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)
Author Information <http://jama.ama-assn.org/issues/v288n23/rfull/#aainfo>
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
JOC21962
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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r1>
Antihypertensive drug therapy substantially reduces the risk of
hypertension-related morbidity and mortality. 2-6
<http://jama.ama-assn.org/issues/v288n23/rfull/#r2> However, the optimal
choice for initial pharmacotherapy of hypertension is uncertain. 7
<http://jama.ama-assn.org/issues/v288n23/rfull/#r7>
Earlier clinical trials documented the benefit of lowering blood pressure
(BP) using primarily thiazide diuretics or beta-blockers. 2
<http://jama.ama-assn.org/issues/v288n23/rfull/#r2> , 3
<http://jama.ama-assn.org/issues/v288n23/rfull/#r3> , 8
<http://jama.ama-assn.org/issues/v288n23/rfull/#r8> After these studies,
several newer classes of antihypertensive agents (ie, angiotensin-converting
enzyme [ACE] inhibitors, calcium channel blockers [CCBs], alpha-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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r9>
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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r6> , 12-16
<http://jama.ama-assn.org/issues/v288n23/rfull/#r12> 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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r17>
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 alpha-blocker (represented by doxazosin), each compared
with diuretic treatment (represented by chlorthalidone). 18
<http://jama.ama-assn.org/issues/v288n23/rfull/#r18> Chlorthalidone was
found to be superior to doxazosin and was previously reported after early
termination of the doxazosin arm of the trial. 19
<http://jama.ama-assn.org/issues/v288n23/rfull/#r19> , 20
<http://jama.ama-assn.org/issues/v288n23/rfull/#r20> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r18> , 21
<http://jama.ama-assn.org/issues/v288n23/rfull/#r21> 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.
METHODS
Study Design
The rationale and design of ALLHAT have been presented elsewhere. 18
<http://jama.ama-assn.org/issues/v288n23/rfull/#r18> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r18> , 22
<http://jama.ama-assn.org/issues/v288n23/rfull/#r22> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r20> ) 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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r20> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r4> , 23
<http://jama.ama-assn.org/issues/v288n23/rfull/#r23> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r18> , 20
<http://jama.ama-assn.org/issues/v288n23/rfull/#r20>
Outcomes
The primary outcome was fatal CHD or nonfatal myocardial infarction
combined. 18 <http://jama.ama-assn.org/issues/v288n23/rfull/#r18> 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 rate 24
<http://jama.ama-assn.org/issues/v288n23/rfull/#r24> , 25
<http://jama.ama-assn.org/issues/v288n23/rfull/#r25> was examined post hoc.
Study outcomes were assessed at follow-up visits and reported to the
clinical trials center. 18
<http://jama.ama-assn.org/issues/v288n23/rfull/#r18> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r18> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r26> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r27> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r18> 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
alpha= .0178 (z = 2.37) to account for the 3 original comparisons. 28
<http://jama.ama-assn.org/issues/v288n23/rfull/#r28> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r29> For consistency with
alpha= .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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r29> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r30> , 31
<http://jama.ama-assn.org/issues/v288n23/rfull/#r31>
RESULTS
Patient Characteristics
Table 1 <http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t1.html>
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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r22>
Visit and Medication Adherence
Figure 1 <http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_f1.html>
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
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t2.html> ). 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
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t3.html> and
Table 4
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t4.html> ). 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
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t1.html> ).
Follow-up BPs in all 3 groups are shown in Table 3
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t3.html> and
Figure 2 <http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_f2.html>
.
Mean total serum cholesterol levels at baseline and 4 years follow-up are
shown in Table 4
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t4.html> . 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 <http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t5.html> ,
Figure 3 <http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_f3.html>
, and Figure 4
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_f4.html> ). 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
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_f5.html> ) 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
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t6.html> ).
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
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t5.html> , Figure
3 <http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_f3.html> and
Figure 4
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_f4.html> ).
Cause-specific mortality rates were also similar in the 2 groups ( Table 6
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t6.html> ). 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
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_f6.html> ), 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
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t5.html> ).
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.
COMMENT
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 alpha-blockers) in
reducing BP and preventing cardiovascular events, particularly HF. 19
<http://jama.ama-assn.org/issues/v288n23/rfull/#r19> , 20
<http://jama.ama-assn.org/issues/v288n23/rfull/#r20>
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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r8> , 9
<http://jama.ama-assn.org/issues/v288n23/rfull/#r9> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r32> , 33
<http://jama.ama-assn.org/issues/v288n23/rfull/#r33> Some of these
individual trials have had limited power to evaluate differences between
treatments. 34 <http://jama.ama-assn.org/issues/v288n23/rfull/#r34> 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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r13> , 14
<http://jama.ama-assn.org/issues/v288n23/rfull/#r14> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r9> , 35
<http://jama.ama-assn.org/issues/v288n23/rfull/#r35> In the INSIGHT trial,
HF was approximately twice as frequent in the CCB vs the diuretic arm. 33
<http://jama.ama-assn.org/issues/v288n23/rfull/#r33> 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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r13> , 14
<http://jama.ama-assn.org/issues/v288n23/rfull/#r14>
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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r14>
, 36 <http://jama.ama-assn.org/issues/v288n23/rfull/#r36> , 37
<http://jama.ama-assn.org/issues/v288n23/rfull/#r37> 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
<http://jama.ama-assn.org/issues/v288n23/fig_tab/joc21962_t6.html> ).
There were no significant differences in the incidence of ESRD between
chlorthalidone and amlodipine, consistent with findings from the INSIGHT
trial. 33 <http://jama.ama-assn.org/issues/v288n23/rfull/#r33> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r38>
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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r13> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r41> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r8> , 10
<http://jama.ama-assn.org/issues/v288n23/rfull/#r10> , 44
<http://jama.ama-assn.org/issues/v288n23/rfull/#r44> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r3> , 13
<http://jama.ama-assn.org/issues/v288n23/rfull/#r13> 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 beta-blockers), showed no significant differences in CHD, stroke, HF,
or all-cause mortality. 32
<http://jama.ama-assn.org/issues/v288n23/rfull/#r32> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r45> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r45> , 46
<http://jama.ama-assn.org/issues/v288n23/rfull/#r46> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r8> , 47
<http://jama.ama-assn.org/issues/v288n23/rfull/#r47> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r48>
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 <http://jama.ama-assn.org/issues/v288n23/rfull/#r49> They are also
consistent with reports of lesser effects of ACE inhibitors in secondary
prevention of HF in this population, 52
<http://jama.ama-assn.org/issues/v288n23/rfull/#r52> , 53
<http://jama.ama-assn.org/issues/v288n23/rfull/#r53> although these
findings have been recently questioned. 54
<http://jama.ama-assn.org/issues/v288n23/rfull/#r54> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r18> 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
<http://jama.ama-assn.org/issues/v288n23/rfull/#r55> 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
alpha-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 beta-blocker to
chlorthalidone, previous trials have suggested equivalence 45
<http://jama.ama-assn.org/issues/v288n23/rfull/#r45> or even inferiority 3
<http://jama.ama-assn.org/issues/v288n23/rfull/#r3> 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] <mailto:[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] <mailto:[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.
REFERENCES
1. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr1>
American Heart Association.
2002 Heart and Stroke Statistical Update.
Dallas, Tex: American Heart Association; 2001.
2. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr2>
Cutler JA, MacMahon SW, Furberg CD.
Controlled clinical trials of drug treatment for hypertension: a review.
Hypertension.
1989;13:I36-I44.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
2490827>
3. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr3>
Psaty BM, Smith NL, Siscovick DS, et al.
Health outcomes associated with antihypertensive therapies used as
first-line agents: a systematic review and meta-analysis.
JAMA.
1997;277:739-745.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9042847>
4. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr4>
The sixth report of the Joint National Committee on prevention, detection,
evaluation, and treatment of high blood pressure.
Arch Intern Med.
1997;157:2413-2446.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9385294>
5. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr5>
Chalmers J, Zanchetti A.
The 1996 report of a World Health Organization expert committee on
hypertension control.
J Hypertens.
1996;14:929-933.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8884546>
6. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr6>
Collins R, Peto R, Godwin J, MacMahon S.
Blood pressure and coronary heart disease.
Lancet.
1990;336:370-371.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
1975346>
7. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr7>
World Health Organization-International Society of Hypertension Blood
Pressure Lowering Treatment Trialists' Collaboration.
Protocol for prospective collaborative overviews of major randomized trials
of blood pressure lowering treatments.
J Hypertens.
1998;16:127-137.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9535138>
8. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr8>
SHEP Cooperative Research Group.
Prevention of stroke by antihypertensive drug treatment in older persons
with isolated systolic hypertension: final results of the Systolic
Hypertension in the Elderly Program (SHEP).
JAMA.
1991;265:3255-3264.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
2046107>
9. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr9>
Staessen JA, Fagard R, Thijs L, et al.
Randomised double-blind comparison of placebo and active treatment for older
patients with isolated systolic hypertension: the Systolic Hypertension in
Europe (Syst-Eur) Trial Investigators.
Lancet.
1997;350:757-764.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9297994>
10. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr10>
Yusuf S, Sleight P, Pogue J, et al.
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients: the Heart Outcomes Prevention
Evaluation Study Investigators.
N Engl J Med.
2000;342:145-153.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10639539>
11. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr11>
PROGRESS Collaborative Group.
Randomised trial of a perindopril-based blood-pressure-lowering regimen
among 6,105 individuals with previous stroke or transient ischaemic attack.
Lancet.
2001;358:1033-1041.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11589932>
12. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr12>
Grimm RH Jr.
Antihypertensive therapy: taking lipids into consideration.
Am Heart J.
1991;122:910-918.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
1678922>
13. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr13>
Neal B, MacMahon S, Chapman N.
Effects of ACE inhibitors, calcium antagonists, and other
blood-pressure-lowering drugs: results of prospectively designed overviews
of randomised trials: Blood Pressure Lowering Treatment Trialists'
Collaboration.
Lancet.
2000;356:1955-1964.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11130523>
14. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr14>
Pahor M, Psaty BM, Alderman MH, et al.
Health outcomes associated with calcium antagonists compared with other
first-line antihypertensive therapies: a meta-analysis of randomised
controlled trials.
Lancet.
2000;356:1949-1954.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11130522>
15. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr15>
Poulter NR.
Treatment of hypertension: a clinical epidemiologist's view.
J Cardiovasc Pharmacol.
1991;18(suppl 2):S35-S38.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
1725040>
16. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr16>
Neaton JD, Grimm RH Jr, Prineas RJ, et al.
Treatment of mild hypertension study: final results: Treatment of Mild
Hypertension Study Research Group.
JAMA.
1993;270:713-724.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8336373>
17. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr17>
Materson BJ, Reda DJ, Cushman WC, et al.
Single-drug therapy for hypertension in men: a comparison of six
antihypertensive agents with placebo: the Department of Veterans Affairs
Cooperative Study Group on Antihypertensive Agents.
N Engl J Med.
1993;328:914-921.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8446138>
18. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr18>
Davis BR, Cutler JA, Gordon DJ, et al.
Rationale and design for the Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial (ALLHAT).
Am J Hypertens.
1996;9:342-360.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8722437>
19. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr19>
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
Group.
Major cardiovascular events in hypertensive patients randomized to doxazosin
vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT).
JAMA.
2000;283:1967-1975.
ABSTRACT <http://jama.ama-assn.org/issues/v283n15/abs/joc00401.html> |
FULL TEXT <http://jama.ama-assn.org/issues/v283n15/rfull/joc00401.html> |
PDF <http://jama.ama-assn.org/issues/v283n15/rpdf/joc00401.pdf> |
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10789664>
20. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr20>
Davis BR, Cutler JA, Furberg CD, et al.
Relationship of antihypertensive treatment regimens and change in blood
pressure to risk for heart failure in hypertensive patients randomly
assigned to doxazosin or chlorthalidone: further analyses from the
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.
Ann Intern Med.
2002;137:313-320.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
12204014>
21. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr21>
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
Group.
Major outcomes in moderately hypercholesterolemic, hypertensive patients
randomized to pravastatin vs usual care: the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial.
JAMA.
2002;288:2998-3007.
ABSTRACT <http://jama.ama-assn.org/issues/v288n23/abs/joc21963.html> |
FULL TEXT <http://jama.ama-assn.org/issues/v288n23/rfull/joc21963.html> |
PDF <http://jama.ama-assn.org/issues/v288n23/rpdf/joc21963.pdf>
22. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr22>
Grimm RH Jr, Margolis KL, Papademetriou V, et al.
Baseline characteristics of participants in the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
Hypertension.
2001;37:19-27.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11208751>
23. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr23>
The fifth report of the Joint National Committee on Detection, Evaluation,
and Treatment of High Blood Pressure (JNC V).
Arch Intern Med.
1993;153:154-183.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8422206>
24. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr24>
Levey AS, Bosch JP, Lewis JB, et al.
A more accurate method to estimate glomerular filtration rate from serum
creatinine: a new prediction equation: Modification of Diet in Renal Disease
Study Group.
Ann Intern Med.
1999;130:461-470.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10075613>
25. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr25>
Levey AS, Greene T, Kusek JW, et al.
A simplified equation to predict glomerular filtration rate from serum
creatinine.
J Am Soc Nephrol.
2000;11:155A.
26. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr26>
Piller LB, Davis BR, Cutler JA, et al.
Validation of heart failure events in ALLHAT participants assigned to
doxazosin.
Curr Control Trials Cardiovasc Med.
2002;3:10.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
12459039>
27. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr27>
Public Health Service-Health Care Financing Administration.
International Classification of Diseases, Ninth Revision (ICD-9).
6th ed. Bethesda, Md: US Dept of Health and Human Services; 2001. DHHS
Publication No. (PHS) 80-1260.
28. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr28>
Dunnett CW.
A multiple comparisons procedure for comparing several treatments with a
control.
J Am Stat Assoc.
1955;50:1096-1121.
29. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr29>
Klein JP, Moeschberger ML.
Survival Analysis: Techniques for Censored and Truncated Regression.
New York, NY: Springer-Verlag; 1997.
30. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr30>
Davis BR, Hardy RJ.
Upper bounds for type I and II error rates in conditional power
calculations.
Commun Stat.
1990;19:3571-3584.
31. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr31>
Lan KKG, DeMets DL.
Discrete sequential boundaries for clinical trials.
Biometrika.
1983;70:659-663.
32. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr32>
Hansson L, Lindholm LH, Ekbom T, et al.
Randomised trial of old and new antihypertensive drugs in elderly patients:
cardiovascular mortality and morbidity: the Swedish Trial in Old Patients
with Hypertension-2 study.
Lancet.
1999;354:1751-1756.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10577635>
33. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr33>
Brown MJ, Palmer CR, Castaigne A, et al.
Morbidity and mortality in patients randomised to double-blind treatment
with a long-acting calcium-channel blocker or diuretic in the International
Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment
(INSIGHT).
Lancet.
2000;356:366-372.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10972368>
34. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr34>
MacMahon S, Neal B.
Differences between blood-pressure-lowering drugs.
Lancet.
2000;356:352-353.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10972362>
35. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr35>
Kostis JB, Davis BR, Cutler J, et al.
Prevention of heart failure by antihypertensive drug treatment in older
persons with isolated systolic hypertension: SHEP Cooperative Research
Group.
JAMA.
1997;278:212-216.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9218667>
36. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr36>
Ad Hoc Subcommittee of the Liaison Committee of the World Health
Organisation and the International Society of Hypertension.
Effects of calcium antagonists on the risks of coronary heart disease,
cancer and bleeding.
J Hypertens.
1997;15:105-115.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9469785>
37. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr37>
Furberg CD, Psaty BM, Meyer JV.
Nifedipine: dose-related increase in mortality in patients with coronary
heart disease.
Circulation.
1995;92:1326-1331.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
7648682>
38. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr38>
Agodoa LY, Appel L, Bakris GL, et al.
Effect of ramipril vs amlodipine on renal outcomes in hypertensive
nephrosclerosis: a randomized controlled trial.
JAMA.
2001;285:2719-2728.
ABSTRACT <http://jama.ama-assn.org/issues/v285n21/abs/joc10545.html> |
FULL TEXT <http://jama.ama-assn.org/issues/v285n21/rfull/joc10545.html> |
PDF <http://jama.ama-assn.org/issues/v285n21/rpdf/joc10545.pdf> |
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11386927>
39. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr39>
Hall WD, Kusek JW, Kirk KA, et al.
Short-term effects of blood pressure control and antihypertensive drug
regimen on glomerular filtration rate: the African-American Study of Kidney
Disease and Hypertension Pilot Study.
Am J Kidney Dis.
1997;29:720-728.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9159306>
40. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr40>
ter Wee PM, De Micheli AG, Epstein M.
Effects of calcium antagonists on renal hemodynamics and progression of
nondiabetic chronic renal disease.
Arch Intern Med.
1994;154:1185-1202.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8203987>
41. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr41>
Lonn EM, Yusuf S, Jha P, et al.
Emerging role of angiotensin-converting enzyme inhibitors in cardiac and
vascular protection.
Circulation.
1994;90:2056-2069.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
7923694>
42. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr42>
Weir MR, Dzau VJ.
The renin-angiotensin-aldosterone system: a specific target for hypertension
management.
Am J Hypertens.
1999;12:205S-213S.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10619573>
43. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr43>
Jafar TH, Schmid CH, Landa M, et al.
Angiotensin-converting enzyme inhibitors and progression of nondiabetic
renal disease: a meta-analysis of patient-level data.
Ann Intern Med.
2001;135:73-87.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11453706>
44. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr44>
Effect of enalapril on mortality and the development of heart failure in
asymptomatic patients with reduced left ventricular ejection fractions: the
SOLVD Investigators.
N Engl J Med.
1992;327:685-691.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
1463530>
45. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr45>
Collins R, Peto R, MacMahon S, et al.
Blood pressure, stroke, and coronary heart disease: Part 2, short-term
reductions in blood pressure: overview of randomised drug trials in their
epidemiological context.
Lancet.
1990;335:827-838.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
1969567>
46. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr46>
MacMahon S, Peto R, Cutler J, et al.
Blood pressure, stroke, and coronary heart disease: Part 1, prolonged
differences in blood pressure: prospective observational studies corrected
for the regression dilution bias.
Lancet.
1990;335:765-774.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
1969518>
47. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr47>
Staessen JA, Byttebier G, Buntinx F, et al.
Antihypertensive treatment based on conventional or ambulatory blood
pressure measurement: a randomized controlled trial: Ambulatory Blood
Pressure Monitoring and Treatment of Hypertension Investigators.
JAMA.
1997;278:1065-1072.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9315764>
48. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr48>
Franklin SS.
Cardiovascular risks related to increased diastolic, systolic and pulse
pressure: an epidemiologist's point of view.
Pathol Biol (Paris).
1999;47:594-603.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10472070>
49. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr49>
Saunders E, Weir MR, Kong BW, et al.
A comparison of the efficacy and safety of a beta-blocker, a calcium channel
blocker, and a converting enzyme inhibitor in hypertensive blacks.
Arch Intern Med.
1990;150:1707-1713.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
2200382>
50. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr50>
Rahman M, Douglas JG, Wright JT.
Pathophysiology and treatment implications of hypertension in the
African-American population.
Endocrinol Metab Clin North Am.
1997;26:125-144.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9074856>
51. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr51>
Cushman WC, Reda DJ, Perry HM, et al.
Regional and racial differences in response to antihypertensive medication
use in a randomized controlled trial of men with hypertension in the United
States.
Arch Intern Med.
2000;160:825-831.
ABSTRACT <http://archinte.ama-assn.org/issues/v160n6/abs/ioi81248.html> |
FULL TEXT <http://archinte.ama-assn.org/issues/v160n6/rfull/ioi81248.html>
| PDF <http://archinte.ama-assn.org/issues/v160n6/rpdf/ioi81248.pdf> |
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10737282>
52. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr52>
Exner DV, Dries DL, Domanski MJ, Cohn JN.
Lesser response to angiotensin-converting-enzyme inhibitor therapy in black
as compared with white patients with left ventricular dysfunction.
N Engl J Med.
2001;344:1351-1357.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11333991>
53. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr53>
Carson P, Ziesche S, Johnson G, Cohn JN.
Racial differences in response to therapy for heart failure: analysis of the
vasodilator-heart failure trials: Vasodilator-Heart Failure Trial Study
Group.
J Card Fail.
1999;5:178-187.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10496190>
54. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr54>
Dries DL, Strong MH, Cooper RS, Drazner MH.
Efficacy of angiotensin-converting enzyme inhibition in reducing progression
from asymptomatic left ventricular dysfunction to symptomatic heart failure
in black and white patients.
J Am Coll Cardiol.
2002;40:311-317.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
12106937>
55. <http://jama.ama-assn.org/issues/v288n23/rfull/#rr55>
Manolio TA, Cutler JA, Furberg CD, et al.
Trends in pharmacologic management of hypertension in the United States.
Arch Intern Med.
1995;155:829-837.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
7717791>
Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.
|
