Major Outcomes in Moderately Hypercholesterolemic,
Hypertensive Patients Randomized to Pravastatin vs Usual Care
The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group
Context Studies have demonstrated that statins administered to individuals
with risk factors for coronary heart disease (CHD) reduce CHD events. However,
many of these studies were too small to assess all-cause mortality or outcomes
in important subgroups.
Objective To determine whether pravastatin compared with usual care reduces
all-cause mortality in older, moderately hypercholesterolemic, hypertensive
participants with at least 1 additional CHD risk factor.
Design and Setting Multicenter (513 primarily community-based North American clinical
centers), randomized, nonblinded trial conducted from 1994 through March 2002
in a subset of participants from the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT).
Participants Ambulatory persons (n = 10 355), aged 55 years or older, with
low-density lipoprotein cholesterol (LDL-C) of 120 to 189 mg/dL (100 to 129
mg/dL if known CHD) and triglycerides lower than 350 mg/dL, were randomized to
pravastatin (n = 5170) or to usual care (n = 5185). Baseline mean total
cholesterol was 224 mg/dL; LDL-C, 146 mg/dL; high-density lipoprotein
cholesterol, 48 mg/dL; and triglycerides, 152 mg/dL. Mean age was 66 years, 49%
were women, 38% black and 23% Hispanic, 14% had a history of CHD, and 35% had
type 2 diabetes.
Intervention Pravastatin, 40 mg/d, vs usual care.
Main Outcome
Measures The primary outcome was
all-cause mortality, with follow-up for up to 8 years. Secondary outcomes
included nonfatal myocardial infarction or fatal CHD (CHD events) combined,
cause-specific mortality, and cancer.
Results Mean follow-up was 4.8 years. During the trial, 32% of usual care
participants with and 29% without CHD started taking lipid-lowering drugs. At
year 4, total cholesterol levels were reduced by 17% with pravastatin vs 8%
with usual care; among the random sample who had LDL-C levels assessed, levels
were reduced by 28% with pravastatin vs 11% with usual care. All-cause
mortality was similar for the 2 groups (relative risk [RR], 0.99; 95%
confidence interval [CI], 0.89-1.11; P
= .88), with 6-year mortality rates of 14.9% for pravastatin vs 15.3% with
usual care. CHD event rates were not significantly different between the groups
(RR, 0.91; 95% CI, 0.79-1.04; P =
.16), with 6-year CHD event rates of 9.3% for pravastatin and 10.4% for usual
care.
Conclusions Pravastatin did not reduce either all-cause mortality or CHD
significantly when compared with usual care in older participants with
well-controlled hypertension and moderately elevated LDL-C. The results may be
due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%)
between pravastatin and usual care compared with prior statin trials supporting
cardiovascular disease prevention.
JAMA. 2002;288:2998-3007
The important etiologic role of circulating
levels of low-density lipoprotein cholesterol (LDL-C) in the development of
atherosclerotic coronary heart disease (CHD) is well established. Numerous
randomized trials in the 1970s and 1980s affirmed that lowering LDL-C levels
with diet and/or drugs, such as bile acid sequestrant resins and fibrates,
reduced CHD event rates.1 However, the total
cholesterol reductions attained in these trials were modest (approximately
10%), and the correspondingly modest reductions in CHD mortality were offset by
small increases in noncardiovascular mortality, with no net effect on overall
mortality.1 In the
mid-1980s, a new potent and well-tolerated class of drugs, the
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins)
provided the means to conduct randomized trials in which total cholesterol
reductions of 20% and greater could be sustained long-term. These trials also
allowed questions about the overall benefits and risks of cholesterol lowering
to be effectively addressed.
The lipid-lowering trial (LLT) component of the
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT)2 (ALLHAT-LLT)
was originally envisioned as a free-standing double-blind trial to evaluate the
effects of cholesterol lowering with a statin drug in a population that was
older and more inclusive than those studied in prior trials. After successful
completion of the Cholesterol Reduction In Seniors Program (CRISP),3 a 2-year feasibility
study, the concept was modified and incorporated into ALLHAT as a randomized,
nonblinded trial comparing pravastatin treatment with a usual care control
group in a moderately hypercholesterolemic subset of the planned 40 000 ALLHAT
participants. The principal objectives of the ALLHAT-LLT were to evaluate the
impact of large sustained cholesterol reductions on all-cause mortality in a
hypertensive cohort with at least 1 other CHD risk factor and to assess CHD
reduction and other benefits in populations that had been excluded or
underrepresented in previous trials, particularly older persons, women, racial
and ethnic minority groups, and persons with diabetes.2 Emphasis on primary
care settings was deemed important because of the study's substantial
implications for these providers and their patients. Despite the publication of
more than 20 long-term statin trials4-13 since ALLHAT began
in 1994 and the publication of the National Cholesterol Education Program
(NCEP) Adult Treatment Panel Guidelines (ATP III)14 in 2001, ALLHAT-LLT
remains the second largest long-term statin trial and addresses a unique
population.
This article presents results of the pravastatin
vs usual care comparison for all-cause mortality and CHD end points in
ALLHAT-LLT. Results of the ALLHAT antihypertensive trial appear in an
accompanying article.15
The design of ALLHAT, including the LLT, and its
participant and clinical site recruitment and selection have been described
previously.2, 16, 17 Briefly, ALLHAT-LLT
was a randomized, nonblinded, large simple trial conducted from February 1994
through March 2002 at 513 clinical centers in the United States, Puerto Rico,
US Virgin Islands, and Canada. The intervention was open-label pravastatin (40
mg/d) vs usual care. Participants were drawn exclusively from ALLHAT, a 4-armed
antihypertensive trial in which a calcium channel blocker (amlodipine), an
angiotensin-converting enzyme inhibitor (lisinopril), and an -adrenergic blocking agent (doxazosin) were each
compared with a thiazide-like diuretic (chlorthalidone). The doxazosin arm of
ALLHAT was discontinued in March 2000.18 ALLHAT-LLT
participants originally assigned to doxazosin continued in the LLT with their
original visit schedule and were offered open-label chlorthalidone for
antihypertensive treatment.
Eligibility for ALLHAT-LLT
The specific eligibility criteria for the ALLHAT-LLT included prior enrollment
in ALLHAT (age 55 years and stage 1 or 2
hypertension with at least 1 additional CHD risk factor); fasting LDL-C level
of 120 to 189 mg/dL (3.1 to 4.9 mmol/L) for those with no known CHD, or 100 to
129 mg/dL (2.6 to 3.3 mmol/L) for those with known CHD (the upper limit was 159
mg/dL [4.1 mmol/L] prior to April 5, 1994, but was changed in light of 4S4 findings); and fasting
triglyceride levels lower than 350 mg/dL (3.9 mmol/L). Participants were
excluded who were currently receiving lipid-lowering therapy, taking large
doses of niacin, or taking probucol in the last year; were known to be
intolerant of statins or to have significant liver or kidney disease (serum
alanine aminotransferase [ALT] >100 IU/L or serum creatinine >2.0 mg/dL
[176.8 µmol/L]) or other contraindications for statin therapy; or had a known
secondary cause of hyperlipidemia. Enrollment was discouraged for participants
whose personal physicians recommended cholesterol-lowering medications.
Eligibility for ALLHAT-LLT was based on the
average of 2 fasting (calculated) LDL-C measurements19 taken at the ALLHAT
baseline and 1-month follow-up visits. Enrollment in the LLT took place an
average of 88 days after randomization into ALLHAT, from March 1994 through May
1998. By telephone, participants were randomly assigned to pravastatin or usual
care in a ratio of 1:1. The concealed randomization scheme was generated by
computer, implemented at the clinical trials center (CTC), stratified by center
and antihypertensive treatment arm, and blocked in random block sizes of 4, 6,
and 8 to maintain balance. All participants signed an informed consent form,
and all centers received institutional review board approval.
Follow-up
Follow-up visits for the ALLHAT-LLT were scheduled to coincide with follow-up
visits for the ALLHAT parent trial, ie, at 3, 6, 9, and 12 months following
randomization into ALLHAT and every 4 months thereafter. At each visit,
participants were questioned about intervening events since the previous visit
and were provided refills of study medications. Baseline fasting lipid profiles
and electrocardiograms (ECGs) were performed. Total cholesterol measurements
and resting ECGs were also obtained at the 2-, 4-, and 6-year visits. At these
same visits, a fasting lipid profile was obtained in random preselected samples
of usual care (5%) and pravastatin (10%) participants. Levels of ALT were
obtained for all ALLHAT-LLT participants at baseline and during follow-up in
accordance with US Food and Drug Administration requirements. All blood samples
were shipped with a frozen refrigerant pack to be analyzed at the ALLHAT
Central Laboratory (Fairview-University Medical Center Clinical Laboratories,
Minneapolis, Minn), a Centers for Disease Control and Prevention Standardized
Laboratory.
Treatment
All ALLHAT-LLT participants were advised to follow the NCEP Step I diet.20 Initially,
pravastatin participants began with a dosage of 20 mg taken each evening. The
dosage was increased to 40 mg/d as needed to achieve at least a 25% decrease in
LDL-C. After the first 1000 participants had been enrolled, a uniform dosage of
40 mg/d was adopted for all participants in the pravastatin group. Study
practitioners retained the option to lower the dose of pravastatin, discontinue
the drug if significant adverse effects occurred, or prescribe other
lipid-lowering interventions, including cholesterol-lowering drugs not supplied
by the study.2
The usual care group was treated for LDL-C
lowering according to the discretion of their primary care physicians. However,
vigorous cholesterol-lowering therapy in the usual care group was discouraged
unless warranted by a change in clinical circumstances.
Sample Size
Originally, the sample size estimate of 20 000 provided 80% power to
detect a 12.5% reduction in mortality rate in the pravastatin vs usual care
group with a 2-sided = .05.2 With changing
scientific and community standards of practice for persons with prevalent CHD,4 evolving recruitment
experience of the ALLHAT-LLT indicated that a sample size of approximately
10 000 participants was the largest that could be realistically enrolled
within the constraint of drawing exclusively from participants already enrolled
in ALLHAT. Although 10 000 participants would not provide adequate power
for the originally assumed 12.5% reduction in mortality, this revised sample
size was estimated to provide 84% power to detect a 20% reduction in mortality,
a degree of reduction comparable to that observed in the 4S study.4 This estimated power
was considered sufficient to continue the study.
Outcomes
The primary outcome for the LLT was all-cause mortality. Secondary outcomes
included (1) composite of fatal CHD or nonfatal myocardial infarction (MI) (CHD
events), (2) cause-specific mortality, (3) total and site-specific cancers, (4)
Q-wave MI identified in the biennial centrally and blindly coded ECGs (included
in CHD events), (5) health-related quality of life, and (6) major costs of
medical care. The last 2 outcomes are to be addressed in subsequent reports.
Other end points of interest (though not specified a priori as secondary end
points) were total incidence of stroke and heart failure.
Study end points, ascertained at follow-up
visits, were reported to CTC by the site investigators, who submitted death
certificates for each death and hospital discharge summaries for each
hospitalized study event. Outcomes were primarily based on clinic investigator
reports, and pathology reports were requested for cancer diagnoses. Each event
report along with its documentation underwent medical review at the CTC to
verify the investigator-assigned diagnosis or cause of death. In addition,
searches for outcomes were conducted through the Center for Medicare and
Medicaid Services, the Department of Veterans Affairs, the National Death
Index, and the Social Security Administration. A death was ascertained by clinic
report or by match with the aforementioned databases plus a confirmatory death
certificate. Death certificates with unspecified causes of death were submitted
to a nosologist for International
Classification of Diseases, Ninth Revision (ICD-9)21 coding. In addition
to the death certificates and hospital summaries, further documentation was
requested for a random 10% sample of episodes of fatal CHD, hospitalized
nonfatal MIs, and strokes (hospitalized and fatal) for quality control review.
Statistical Analyses
Data were analyzed according to participants' randomized treatment assignments
regardless of their subsequent medication status (intention-to-treat). No
imputation was used for missing data. Cumulative event rates were calculated
using the Kaplan-Meier procedure.22 An individual's
duration in the study began at randomization to ALLHAT-LLT and ended at the date
of last known follow-up. The log-rank test and the Cox proportional hazards
model were used to evaluate differences between cumulative event curves and to
obtain 2-sided P values. Only the
proportional hazards results are presented because P values obtained by both methods were essentially
identical. Hazard ratios, hereafter referred to as relative risks (RRs), and
95% confidence intervals (CIs) were obtained from the Cox proportional hazards
model.22 For fatal and
nonfatal CHD, fatal and nonfatal cancer, cause-specific mortality, and stroke,
the Cox model was also used. Heterogeneity of effect in prespecified and other
subgroups was examined by testing for treatment-covariate interaction with the
proportional hazards model, using P<.05.
For other outcomes, including cancer deaths and overall and site-specific
cancers, comparison of proportions was used to evaluate differences between
pravastatin and usual care. Analyses are presented for total follow-up unless
specified otherwise.
A data and safety monitoring board appointed by
the National Heart, Lung, and Blood Institute met at least annually to review
the accumulating data for safety and to monitor the trial for either
superiority or inferiority of pravastatin compared with usual care. 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.23, 24 Data analyses were
performed using SAS version 8 (SAS Institute, Cary, NC) and STATA version 7
(STATA Corp, College Station, Tex).
Numbers of individuals screened and enrolled,
vital status, and losses to follow-up are depicted by treatment group in Figure 1.
Ultimately, 10 355 participants were enrolled in ALLHAT-LLT after
exclusion of 2 participants due to poor documentation of informed consent. The
mean (SD) duration of follow-up was 4.8 (1.3) years (maximum, 7.8 years). At
the end of the trial, 84.8% of participants were known to be alive, 12.3% were
confirmed dead, 0.5% were reported dead with confirmation pending, and 2.4% had
unknown vital status.
Baseline Characteristics
Baseline characteristics, including serum lipid levels, are shown in Table 1.
Mean total cholesterol was 224 mg/dL (5.8 mmol/L); LDL-C, 146 mg/dL (3.8
mmol/L); high-density lipoprotein cholesterol, 48 mg/dL (1.2 mmol/L); and
triglycerides, 152 mg/dL (1.7 mmol/L). Participants' mean age was 66 years; 49%
were women, 38% were black, 23% were Hispanic, and 35% had diagnosed type 2
diabetes. A history of previous CHD diagnosis was reported by 13% of
pravastatin participants and 15% of usual care participants. Higher mean total
cholesterol and LDL-C values in LLT participants without a history of CHD
reflect differences in eligibility criteria. Other baseline characteristics were
similar in the 2 treatment groups.
Visit and Medication Adherence
Visit adherence is shown in Table 2.
The percentage refusing to continue participation during the trial was 0.3%
(15/5170 pravastatin) and 0.6% (31/5185 usual care). At the close of the trial
2.2% (113) in the pravastatin and 2.7% (139) in the usual care groups had
unknown vital status.
Adherence to assigned treatment declined over
time (Table 2).
For those assigned to pravastatin, adherence dropped from 87% at year 2 to 80%
at year 4 (and 77% at year 6, though the participant number was small).
Approximately 70% to 75% of the participants reported taking 80% or more of
their assigned pravastatin. About half of those discontinuing pravastatin did
so without citing a specific reason, while the remainder cited adverse effects
and other medical and nonmedical reasons. Specific adverse effects data were
not collected. Elevation of ALT to levels greater than 3 times the upper limit
of normal (>150 IU/L) occurred in 0.4% (21/5170) of the pravastatin group.
In the usual care group, crossovers to statin
treatment increased from 8% at year 2 to 17% by year 4 (Table 2).
This increase continued in year 6, but the number of participants was small.
Among usual care participants with CHD at
baseline, 32% (251/780) started lipid-lowering drugs at some time during the
trial. For those without CHD at baseline, 29% (1279/4405) started
lipid-lowering drugs; of these, less than 5% (61/1279) had a preceding CHD
event (data not shown).
Lipid Levels
Lipid and lipoprotein changes during the trial are shown in Table 3
and Figure 2.
After 4 years of follow-up, total cholesterol levels decreased by 17.2% in the
pravastatin group and by 7.6% in usual care (Figure 2A).
The resultant total cholesterol differential was 9.6%. At 4 years calculated
LDL-C levels decreased by 27.7% in the pravastatin group and by 11.0% in usual
care (Figure 2B).
The resultant LDL-C differential was 16.7%. Mean total cholesterol differences
(usual care - pravastatin) were 25.3 mg/dL at 2 years, 21.6 mg/dL at 4 years,
and 18.9 mg/dL at 6 years. Mean LDL differences (usual care - pravastatin) were
23.8 mg/dL at 2 years, 24.2 mg/dL at 4 years, and 17.2 mg/dL at 6 years. (To
convert values to mmol/L, multiply by 0.0259.) High-density lipoprotein
cholesterol increased by 3.3% in the pravastatin group and 2.4% in the usual
care group (data not shown). Body weight data were not gathered following
randomization.
Clinical Outcomes
The effect of pravastatin treatment on clinical outcomes is shown in Table 4;
Kaplan-Meier plots and subgroup analyses for mortality and CHD events are shown
in Figure 3
and Figure 4.
All-cause mortality, the primary end point, did not differ significantly
between the pravastatin and usual care treatment groups (Table 4
and Figure 3A).
There were 631 deaths in the pravastatin group and 641 deaths in the usual care
group (RR, 0.99; 95% CI, 0.89-1.11; P
= .88). The 6-year mortality rate for pravastatin was 14.9%, and for usual
care, 15.3%. The results were similar when the unconfirmed deaths (27
pravastatin vs 28 usual care) were included (data not shown). Numbers of
cardiovascular deaths were similar in the 2 groups. There were more cancer deaths
and slightly fewer other medical deaths with pravastatin than usual care. None
of the differences in cause-specific mortality was statistically significant (Table 4).
Rates of CHD (fatal CHD plus nonfatal MI; Table 4
and Figure 3B)
and stroke (Table 4)
were somewhat lower in the pravastatin than in the usual care group. There were
380 CHD events in the pravastatin group and 421 in the usual care group (RR,
0.91; 95% CI, 0.79-1.04; P =
.16). The 6-year incidence rate was 9.3% for the pravastatin group and 10.4%
for usual care. There were 209 total strokes in the pravastatin group and 231
in usual care (RR, 0.91; 95% CI, 0.75-1.09; P
= .31). Heart failure rates were similar in the 2 groups (Table 4).
The 6-year incident cancer rates (Table 4)
were similar in the 2 groups. The largest differences for cancers at specific
sites were for lung cancer (63 pravastatin vs 78 usual care) and colon cancer
(46 pravastatin vs 38 usual care). The number of participants who developed breast
cancer was similar in the 2 groups (34 pravastatin vs 37 usual care). All
comparisons were nonsignificant
An important secondary objective of the
ALLHAT-LLT was to address the generalizability of the effects of cholesterol
lowering to population groups that had been underrepresented in prior trials.
Thus, the homogeneity of the results for mortality and for CHD events was
assessed in prespecified subgroups by age (65 vs
<65 years), sex, race (black vs nonblack), and presence or absence of
diabetes (Figure 4).
There was no significant heterogeneity for any of these outcomes with regard to
age, sex, or history of type 2 diabetes. However, pravastatin showed a
significantly more favorable effect on CHD events (RR, 0.73 vs 1.02) in blacks
than in nonblacks (P = .03).
Parallel analyses for stroke showed a significantly less favorable effect (RR,
1.12 vs 0.74) in blacks than in nonblacks (P
= .03). No difference in effect was observed in a parallel analysis of combined
cardiovascular disease outcomes (data not shown).
No statistically significant heterogeneity of
the pravastatin treatment effect was observed across the 4 ALLHAT hypertensive
treatment groups. For mortality, the RR in the chlorthalidone group was 1.03;
amlodipine, 1.06; lisinopril, 0.95; and doxazosin, 0.91; for the interaction P = .77. For CHD the RR in the
chlorthalidone group was 1.05; amlodipine, 0.79; lisinopril, 0.90; and
doxazosin, 0.83; for the interaction P
= .43. Similarly, no statistically significant heterogeneity was observed for
subgroups defined by CHD status and LDL-C levels (with CHD, without CHD plus
LDL-C 130 mg/dL [3.4 mmol/L],
and without CHD plus LDL-C <130 mg/dL [3.4 mmol/L]) (Figure 4).
ALLHAT provided a diverse population base for
ALLHAT-LLT. This study, comparing pravastatin with usual care, assessed the
value of cholesterol lowering in a population underrepresented in prior
cholesterol trialsindividuals with
well-controlled hypertension, almost half women, 38% black, 35% with a history
of diabetes, 55% at least 65 years of age, and 25% with LDL-C lower than 130
mg/dL (3.4 mmol/L). Adherence to pravastatin in ALLHAT-LLT, 80% at 4 years of
follow-up, was comparable to adherence in other large statin trials4-11, 18 and decreased levels
of total cholesterol by 17% and LDL-C by 28% from baseline. However, unlike
other statin trials, our study found no significant reductions in total
mortality, CHD, or stroke with pravastatin vs usual care.
There are several possible explanations for the
findings of ALLHAT-LLT, including the smaller than expected differential in
total cholesterol between the 2 treatment groups; the trial's unique
participant population; and the study's nonblinded design.
Cholesterol Differential
Between Pravastatin and Usual Care
The usual care group had reductions of 8% in total cholesterol and 11% in LDL-C
at 4 years, in contrast to other placebo-controlled statin trials, which
observed little or no cholesterol reduction in the placebo groups.4-9, 11 The resulting 9.6%
total cholesterol differential was less than half the average for the 8 other
long-term statin trials with at least 1000 participants4-11 (Table 5)
and comparable to the cholesterol differential attained in prestatin trials
using resins, niacin, diet, or fibrates.1 Under the assumption
of no change from baseline total cholesterol levels among participants in whom
follow-up extended to 4 years but whose cholesterol was not measured at their
fourth annual visit, the true total cholesterol differential might have been as
low as 8.8% (14.9% in pravastatin vs 6.1% in usual care), and the true LDL-C
differential might have been as low as 15.1% (24.0% in pravastatin vs 8.9% in
usual care).
The effect of attaining only a modest total
cholesterol differential is best appreciated by plotting the natural log of the
odds ratio (ln OR) and the 95% CI for mortality (Figure 5A)
and CHD events (Figure 5B)
in each of the trials in Table 5
vs the mean cholesterol differential between the treatment and control groups
in that trial. In addition, regression lines based on a prior meta-analysis of
45 cholesterol-lowering trials of 2 or more years' duration published before
the end of 200025 are plotted
for comparison. While the observed 95% CI of ln OR for all-cause mortality and
CHD in ALLHAT-LLT do not exclude the null value, they are also consistent with
the predicted OR for a 10% cholesterol reduction. However, because of the
modest cholesterol differential between pravastatin and usual care, ALLHAT-LLT
lacked the power to discriminate between the expected reductions in mortality
and CHD events and the null hypothesis.
The reduction in study power was not due to low
mortality rates; the number of deaths in the ALLHAT-LLT usual care group (641)
differed only slightly from the estimate (625) used in the revised power
calculation for a sample size of 10 000. Moreover, the numbers of
participants and deaths in ALLHAT-LLT were larger than in any other statin
trial except the Heart Protection Study (HPS).9 The lack of study power
likely was due to a failure to achieve a total cholesterol differential
sufficient to yield the anticipated 20% reduction in mortality, which would be
about 20% according to the regression model (Figure 5A).
Finally, ALLHAT-LLT did not test the widely
advanced hypothesis that statin treatment reduces CHD risk and mortality by
mechanisms independent of cholesterol lowering (eg, anti-inflammatory effects).26 Furthermore, the
observed differences in both CHD events and all-cause mortality in ALLHAT-LLT
were consistent with those predicted for a 10% total cholesterol differential
in a model based on trials using a wide array of cholesterol-lowering
interventions.
Unique Participant Population
ALLHAT-LLT is the only published statin trial, to our knowledge, conducted
exclusively in treated hypertensive participants. In a meta-analysis of 3
published pravastatin trials,26 treatment was
associated with only a 14% CHD event rate reduction (P = .03) in 6568 hypertensive participants vs 33% (P<.001) in 13 200 nonhypertensive
participants. The difference in CHD event rate reduction between hypertensive
and nonhypertensive participants was statistically significant and might help
explain the modest 10% CHD event rate reduction in ALLHAT-LLT. However, in the
hypertensive subgroup of the HPS,9 simvastatin treatment
was associated with the same 24% reduction in CHD event rates (P<.001) as in nonhypertensive
participants.
ALLHAT-LLT included larger proportions of older
participants, women, blacks, and Hispanics than any other statin trial
completed. However, subgroup analyses of ALLHAT-LLT, like those of prior statin
trials,9, 27 do not show age- or
sex-related differences in RRs for CHD event rates. The RR for pravastatin vs
usual care was significantly lower in blacks than nonblacks for CHD events (Figure 4B)
but was higher for strokes, with no overall difference for combined
cardiovascular events (data not shown). In the absence of racial differences
for the efficacy of pravastatin regarding all-cause mortality or other end
points, the biological significance of the racial differences for CHD and
stroke is unclear.
Although only a small proportion of ALLHAT-LLT
participants had overt CHD at entry, they were predominantly a cohort with
multiple CHD risk factors, considered "CHD equivalents" by the 2001
NCEP-ATP III.14 Other than the
HPS,9 which contained
a different mixture of participants with CHD, atherosclerotic cardiovascular
disease, diabetes, and treated hypertension, this category of participantsnot purely primary or
secondary preventionhas not been explicitly
addressed by prior statin trials. While the 14% of LLT participants with overt
CHD at entry had higher event rates than those with comparable LDL-C levels
(<130 mg/dL [3.4 mmol/L]) but without CHD, the pravastatin/usual care RRs
for mortality and CHD were similar in both groups. These RRs were also unaffected
by LDL-C level at baseline. By contrast, HPS9 reported similar
estimates of benefits with simvastatin at all levels of LDL-C, while a pooled
analysis of 3 large pravastatin trials27 suggested benefit
only in participants with LDL-C levels higher than 125 mg/dL (3.2 mmol/L). None
of these unique subgroups, including blacks, seems a likely explanation for the
results of ALLHAT-LLT.
Nonblinded Study Design
ALLHAT-LLT was a nonblinded trial, designed and carried out during a period in
which a series of landmark trials4-11 and guidelines14, 20 stimulated the
prescription of statins and progressively broadened the indications for their
use in individuals targeted by ALLHAT-LLT. This may have contributed to the use
of open-label statins in the usual care group. Because the study was not
blinded, there may also have been greater use of nonpharmacologic
cholesterol-lowering interventions in usual care than in pravastatin, although
changes in participants' diets, exercise habits, and weight were not examined
in ALLHAT.
Overview of Statin Trials
Do the results of ALLHAT-LLT indicate a need to draw back from the widespread
use of statins? When viewed in context, the overall experience with statins
remains highly favorable (Table 5,
Figure 5).
In the 8 prior large long-term statin trials,4-11 a mean 20%
cholesterol reduction was associated with a 30% reduction in CHD events (95%
CI, 26%-33%) and a 17% reduction in all-cause mortality (95% CI, 12%-22%).
After including ALLHAT-LLT, the 9 large long-term statin trials now show a 27%
reduction in CHD events (95% CI, 23%-31%) and a 14% reduction in all-cause
mortality (95% CI, 10%-18%) associated with an 18% reduction in mean total
cholesterol level. Both results remain highly significant statistically. There
remains little evidence in ALLHAT-LLT or elsewhere that statins specifically
increase any category of noncardiovascular mortality.
ALLHAT-LLT demonstrated no significant
difference between pravastatin and usual care groups in all-cause mortality or
combined fatal and nonfatal CHD. However, in the context of the modest
cholesterol differential, the results are consistent with the evidence from
other large trials. Indeed, the overall findings from the 9 large long-term
statin trials (including ALLHAT-LLT) leave little doubt regarding the broad
efficacy and safety of this treatment in the prevention and treatment of
atherosclerotic cardiovascular disease. In the absence of evidence for
increases in any category of noncardiovascular mortality, the ALLHAT-LLT
results should be interpreted as consistent with current recommendations for
cholesterol control in the prevention and treatment of cardiovascular disease.
These results emphasize the need for obtaining an adequate reduction in LDL-C
in clinical practice when lipid-lowering therapy is implemented.
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:
Jeffrey L. Probstfield, MD, University of Washington School of Medicine,
University of Washington Medical Center, 1959 NE Pacific St, Box 356422,
Seattle, WA 98195-6422 (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]).
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 2981 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.
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.
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.
Funding/Support: This study was supported by contract NO1-HC-35130 with the
National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge
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 National Heart, Lung, and Blood Institute 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
plus the decision to submit the manuscript for publication.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.