually 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 differences, and conditional power was used to assess
futility.30, 31
Patient Characteristics
Table 1
presents baseline characteristics for the 33 357 participants in the
chlorthalidone, amlodipine, and lisinopril 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 factors in the
3 treatment groups.22
Visit and Medication Adherence
Figure 1
shows the number of participants randomized and followed up to the time of
closeout. In all 3 treatment groups, the mean (SD) length of follow-up was 4.9
years (1.4 years), and 99% of expected person-years were observed. The maximum
range of follow-up was 8.0, 7.9, and 8.1 years in the chlorthalidone,
amlodipine, and lisinopril groups, respectively. At trial closeout, 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 status, the distributions of most baseline factors were similar
among the 3 treatment groups, but participants assigned to lisinopril were less
likely to be black and more likely to be women, have untreated hypertension,
evidence of CHD or atherosclerotic CVD, and a lower mean serum glucose.
Visit adherence decreased over time from about
92% at 1 year to 84% to 87% at 5 years in all 3 treatment groups (Table 2).
Among participants in the chlorthalidone group who were contacted in the clinic
or by telephone within 12 months of annual scheduled visits, 87.1% were taking
chlorthalidone or another diuretic at 1 year, decreasing to 80.5% at 5 years;
67.5% (n = 4387) were taking a diuretic without 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 taking either a CCB (5.8% [n = 399]) or an ACE
inhibitor (5.6% [n = 385]) without a diuretic at 5 years.
Among participants in the amlodipine group,
87.6% were taking amlodipine or another CCB at 1 year, decreasing to 80.4% at 5
years; and 63.8% (n = 2502) were taking a CCB alone without a diuretic. Another
16.6% were taking 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, decreasing to 72.6% at 5 years;
56.9% (n = 2143) were taking an ACE inhibitor alone without a diuretic; and
15.7% were taking an ACE inhibitor with a diuretic at 5 years. About 8.5% were
taking a diuretic without an ACE inhibitor.
The most common reasons for not taking step 1
medication at 5 years in the chlorthalidone, amlodipine, and lisinopril groups
were unspecified refusals (41.4% [n = 775], 40.5% [n = 443], and 37.9% [n =
552], respectively) and symptomatic 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, amlodipine, 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%, respectively. 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 lisinopril, respectively, still
taking their blinded medication were receiving the maximal study dose. At 5
years, the percentages were 56.9% (n = 2629), 65.7% (n = 1856), and 60.3% (n =
1391), respectively.
Intermediate Outcomes
Given the large sample size in ALLHAT, almost all differences in follow-up BP
and biochemical measurements were statistically significant (Table 3
and Table 4).
Mean seated BP at randomization was about 146/84 mm Hg in all 3 groups, with
90% of participants reporting current antihypertensive drug treatment (Table 1).
Follow-up BPs in all 3 groups are shown in Table 3
and Figure 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 participation in the
ALLHAT lipid trial. Mean serum potassium levels at baseline and follow-up are
also shown; about 8% of the chlorthalidone group were receiving potassium
supplementation at 5 years compared with 4% in the amlodipine group and 2% in
the lisinopril group. Among individuals classified as nondiabetic at baseline,
with baseline fasting serum glucose less than 126 mg/dL (7.0 mmol/L), incidence
of diabetes (fasting serum glucose, 126
mg/dL [7.0 mmol/L]) at 4 years was 11.6%, 9.8%, and 8.1%, respectively.
Mean estimated glomerular filtration rate at
baseline was about 78 mL/min per 1.73 m2 in all groups. At 4 years,
it was 70.0, 75.1, and 70.7 mL/min per 1.73 m2 in the
chlorthalidone, amlodipine, and lisinopril groups, respectively. The slopes of
the reciprocal of serum creatinine over time were virtually identical in the
chlorthalidone 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 significant difference was observed between amlodipine and chlorthalidone
for the primary outcome (RR, 0.98; 95% CI, 0.90-1.07) or for the secondary
outcomes of all-cause mortality, combined CHD, stroke, combined CVD, angina,
coronary revascularization, peripheral arterial disease, cancer, or ESRD (Table 5,
Figure 3,
and Figure 4).
The amlodipine group had a 38% higher risk of HF (P<.001) with a 6-year absolute risk difference of 2.5% and
a 35% higher risk of hospitalized/fatal HF (P<.001).
The treatment effects for all outcomes were consistent across the predefined
subgroups (Figure 5)
and by absence or presence of CHD at baseline. Cause-specific mortality rates
(except for unintentional injuries/suicides/homicides in amlodipine compared
with chlorthalidone, not a prespecified hypothesis) were similar for the 2
groups (Table 6).
Lisinopril vs Chlorthalidone
No significant difference was observed between lisinopril and chlorthalidone
for the primary outcome (RR, 0.99; 95% CI, 0.91-1.08) or for the secondary outcomes
of all-cause mortality, combined CHD, peripheral arterial disease, cancer, or
ESRD (Table 5,
Figure 3
and Figure 4).
Cause-specific mortality rates were also similar in the 2 groups (Table 6).
The lisinopril group had a 15% higher risk for stroke (P = .02) and a 10% higher risk of combined
CVD (P<.001), with a 6-year
absolute risk difference for combined CVD of 2.4%. Included in this analysis was
a 19% higher risk of HF (P<.001),
a 10% higher risk of hospitalized/fatal HF (P
= .11), an 11% higher risk of hospitalized/treated angina (P = .01), and a 10% higher risk of
coronary revascularization (P =
.05). The treatment effects for all outcomes were consistent across subgroups
by sex, diabetic status (Figure 6),
and baseline CHD status. For combined CHD, there was a significant differential
effect by age (P = .01 for
interaction) with RRs (lisinopril vs chlorthalidone) of 0.94 for those less
than 65 years vs 1.11 in those 65 years or older. However, when age was modeled
as a continuous variable, there was no significant interaction. For stroke and
combined CVD, there was a significant differential effect by race (P = .01 and P = .04 for interaction, respectively). The RRs (lisinopril
vs chlorthalidone) were 1.40 (95% CI, 1.17-1.68) and 1.00 (95% CI, 0.85-1.17)
for stroke and 1.19 (95% CI, 1.09-1.30) and 1.06 (95% CI, 1.00-1.13) for
combined CVD in blacks and nonblacks, respectively.
The mean follow-up systolic BP for all
participants was 2 mm Hg higher in the lisinopril group than the chlorthalidone
group, 4 mm Hg higher in blacks, and 3 mm Hg higher in those 65 years or older.
Adjustment for follow-up BP as time-dependent covariates in a Cox proportional
hazards regression model slightly reduced the RRs for stroke (1.15 to 1.12) and
HF (1.20 to 1.17) overall and in the black subgroup (stroke, 1.40 to 1.35; and
HF, 1.32 to 1.26), but the results remained statistically significant.
Primary Safety Outcomes
Six-year rates of hospitalization for gastrointestinal bleeding, available only
in Medicare and Department of Veterans Affairs participants, occurred in 8.8%,
8.0%, and 9.6% participants in the chlorthalidone, amlodipine, and lisinopril
treatment groups, respectively, with no significant differences (Table 5).
Angioedema occurred in 8 of 15 255 (0.1%), 3 of 9048 (<0.1%), and 38 of
9054 (0.4%) persons in the chlorthalidone, amlodipine, and lisinopril treatment
groups, respectively. Significant differences were seen for the lisinopril vs
chlorthalidone comparison overall (P<.001),
in blacks (2 of 5369 [<0.1%] for chlorthalidone, 23 of 3210 [0.7%] for
lisinopril; P<.001), and in
nonblacks (6 of 9886 [0.1%] for chlorthalidone, 15 of 5844 for lisinopril
[0.3%]; P = .002). The only death
from angioedema was in the lisinopril group.
Neither amlodipine (representing CCBs,
particularly dihydropyridine [DHP]–CCBs) nor lisinopril (representing ACE
inhibitors) was superior to chlorthalidone (representing thiazide-type
diuretics) in preventing major coronary events or in increasing survival.
Chlorthalidone was superior to amlodipine (by about 25%) in preventing HF,
overall, and for hospitalized or fatal cases, although it did not differ from
amlodipine in overall CVD prevention. Chlorthalidone was superior to lisinopril
in lowering BP and in preventing aggregate cardiovascular events, principally
stroke, HF, angina, and coronary revascularization. ALLHAT previously reported
that chlorthalidone was superior to doxazosin (representing -blockers) in reducing BP and preventing cardiovascular
events, particularly HF.19, 20
It is not surprising that no significant differences
in CHD and stroke rates were found between chlorthalidone and amlodipine-based
therapy in ALLHAT. In the Systolic Hypertension in the Elderly Program and the
Systolic Hypertension in Europe trial, in which a thiazide-like diuretic
(chlorthalidone) or a DHP-CCB was compared with a placebo, major CHD events
were reduced by 27% and 30%, and stroke by 37% and 42%, respectively.8, 9 More direct evidence
comes from 2 large active-controlled trials that compared DHP-CCB and
traditional first-step drugs. The Swedish Trial in Old Patients with
Hypertension-2 and the International Nifedipine GITS (long-acting gastrointestinal
formulation) Study: Intervention as a Goal in Hypertension Treatment (INSIGHT),
found no significant differences for major CHD or stroke rates between the
treatment groups.32, 33 Some of these
individual trials have had limited power to evaluate differences between
treatments.34 In meta-analyses
of 5 positive-controlled trials, which included both DHP-CCB and non–DHP-CCB
trials, there were trends that favored CCB-based therapy for stroke and
traditional treatment for CHD, with no difference for all-cause mortality.13, 14 However, ALLHAT
observed approximately the same number of strokes and nearly twice as many CHD
events as all 5 trials combined, which suggests that the aggregate of the
evidence would indicate no difference between CCB-based treatment and
diuretic-based treatment for these outcomes.
The amlodipine vs chlorthalidone findings for HF
reinforce previous trial results. In the diuretic-based Systolic Hypertension
in the Elderly Program, active therapy reduced HF occurrence by 49% compared
with placebo (P<.001),
although in the DHP-CCB–based Systolic Hypertension in Europe trial, it was
reduced by 29% (not statistically significant).9, 35 In the INSIGHT trial,
HF was approximately twice as frequent in the CCB vs the diuretic arm.33 The previously cited
meta-analyses reported a higher rate of HF with CCB-based treatment than
traditional regimens, with no difference in RR for DHPs compared with non–DHPs.13, 14
A body of literature based on observational
studies and secondary CHD prevention trials of short-acting CCBs has suggested
that CCBs, especially DHP-CCBs, may increase the risk of cancer,
gastrointestinal bleeding, and all-cause mortality.14, 36, 37 The results of ALLHAT
do not support these findings. In fact, the mortality from noncardiovascular
causes was significantly lower in the CCB group (Table 6).
There were no significant differences in the
incidence of ESRD between chlorthalidone and amlodipine, consistent with
findings from the INSIGHT trial.33 Comparison of the
reciprocal serum creatinine slopes suggested a slower decline in kidney
function in the amlodipine group. However, this finding requires cautious
interpretation because studies assessing glomerular filtration rate more
directly have shown a hemodynamically mediated acute increase in glomerular
filtration rate followed by a more rapid rate of decline with chronic therapy
using amlodipine and other CCBs.38-40
Comparison of the lisinopril and chlorthalidone
groups revealed better drug tolerance and BP control with chlorthalidone.
Angioedema, a rare but potentially serious adverse effect of ACE inhibitor use,
occurred 4 times more frequently in participants randomized to lisinopril than
in those randomized to chlorthalidone. Cholesterol levels, the prevalence of
hypokalemia (serum potassium <3.5 mEq/L), and new diabetes (fasting glucose 126 mg/dL [7.0 mmol/L]) were higher in the chlorthalidone than the other
groups following 2 and 4 years of follow-up. Overall, these metabolic
differences did not translate into more cardiovascular events or into higher
all-cause mortality in the chlorthalidone group compared with the other 2
groups.
The ALLHAT findings for some major outcomes are
consistent with predictions from placebo-controlled trials involving ACE
inhibitors and diuretics. Specifically, for ACE inhibitor and diuretic trials,
respectively, the reductions in CHD rates were 20% and 18%, and for all-cause
mortality, 16% and 10%.13 The 10% greater rate
of combined CVD in the lisinopril than in the chlorthalidone group was due to
increased occurrences of stroke, HF, angina, and coronary revascularization. Results
for some of these outcomes may seem surprising, because of reports of
beneficial effects of ACE inhibitors on surrogate markers of atherosclerosis
and reductions in vascular and renal events in individuals with HF, diabetes,
kidney disease, and cerebrovascular disease in placebo-controlled trials.41-43 However, the
finding in ALLHAT that HF incidence was lower in the diuretic vs the ACE
inhibitor group is also consistent with previous reports. In the Systolic
Hypertension in the Elderly Program trial (chlorthalidone vs placebo), there
was a 49% decrease in the development of HF, whereas in the Studies of Left
Ventricular Dysfunction Prevention (enalapril vs placebo) and Heart Outcomes
Prevention Evaluation trials (ramipril vs placebo), there were only 20% and 23%
reductions, respectively.8, 10, 44 In published
meta-analyses of placebo-controlled trials, the reductions in rates for stroke
with ACE inhibitor and diuretics were 30% and 34%, translating into nearly
equivalent results.3, 13 The 15% relative
increase in stroke incidence for lisinopril compared with chlorthalidone
treatment in ALLHAT must be considered in the context of heterogeneity of the
results by race. The Swedish Trial in Old Patients with Hypertension-2 trial,
which compared ACE inhibitors with conventional treatment (diuretics and/or -blockers), showed
no significant differences in CHD, stroke, HF, or all-cause mortality.32 Although these
findings are somewhat different from the experience in ALLHAT, consideration
needs to be given to respective confidence limits, population differences
(especially race), and study designs (open vs double-blind).
No substantial differences in incidence of ESRD,
glomerular filtration rate, or reciprocal creatinine slopes were noted for the
lisinopril vs chlorthalidone comparisons. The ALLHAT study population was
selected for high CVD risk and had a baseline mean creatinine of only 1.0 mg/dL
(88.4 µmol/L). More detailed analyses of high renal risk subgroups (ie,
diabetic, renal-impaired, and black patients) will be the subject of subsequent
reports.
Analyses of RRs for stroke and HF adjusted for
follow-up BP suggest that the 2-mm Hg systolic BP difference overall (4 mm Hg
in black patients) between the lisinopril and chlorthalidone groups only
partially accounts for the observed CVD event difference. However, such
analyses are limited by the infrequency and imprecision of BP measurements for
individual participants and regression dilution, which underestimates CVD risk
associated with BP differences based on single-visit (or even visit-averaged)
measurements.45 Such modeling
is also unable to account for differences among individuals due to other
unmeasured or poorly represented risk factors; thus, participants who lower
their BP by a given amount with one drug may not be comparable to those who
lower their BP by the same magnitude with another drug.
Using an external standard of pooled results of
long-term hypertension treatment trials and observational studies (10-12 mm Hg
systolic BP difference associated with 38% stroke reduction), a 2- to 3-mm Hg
difference in BP might account for a 6% to 12% difference in stroke rates.45, 46 This is consistent
with the observed 15% difference for stroke overall but not with the difference
seen in black patients (13%-16% expected, 40% observed). For the HF outcome,
trial results in isolated systolic hypertension suggest that a 3-mm Hg higher
systolic BP could explain a 10% to 20% increase in risk.8, 47 The forgoing ignores
the absence of a diastolic BP difference in ALLHAT; however, the relationship
of diastolic pressure and CVD events in elderly persons who often have
increased pulse pressure is not entirely clear.48
The primary and secondary outcome results for
the amlodipine vs chlorthalidone group comparisons were consistent for all
subgroups of participants: older and younger, men and women, black and
nonblack, diabetic and nondiabetic. For the lisinopril vs chlorthalidone
comparisons, results were generally consistent by age, sex, and diabetic
status. Thus, for the important diabetic population, lisinopril appeared to
have no special advantage (and amlodipine no particular detrimental effect) for
most CVD and renal outcomes when compared with chlorthalidone. In fact,
chlorthalidone was superior to lisinopril for several CVD outcomes and superior
to amlodipine for HF in both diabetic and nondiabetic participants. The
consistency of the ALLHAT findings across multiple patient subgroups provides
confidence in the ability to generalize the findings to most patients with
hypertension.
In the lisinopril vs chlorthalidone comparisons,
there were 2 outcomes with significant interactions. The greater differences
observed in black vs nonblack patients for combined CVD and stroke, along with
a similar trend for HF and lesser BP lowering with lisinopril, are in accord
with the multiple reports of poorer BP response with ACE inhibitor in black
patients.49-51 They are
also consistent with reports of lesser effects of ACE inhibitors in secondary
prevention of HF in this population,52, 53 although these
findings have been recently questioned.54 The differential
responses for disease outcomes parallel the lesser response in the black
subgroup for BP, although the differences in outcomes are not substantially
reduced by statistically adjusting for systolic BP.
Although subordinate to safety and efficacy, the
cost of drugs and medical care for the individual and society is a factor that
should be considered in the selection of antihypertensives. One of the stated
objectives of ALLHAT was to answer the question, "Are newer types of
antihypertensive agents, which are currently more costly, as good or better
than diuretics in reducing CHD incidence and progression?"18 Consideration of drug
cost could have a major impact on the nation's health care expenditures. Based
on previous data that showed that diuretic use declined from 56% to 27% of
antihypertensive prescriptions between 1982 and 1992, the health care system
would have saved $3.1 billion in estimated cost of antihypertensive drugs had
the pattern of prescriptions for treatment of hypertension remained at the 1982
level.55 Further
economic analyses based on the results of ALLHAT are under way.
The strengths of ALLHAT include its randomized
double-blind design, statistical power to detect clinically meaningful
differences in CVD outcomes of interest, diverse population with adequate
representation from subgroups of special interest in the treatment of
hypertension, and varied practice-based settings. In addition, the agents that
were directly compared represent 3 of the most commonly used newer classes of
antihypertensives vs the best studied of the older classes.
Some limitations are worth noting. After ALLHAT
was designed, newer agents have been or may soon be released (eg,
angiotensin-receptor blockers, selective aldosterone antagonists), which were
not evaluated. Although clinical centers were blinded to the regimen and urged
to achieve recommended BP goals, equivalent BP reduction was not fully achieved
in the treatment groups. Furthermore, because diuretics, ACE inhibitors, CCBs,
and -blockers were
evaluated in the trial, the agents available for step-up led to a somewhat
artificial regimen (use of sympatholytics rather than diuretics and CCBs) of step-up
drugs in the ACE inhibitor group. This may have contributed to the higher BPs
in the ACE inhibitor group, especially in the black subgroup. However, mean
follow-up BPs were well below 140/90 mm Hg in all treatment groups. Although
ALLHAT did not compare a -blocker to
chlorthalidone, previous trials have suggested equivalence45 or even inferiority3 for major CVD events.
The ALLHAT results apply directly to
chlorthalidone, amlodipine, and lisinopril. Combined with evidence from other trials,
we infer that the findings also broadly apply to the drug classes (or subclass
in the case of the dihydropyridine CCBs) that the study drugs represent. The
evidence base for selection of antihypertensive agents has been markedly
strengthened by the addition of ALLHAT.
In conclusion, the results of ALLHAT indicate
that thiazide-type diuretics should be considered first for pharmacologic
therapy in patients with hypertension. They are unsurpassed in lowering BP,
reducing clinical events, and tolerability, and they are less costly. For
patients who cannot take a diuretic (which should be an unusual circumstance),
first-step therapy with CCBs and ACE inhibitors could be considered with due
regard for their higher risk of 1 or more major manifestations of CVD. Since a
large proportion of participants required more than 1 drug to control their BP,
it is reasonable to infer that a diuretic be included in all multidrug
regimens, if possible. Although diuretics already play a key role in most
antihypertensive treatment recommendations, the findings of ALLHAT should be
carefully evaluated by those responsible for clinical guidelines and be widely
applied in patient care.
Author/Article Information
ALLHAT Authors/Officers and Coordinators:
Curt D. Furberg, MD, PhD; Jackson T. Wright, Jr, MD, PhD; Barry R. Davis, MD,
PhD; Jeffrey A. Cutler, MD, MPH; Michael Alderman, MD; Henry Black, MD; William
Cushman, MD; Richard Grimm, MD, PhD; L. Julian Haywood, MD; Frans Leenen, MD;
Suzanne Oparil, MD; Jeffrey Probstfield, MD; Paul Whelton, MD, MSc; Chuke
Nwachuku, MA, MPH; David Gordon, MD, PhD; Michael Proschan, PhD; Paula Einhorn,
MD, MS; Charles E. Ford, PhD; Linda B. Piller, MD, MPH; J. Kay Dunn, PhD; David
Goff, MD, PhD; Sara Pressel, MS; Judy Bettencourt, MPH; Barbara deLeon, BA;
Lara M. 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 Sullivan, BA; Jeanne Russo, BSN; Gail
Barone, RN; Rudy Christian, MPH; Sharon Feldman, MPH; Tracy Lucente, MPH; David
Calhoun, MD; Kim Jenkins, MPH; Peggy McDowell, RN; Janice Johnson, BS; Connie
Kingry, RN, BSN; Juan Alzate, MD; Karen L. Margolis, MD; Leslie Ann
Holland-Klemme, BA; Brenda Jaeger; Jeffrey Williamson, MD, MHS; Gail Louis, RN;
Pamela Ragusa, RN, BSN; Angela Williard, RN, BSN; R. L. Sue Ferguson, RN;
Joanna Tanner; John Eckfeldt, MD, PhD; Richard Crow, MD; John Pelosi, RPh, MS.
Corresponding Authors and Reprints:
Jackson T. Wright, Jr, MD, PhD, Case Western Reserve University, General
Clinical Research Center, Suite 7311, Horvitz Tower, 11000 Euclid Ave,
Cleveland, OH 44106-5041 (e-mail: [log in to unmask]);
Barry R. Davis, MD, PhD, University of Texas-Houston Health Science Center,
School of Public Health, 1200 Herman Pressler St, Suite E801, Houston, TX 77030
(e-mail: [log in to unmask]).
Financial Disclosures: The following listed authors have served as consultants for,
received personal compensation from, were grant recipients of, or own stock in
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: Abbott, Bristol-Myers Squibb,
Forrest Labs, Merck, Pfizer, Pharmacia & Upjohn, GlaxoSmithKline; Alderman: Bristol-Myers Squibb, Merck,
Novartis, Pfizer, GlaxoSmithKline; Black:
Abbott, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Pharmacia &
Upjohn, GlaxoSmithKline, Solvay; Cushman:
AstraZeneca, Bristol-Myers Squibb, Forrest Labs, Merck, Pfizer, Pharmacia &
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:
Abbott, AstraZeneca, Aventis, Bayer, Bristol-Myers Squibb, DuPont, Forrest
Labs, King/Monarch, Merck, Novartis, 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; Rahman:
Abbott, Novartis, Pfizer, Searle; Lucente:
GlaxoSmithKline; Calhoun:
AstraZeneca, Aventis, Merck, Novartis, GlaxoSmithKline; Solvay; McDowell: Amgen, King/Monarch, Merck, Pfizer;
Alzate: Pfizer; Tanner: SGP; Eckfeldt: Johnson & Johnson.
Author Contributions: Dr Davis had full access to all the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analyses in this article and its companion article on page 2998 in the printed
journal.
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,
Ferguson, 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 intellectual content: Furberg, Wright, Davis, Cutler, Alderman, Black, Grimm, Haywood,
Leenen, Oparil, Probstfield, Whelton, Nwachuku, Gordon, Proschan, Einhorn,
Ford, Piller, Dunn, Goff, Pressel, Bettencourt, 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: This study was supported by contract NO1-HC-35130 with the National
Heart, Lung, and Blood Institute (NHLBI). ALLHAT investigators received
contributions of study medications supplied by Pfizer (amlodipine and
doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb
(pravastatin), and financial support provided by Pfizer.
Role of the Sponsor: The NHLBI sponsored the study and was involved in all aspects
other than direct operations of the study centers. This included collection,
analysis, and interpretation of the data in addition to the decision to submit
the manuscript for publication.
Dedication: Special recognition is due to 3 ALLHAT leaders who died in recent
years after making very significant contributions to initiating the trial and overseeing
most of its course: Richard Carleton, MD, Chairman of the Data and Safety
Monitoring Board (1994-2000); H. Mitchell Perry, Jr, MD, member of the Steering
Committee and Deputy Physician Coordinator for Region 1 (1994-2001); and Peter
Frommer, MD, National Heart, Lung, and Blood Institute Deputy Director
Emeritus, advisor to the Project Officers, and liaison to participating
pharmaceutical companies (1993-2002).
Members of the ALLHAT Group: Steering Committee:
Furberg, Wright, Davis, Cutler, Alderman, Black, Cushman, Grimm, Haywood,
Leenen, Oparil, Probstfield, Whelton; NHLBI
Project Office: Cutler, Nwachuku, Gordon, Proschan, Einhorn; ALLHAT Clinical Trials Center: Davis,
Ford, Piller, Dunn, Pressel, Bettencourt, deLeon, Simpson, Blanton; ALLHAT Regions: Veterans Administration, Memphis,
Tenn: Cushman, Geraci, Walsh, Nelson; Cleveland, Ohio: Wright, Rahman, Juratovac, Pospisil, Suhan;
Bronx, NY: Alderman, 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 Orleans, La (formerly
located in Baltimore, Md): Whelton, Williamson, Louis, Ragusa,
Williard, Adler; Ottawa, Ontario, Canada:
Leenen, Ferguson, Tanner; ALLHAT Central
Laboratory: J. Eckfeldt, J. Bucksa, M. Nowicki; ALLHAT Drug Distribution Center: J.
Pelosi; ALLHAT Electrocardiogram Reading
Center: R. Crow, S. Thomas; ALLHAT
Data and Safety Monitoring Board: R. Califf, W. Applegate, J.
Buring, E. Cooper, K. Ferdinand, M. Fisher, R. Gifford, S. Sheps.
Investigators and Coordinators
Participating in the Antihypertensive and Lipid Trials, United States: Alabama: 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. Yarbrough; 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. Flowers,
S. Goss, M. Guyer, G. Harris, M. Hawkins, D. Hopson, 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. Simmons, C. Vilayvanh, S. Whitmer; California: C. Alvarez, D. Anderson, M.
Ariani, S. Barrett, J. Boggess, B. Brackeen, A. Bui, P. Callaham, M. Calong, J.
Camacho, J. Cavendish, G. Chao, D. Cheung, B. Christianson, W. Dempsey, G.
Dennish, V. DeQuattro, R. Dharawat, D. Dizmang, N. Doherty, M. Donnell, S.
Edmondson, D. Falcone, S. Franklin, J. Frazee, G. Frivold, 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. Kleinman, J. Kozlowski, D. Kramer, E. Lee, D. Li,
C. Libanati, P. Linz, D. Lyle, T. Maekawa, M. Mahig, J. Mallery, D. Martins, B.
Massie, R. Mikelionis, S. Myers, J. Neutel, N. Nguyen, U. Okoronkwo, K. Owens,
T. Pan, R. Petersen, A. Schultz, H. Schultz, E. Schwartz, J. Schwartz, P.
Schwartz, C. Scott, Z. Song, J. Taylor, D. Townsend, S. Turitzin, D. Ujiiye, A.
Usman, D. Van Ostaeyen, R. Wadlington, C. Wan, L. Wang, H. Ward, L. Wieland, P.
Williams-Brown, N. Wong, R. Wright; Colorado:
K. Castleman, M. Chase, R. Hildenbrand, P. Lowe, P. Mehler, S. Mroz, R.
Simpson, R. Tello; Connecticut:
J. Bernene, L. Ciarcia, A. Grover, J. Judge, A. Lachman, J. Lawson, N. Medina,
E. Nestler, R. Schwartz, B. Sicignano, S. Solinsky; Washington, DC: J. Golden, E. Lewis, D. Mateski, P. Narayan,
A. Notargiacomo, D. Ordor, V. Papademetriou, O. Randall, T. Retta, J.
Theobalds, S. Xu; Delaware: D.
Crane, J. Lenhard; Florida: K.
Anderson, S. Beery, G. Bhaskar, B. Booker, K. Broderick, E. Capili-Rosenkranz,
J. Ciocon, G. Cohn, T. Connelly, V. Dallas, G. Duren, J. Durr, J. Evans, S.
Feld, R. Feldman, L. Fischer, S. Fisher, M. Formoso, S. Fulford, M. Galler, J.
Hildner, K. Holman, A. Jackson, C. Jackson, G. Khan, M. Khan, S. Kronen, J.
Lehmann, A. Littles, R. Lopez, N. Madhany, L. McCarty, K. Mullinax, M. Murray,
J. Navas, A. Peguero-Rivera, R. Preston, N. Rolbiecki, J. Rolle, L. Rosenfield,
O. Saavedra, A. Schlau, M. Stein, J. Stokes, S. Strickland, U. Tran, B. Videau,
J. Webster, T. Webster, A. Weinstein, T. Westfall, D. Williams, M. Yoham; Georgia: D. Anderson, R. Anderson, J.
Barzilay, S. Boyce, P. Brackett, P. Bradley, W. Brown, R. Carter, S. Carter, D.
Castro, L. Duty, H. Ellison, A. Francis, L. Goodman, D. Harrelson, T. Hartney,
J. Heldreth, J. Heneisen, A. Hicks, L. Hornsby, J. Hudson, S. Hurst, L.
Iskhakova; S. James, S. James, Y. Jones, K. Kersey, W. Kitchens, N. London, M.
Loraditch, G. Lowe, R. Maddox, R. Malcolm, D. Mathis, C. Mayers, M. McDaniel,
N. McPhail, A. Mikhail, H. Muecke, R. Noel, W. North, N. Parikh, D. Parish, G.
Peters, P. Poulos, M. Ram, W. Rawlings, R. Remler, C. Rice, M. Salles, D.
Sauers, A. Scheetz, C. Scott, L. Stevenson, J. Sumner, M. Sweeney, E. Taylor,
K. Upadhya, T. Vu, M. Walsh, K. Williams, H. Yager; Illinois: M. Arron, C. Bareis, J. Barnett, G. Barone, C.
Bermele, T. Bertucci, J. Cheng, J. Cruz, T. Denecke-Dattalo, S. Durfee, E.
Edwards, L. Fahrner, D. Farley, T. Flegel, M. Friedman, C. Gaca, J. Gilden, S.
Goldman, J. Graumlich, A. Hoffman, K. Hunt, C. Johnson, P. Kellums, A. Lasala,
N. Lasala, V. Lauderdale, M. Lesko, F. Lopez, M. Mansuri, S. Mansuri, M.
Martin, L. Moody, L. Morowczyneski, S. Mouritzen, N. Novotny, A. Ovalle, P.
Pedersen, N. Perlman, P. Porcelli, B. Ragona, R. Sadiq, P. Sands, C. Simmons,
K. Stevens, G. Sussman, D. Vicencio, A. Villafria, R. Villafria, R. Watkins; Indiana: J. Addo, J. Beliles, V. Dave, D.
Fausset, J. Fox, D. Fryman, J. Hall, J. Koehler, L. Leavy, P. Linden, E. Long,
H. Macabalitaw, T. Nguyen, B. Peterson, J. Pratt, D. Rosanwo, D. Ross, H. Shah,
V. Shah, T. Smith, M. Sobol, B. Viellieu-Fischer, J. Wachs, B. Weinberg; Iowa: V. Butler, A. Durbin, R. Glynn, B.
Hargens, W. Lawton, M. Roberts, J. Roepke, R. Schneider, G. Stanley; Idaho: M. Baker, R. Force, T. Gillespie,
S. Hillman, K. Krell, M. Macdonald; Kansas:
D. Courtney, B. Crawford, D. DeVore, J. Moppin, N. Premsingh, K.
Reuben-Hallock, R. Schanker, D. Wilson; Kentucky:
R. Berkley, M. DeMuro, L. Kazmierzak, A. Rayner, C. Tyler, E. Wells, S.
Winters; Louisiana: E. Aguilar,
L. Bass, V. Batuman, B. Beard, L. Borrouso, M. Campbell, C. Chubb, P. Connor,
C. Conravey, D. Doucet, M. Doucet, J. Dunnick, D. Eldridge, T. Eldridge, P.
Galvan, A. Gupta, J. Hollman, D. Hull, B. Jackson, T. Jones, A. Klenk, P.
Lakshmiprasad, B. Mahl, J. Paranilam, E. Reisin, H. Rothschild, J. Sampson, B.
Samuels, J. Schmitt, A. Smith, V. Valentino, C. Verrett, P. Willhoit; Maine: B. Blake, T. Lebrun, C. Walworth,
R. Weiss; Maryland: J. Burton, W.
Carr, P. Chance, S. Childs, C. Compton, J. Cook, V. Coombs, J. Daniels, P.
Death, L. Essandoh, Y. Ferguson, D. Fraley, M. Freedman, M. Gary, F. Gloth, S.
Gottlieb, M. Gregory, S. Hairston, P. Hall, B. Hamilton, J. Hamilton, D.
Harrison, D. James, B. Kerzner, A. Lancaster, H. Lutz, J. Marks, J. Martin, J.
Mersey, L. Nelson, E. Obah, S. Ong, J. Palacios, S. Park, M. Partlow, M.
Posner, H. Rachocka, M. Rubin, M. Rubinstein, M. Rykiel, C. Smith, B. Socha, K.
Thompson, K. Walker, J. Webber, K. Williams; Massachusetts:
L. Bradshaw, A. Chakraborty, F. DiMario, J. Ingelfinger, J. Pincus, A. Sobrado;
Michigan: L. Bey-Knight, D. Carson,
A. Cavanaugh, M. Chertok, K. Church, H. Colfer, I. Diaz, B. Dobbs, G. Edelson,
J. Fabello-Gamiao, S. Gappy, J. Grove, D. Johnson, M. Johnson, C. Jones, E.
Jones, T. Kelly, N. Kerin, B. Letzring, M. Oleszkowicz, A. Raffee, K. Rasikas,
C. Shaw, M. Siddique, B. VanOver, M. Zervos; Minnesota:
D. Berman, V. Canzanello, J. Curtis, V. Erickson, W. Goodall, J. Graves, K.
Guthrie, J. Haight, S. Hassing, J. Heegard, J. Holtzman, D. Jespersen, L.
Klein, C. Kubajak, L. Nylund, P. Spilseth; Missouri:
B. Appleton, R. Baird, S. Carmody, C. Carter, F. Charles, T. Finnigan, S.
Giddings, K. Gorman, M. Gregory, L. Johnson, S. Joseph, L. Kennington, R.
Kevorkian, J. LaSalle, B. Nolfo, J. Nunnelee, A. Orf, D. Palmer, H. Perry, A.
Quick, B. Rogers, B. Rosemergey, C. Scott, S. Sharma, V. Shortino, D. Smith, K.
Smith, C. Stanford, C. Tudor, T. Wiegmann; Mississippi:
C. Adair, S. Armstrong, C. Brown, N. Brown, R. Brown, S. Burke, L. Burrell, L.
Clark, S. Cooks, W. Crowell, D. Ellis, D. Graham, V. Green, R. Hall, S. Hamler,
D. Haymon, A. Hinton, M. Holman, A. James, P. Karim, K. Kirchner, A. Knotts, A.
Lott, W. McArthur, F. McCune, B. Miller, H. Morrow, R. Murphy, R. Myers, S.
Myers, A. Phillips, M. Puckett, E. Rankin, O. Ransome-Kuti, M. Reddix, R.
Rigsby, E. Searcy, D. Smith, A. Spann, Y. Tanner, E. Taylor-McCune, J. Tramuta,
H. Wheeler, M. Wofford; Montana:
L. Bigwood-Pecarina, S. English, H. Knapp, L. Sokoloski; Nebraska: M. Berry, E. Butkus, S. Byers,
D. Colan, R. Dobesh, N. Hilleman, R. Hranac, P. Klein, T. McKnight, S. Mohiuddin,
A. Mooss, R. Moyer, P. Myers, L. Rasmussen, J. Schafersman; Nevada: J. Chinn, R. Collins, E. Samols; New Jersey: S. Akgun, A. Bastian, L.
Bordone, N. Cosgrove, A. Costa, A. Cuyjet, S. Daniels, L. DeEugenio, L.
DeEugenio, R. Denniston, L. Duh, M. Farber, M. Farber, S. Ferguson, K.
Ferranti, G. Flanagan, J. Garofalo, H. Hassman, J. Hassman, H. Jacobs, J.
Kostis, A. Kudryk, M. Kutza, R. Liang, G. McArthur, B. McGann, R. Miller, E.
Moser, F. Nash, P. Niblack, E. Ogunmefun, M. Raghuwanshi, S. Sastrasinh, T.
Seely, J. Stanley, S. Suarez, A. Vaughn, R. Wong-Liang, J. Young, S.
Yuchnovitz, M. Zolnowski; New Mexico:
D. Graves, M. Groves, E. Iwan, J. Shipley; New
York: N. Almelda, S. Anderson, J. Andres, N. Ankomah, E. Anteola, C.
Assadi, M. Assadi, S. Atlas, J. Baruth, D. Barz, J. Begley, T. Bharathan, A.
Bova, D. Brautigam, C. Brown, S. Canaan, M. Candelas, P. Caraballo, J. Chapman,
L. Clark, K. Desai, D. Dowie, C. Dwyer, A. Farag, C. Flanders, P. Foster, L.
Gage, A. Gartung, S. Gedan, P. Gehring, J. Gorkin, D. Graber, H. Guber, P.
Gugliuzza, J. Halbach, A. Henriquez, M. Henriquez, D. Hoffman, J. Holland, C.
Hopkins, C. Hull, E. Ilamathi, K. Johnston, M. Karim, L. Katz, K. Kellick, S.
Kerlen, M. Krishnamurthy, D. Lainoff, R. Levin, V. Littauer, J. Lohr, M. Lorenz,
C. Lynott, J. Maddi, L. Marquart, K. Martin, M. Maw, R. Mendelson, S. Monrad,
A. Mustapha, A. Nafziger, M. Neary, J. Ngheim, A. Niarchos, M. Noor, M. Omoh,
J. Pickard, M. Pier, V. Pogue, C. Reddy, J. Ringstad, T. Rocco, C. Rosendorff,
H. Sandefur, A. Sass, R. Schifeling, D. Scott, P. Scriber, K. Sharma, C.
Shmukler, D. Shrivastava, M. Siegelheim, G. Smith, B. Snyder, C. Spiller, M.
Srivastava, S. Stevenson, A. Stewart, B. Sumner, M. Sweeney, K. Thomas, L.
Thomas, L. Trawlick, N. Velez, J. Vento, H. Viswaswariah, M. Yevdayeva, D.
Zimmerman; North Carolina: T.
Barringer, V. Bland, M. Burke-Ziglar, K. Caldwell, R. Caldwell, F. Celestino,
G. Cole, M. Darrow, B. Dunn, S. Fox, J. Holbrook, K. Jacobs, J. Lisane, L.
Loggans, A. Lowdermilk, R. Merrill, P. Miller, C. Perkins, L. Rodebaugh, V.
Schlau, R. Smith, J. Spruill, J. Summerson; North
Dakota: N. Chelliah, E. Garten, K. Hagen, S. Jafri, D. Vold, B.
Westacott; Ohio: L. Barnes-Lark,
C. Blanck, K. Casterline, D. Chen, K. Cowens, M. Cubick, D. Davidson, P. Dockery,
J. Finocchio, T. Gundrum, T. Hentenaar, D. Hulisz, D. Hull, K. Keaton, G.
Kikano, K. Klyn, L. Lazaron, D. Lukie, S. Medwid, L. Miller, R. Murden, H.
Neff, E. Ospelt, M. Patel, E. Pelecanos, E. Pfister, L. Sadler, M. Saklayen, A.
Salomon, A. Schmidt, S. Stein, D. Subich, D. Thiel, L. Thompson, R. Toltzis, J.
Tucker, D. Vidt, G. Wise, D. Wray; Oklahoma:
D. Abott, J. Cook-Greenwood, M. Jelley, R. Kipperman, J. Leverett, C. Manion,
S. Mears, B. Parker, R. Ringrose, L. Scholl, J. Schoshke, F. Shelton, M. Stephens,
U. Thadani, K. Walters; Oregon:
M. Dissanayake, S. Falley, H. Harris, S. MacKenzie, F. McBarron, S. Murray; Pennsylvania: G. Abbott, C. Baessler, M.
Benioff, A. Bowens, J. Burke, L. Carradine, K. Devine, M. Duzy, G. Dy, J.
Fontaine, D. Fox, W. Gilhool, J. Grasso, T. Ham, S. Heaney, J. Hefner, D. Herr,
L. Hollywood, L. Jones, M. Kauffman, E. Kemler, S. Koduri, N. Kopyt, S.
Kutalek, M. MacIntyre, R. Martsolf, A. McLeod, A. Miller, A. Minnock, Y.
Mishriki, D. Nace, L. Nagy, R. Olasin, C. Oschwald, N. Potts, R. Reinhard, R.
Reinhard, N. Roberts, B. Rogers, D. Sant Ram, F. Sessoms, M. Shore, S. Shore,
D. Singley, J. Spencer, D. Spigner, B. Springer, W. Swagler, P. Tanzer, S.
Walker, N. Walls, D. Whyte, S. Worley, G. Ziady; Puerto Rico: A. Agosto, J. Aguilera-Montalvo, H.
Algarin-Sanchez, J. Alvarado, I. Andino, J. Aponte Pagan, M. Arce, J. Benabe,
J. Cangiano, L. Catoni, J. Cianchini, J. Claudio, M. Collazo, P. Colon, Y.
Cruz-Lugo, J. DaMore, E. Edwards Volquez, A. Feliberti-Irizarri, P.
Felix-Ramos, J. Fernandez-Quintero, M. Geo, M. Gomez, R. Gomez Adrover, L.
Gonzalez-Bermudez, M. Guerrero, E. Guzman, J. Heredia, C. Irizarry, A. Leon, T.
Lugardo, G. Martinez, R. Martinez, M. Melendez, M. Natal, M. Padilla, W. Pagan,
Z. Perez, J. Pimentel, M. Pimentel Lebron, A. Ramos, M. Rios, C. Rivera, E.
Rivera, J. Rivera Santiago, E. Rodriquez, D. Romero, R. Ruiz, C. Sanchez, J.
Sanchez, M. Sosa-Padilla, I. Sotomayor-Gonzalez, J. Tavarez, I. Toro-Grajales,
B. Torres, N. Vazquez, S. Vazquez, M. Vega, Z. Vidal Oviedo, V. Zapata, I.
Zayas-Toro; Rhode Island: C.
Alteri, J. Galli, A. Hordes, L. Laflamme, K. MacLean, L. Marquis, R. Ruggieri,
S. Sharma; South Carolina: J.
Basile, L. Clarke, I. Coley, D. Devlin, S. Eggleston, G. Goforth, D. Ham, A.
Hampton, P. Hill, K. Jones, R. Jones, P. Jumper, A. Kitchens, C. Lieberman, J.
McAlpine, J. Moloo, A. Saenz, D. Sheek, A. Smith-Salley, P. Snape, J. Sterrett,
C. Stone, M. Strossner, C. Sullivan, T. Vear, D. Weathers, M. Weeks, J.
Williams, M. Williams; South Dakota:
C. Ageton, M. Brown, L. Dale, L. Duncan, S. Eckrich, P. Kearns, B. Lankhorst,
K. McDougall, V. Schuster, J. Wegenke, J. Woehl, E. Zawada; Tennessee: D. Anderson, C. Bounds, J.
Caldwell, W. Cannon, R. Cassidy, W. Cushman, C. DeJesus, L. Dilworth, S. Duffy,
B. Hamilton, T. Harrell, K. Harris, M. Herr, J. Jones, L. Jones, H. Marker, J.
Miller, S. Miller, F. Putman, A. Reaves, V. Rhule, H. Ross-Clunis, S.
Satterfield, G. Siami, R. Smith, A. Smuckler, C. Snorton, T. Stern, D.
Venugopal; Texas: A. Abbas, H.
Adrogue, A. Amador, L. Arango, C. Arroyo, V. Battles, M. Beard, J. Beasley, R.
Bhalla, G. Chauca, P. Damico, S. Davison, P. Dlabal, N. Duronio, C. East, F.
Eelani, C. Farmerie, E. Fowler, O. Gambini, E. Griego, G. Habib, S. Hanna, D.
Harden, T. Harrington, C. Herrera, T. Hicks, B. Hiltscher, D. Hyman, I. Lalani,
A. Levine, S. Lu, I. Martinez, Y. Martinez, N. Mata, R. Motaparthi, B. Norch,
M. Ottosen, V. Pavlik, L. Pearce, J. Periman, M. Pickard, N. Pokala, A. Ray, D.
Richard, K. Rogers, M. Ruggles, L. Seals, D. Shafer, T. Shamsi, D.
Sherwood-Berner, E. Soltero, A. Sy, J. Tomlinson, C. Vallbona, D. Verrett, R.
Victor, W. Vongpatanasin, R. Young; Utah:
R. Callihan, G. Henderson, J. O'Donnell, C. Slot, J. Swauger, C. Westenfelder,
C. Williams; Vermont: B.
Armstrong, B. Buckley, P. Courchesne, P. Cushman, F. Gallant, T. Howard, J.
Osborne, R. Primeau, T. Tanner; Virgin
Islands: K. Bryan-Christian, C. Christian, M. Morris; Virginia: D. Bryan, D. Connito, K. Damico,
L. Gendron, E. Goudreau, M. Juarez, R. Lemly, L. Macklin, K. McCall, J. Moore,
D. Panebianco, D. Paulson, A. Pemberton, R. Renzi, D. Rice, J. Schmitt, S.
Speese, J. Sperling, L. Thompson, G. Vetrovec, A. Williams, D. Williams, B.
Zambrana; Washington: J.
Anderson, K. Capoccia, G. Deger, A. Ellsworth, A. Micketti, W. Neighbor, S.
Yarnall; West Virginia: H.
Blackwood, S. Grubb; Wisconsin:
P. Ackell, A. Arnold, S. Blumenthal, P. Bodmer, R. Dart, D. David, D. Duffy, L.
Egbujiobi, M. Faignant, A. Friedman, B. Friedman, C. Koeppl, M. Lintereur, J.
Morledge, D. Neu, M. Noble, M. Rassier, G. Shove, M. Stevens, R. Wergin, L.
Wollet, B. Yug, C. Zyniecki; Investigators
and Coordinators, Canada: New Brunswick: C. Baer, J. LeBlanc, R.
Withers, J. Yang; Newfoundland:
J. Collingwood, P. Crocker, F. Jardine, S. Newman, G. Rideout, B. Sussex; Ontario: J. Baker, D. Bishop, C. Brose, D.
Carswell, L. Charles, D. Coates, E. Coletta, M. Courtland, S. Crocker, R.
Dhaliwal, T. Doey, D. Guy, D. Harterre, G. Harterre, C. Henry, D. Henry, D.
Hutton, I. Janzen, H. Kafka, W. Kendrick, N. Kumar, R. Lan, F. Leenen, R.
Lovell, B. McAuley, B. Melbourne, S. Melbourne, H. Morwood, S. Munro, S. Nawaz,
T. O'Callahan, S. Prasad, P. Richardson, R. Rose, C. Sanderson-Guy, N. Schmidt,
D. Spink, P. Spink, A. Stajfer, R. Tee, K. Usher, M. Wahby, R. Wahby, D.
Wattam, L. Wells, M. Wiebe, K. Zarnke, P. Zuliani; Prince Edward Island: D. Cameron.
Investigators and Coordinators
Participating in the Antihypertensive Trial Only, United States: California: P. Bailey-Walton, N. Bednarski, M. Chen, S. Fochler, S. Gross, T.
Harper, G. Hilliard, B. Holmes, E. Jacobson, P. Kirkland, N. Lepor, K.
Moorehead, E. Portnoy, S. Rieux, N. Rodriguez, D. Schneidman, F. Yuen; Delaware: J. Holleger, T. Tonwe; Florida: U. Anderson, B. Austin, L.
Bianco, F. Griffith, J. Jaffe, E. Killeavy, A. Kwon, C. Lewis, M. Manoucheri,
L. Nitzberg, G. Ramos, P. Seabrooks, K. Sheikh, H. St John, T. St John, F.
Zafar; Georgia: P. Douglass, R.
Rhoades, R. Williams, A. Woodburn; Illinois:
A. Chavarria, L. Chavarria, M. Davidson, S. Ifft, J. Mathien, B. Smith, D.
Steinmuller, M. Steinmuller; Indiana:
A. Artis, J. Carter, M. Hutchinson, D. Smith; Kansas:
P. Bowen, J. Chambers, J. Fullard, L. Terry, S. Waldren; Louisiana: P. Daigle, J. Diggs, P.
Lakshmiprasad, A. Leitz, B. Richardson; Maryland:
E. Brightwell, J. Chandler, G. Denton, M. Kelemen, D. Tesch; Massachusetts: M. Cassidy, T. Sbarra; Michigan: R. Gudipati, C. Janners, S.
Janners, M. Keshishian, W. Packard, B. Sheridan; Minnesota: L. Loes, K. Margolis; Missouri: S. Brennac, C. Crosdale, K. Gage, T. McKeel, T.
McKeel; New Hampshire: J. Aliseo,
M. Jacobs; New York: C. Anderson,
S. Athanail, D. Castaldo, R. Castaldo, D. Clark, D. Copley, B. Dobrzynski, D.
Dobrzynski, R. Farron, B. Hoffman, J. McLaughlin, K. Ong, T. Peoples, M. Price,
I. Salom, S. Sears, R. Sutton, A. Zugibe, F. Zugibe; Ohio: L. Ballone, G. Barnett, D. Bradford, W. Feeman, C.
Griffin, S. Moore, A. Narraway, G. Novak, G. Schroeder, J. Wiggins; Oklahoma: V. Christy, Y. Ong; Pennsylvania: A. Friedman, C. Matelan, M.
Reyes, F. Sessoms, S. Silver, D. Watson; Puerto
Rico: C. LaSalle-Ruiz; Tennessee:
L. Hays, M. Houston; Texas: L.
Alexander, D. Corral, B. Montgomery, J. Pappas, R. Rocha; Virgin Islands: D. Galiber, S. Healy; Investigators and Coordinators, Canada: Nova Scotia:
T. Machel, J. Morash; Ontario: J.
Cha, D. Dejewski, D. Jones, L. Jones, B. Lubelsky, R. Luton, A. Maczko, J.
Otis.
Acknowledgment: The ALLHAT Collaborative Research Group extends sincere
appreciation to the 42 418 randomized participants without whom the trial
could not have been done. Thanks are also extended to officers and coordinators
of the research group who participated in previous years: Steering Committee: Charles Francis, MD,
John LaRosa, MD; NHLBI Project Office:
Gerald Payne, MD, Terry Manolio, MD, MS, Debra Egan, MS, MPH; ALLHAT Clinical Trials Center: C. Morton
Hawkins, ScD, Cheryl Jones, ScD, Christine Lusk, MPH, Barbara Kimmel, MS, MS,
Heather Parks-Huitron, MHE, CHES, Melanie Gross, Adriana Babiak-Vazquez, MPH,
Gaston Benavides, Patrick Courtney, MA; ALLHAT
Regions: Bronx, NY: Kim Brennan, Crystal Howard, MA; Chicago, Ill: Margaret Gazollo, RD, Julie
Hynes, MS, RD, Charisse O'Neill, RN, BS; Birmingham,
Ala: Cora E. Lewis, MD, MSPH; Seattle,
Wash: Kim Damon, Rebecca Letterer, RN, BSN, Susan Ross, RN, BSN; Minneapolis, Minn: Mukul Ganguli, MVSc,
PhD, Holly Jensen, Salma Koessel, MD, MPH, Carla Yunis, MD, MPH; ALLHAT Drug Distribution Center: Mary
Mease, RPh, MPH; ALLHAT Electrocardiogram
Reading Center: Carmen Christianson, Bernadette Gloeb, MLS, Marsha McDonald.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.