The Antihypertensive and Lipid Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT) is a randomized,
two-component clinical trial sponsored by the National
Heart, Lung, and Blood Institute (NHLBI). A double-blind,
active-controlled hypertension component is designed to
compare the rate of fatal coronary heart disease (CHD) or
nonfatal myocardial infarction (MI) (the primary endpoint)
in high-risk hypertensive participants, aged 55 years or
older, between those randomized to treatment initiated with
a diuretic (chlorthalidone) and treatment initiated with
each of three alternative antihypertensive drugs: a
calcium-channel blocker (amlodipine), an
angiotensin-converting enzyme (ACE)-inhibitor (lisinopril),
or an alpha-adrenergic blocker (doxazosin). An open-label
lipid-lowering component is designed to determine if
lowering LDL cholesterol with pravastatin compared to
"usual care" reduces all-cause mortality in a subset of
moderately hypercholesterolemic patients. Randomization to
the hypertension component began in February, 1994, and
continued through January, 1998, with 42,418 participants
recruited at 623 clinical centers in the United States,
Canada, Puerto Rico and the US Virgin Islands.
Randomization of 10,355 participants into the lipid trial
ended May 31, 1998. Follow-up on all participants continued
through March, 2002 [ 1 ] .
Following independent reviews by the Data and Safety
Monitoring Board (DSMB) on January 6, 2000, and by an Ad
Hoc Committee on January 21, 2000, the Director of the
National Heart, Lung, and Blood Institute accepted a
recommendation to discontinue the doxazosin treatment arm
of the antihypertensive trial. This recommendation was
based on the low probability of doxazosin showing benefit
over chlorthalidone for the primary endpoint, as well as
the significantly increased occurrence of the secondary
endpoint, combined cardiovascular disease (CVD)
(encompassing CHD deaths, nonfatal MI, stroke, coronary
revascularization procedures [coronary artery bypass graft
or CABG, percutaneous transluminal coronary angioplasty or
PTCA/stent], angina [hospitalized or treated as an
outpatient], heart failure [HF/treated in the hospital or
as an outpatient], and peripheral arterial disease
[in-hospital or outpatient revascularization]) in the
doxazosin arm (RR 1.25; 95% CI, 1.17-1.33;
P < .001), with a doubling of risk
of HF (fatal, hospitalized and treated but nonhospitalized)
(RR 2.04; 95% CI, 1.79-2.32;
P < .001). When only fatal and
hospitalized HF were analyzed, the large difference
remained (RR 1.83; 95% CI, 1.58-2.13;
P < .001). The findings and
operational aspects of stopping the doxazosin arm of the
study have been previously described [ 2 3 4 ] .
The observed increase in HF in the doxazosin group as
compared to the chlorthalidone group led to several
additional analyses aimed toward validation of the
diagnoses, with a focus on hospitalized and fatal HF. The
purposes of these analyses were: 1) to evaluate the reality
of HF cases, i.e. whether diagnosis, management, and
clinical course were what might be expected, and 2) to
compare these features between the two treatment
groups.
Methods
Study Design
The rationale and design of ALLHAT are described in
detail elsewhere [ 1 ] . Briefly, those eligible for
randomization had systolic blood pressure (SBP) of at
least 140 mm Hg and/or diastolic blood pressure of at
least 90 mm Hg, or took medication for hypertension, and
had at least one other risk factor for CHD events. Risk
factors included previous MI or stroke, left ventricular
hypertrophy by electrocardiogram or echocardiogram,
history of type 2 diabetes, current cigarette smoking,
and low high-density lipoprotein (HDL) level.
The primary endpoint of the blood pressure (BP) trial
is the composite of nonfatal MI and fatal CHD. The four
protocol-defined secondary clinical outcomes are
all-cause mortality, combined CHD (including CHD death,
nonfatal MI, coronary revascularization procedures and
hospitalized angina), stroke, and combined CVD (including
CHD death, nonfatal MI, stroke, coronary
revascularization procedures, angina treated in the
hospital or as an outpatient, lower extremity peripheral
arterial disease treated in the hospital or with
outpatient revascularization, and HF, fatal or treated in
the hospital or as an outpatient).
The validation of HF diagnosis entailed answering
several questions:
1. Did HF cases meet ALLHAT diagnostic criteria?
2. Were baseline characteristics and medical
management for HF cases as expected and similar across
the drug groups?
3. Were prevalence and severity of systolic
dysfunction as expected and similar across drug
groups?
4. Were case-fatality rates as expected and similar
across drug groups?
Unless otherwise specified, all data for these
analyses were collected as of December, 1999.
Heart Failure Diagnosis
At each follow-up clinic visit the occurrence of study
clinical events was assessed, and, if identified by the
clinical investigator, reported on an endpoint form. For
each event involving hospitalization, a hospital
discharge summary or expiration summary was to be
submitted, and for each death a death certificate was
required. Endpoint forms and supporting documentation
were reviewed at the ALLHAT Clinical Trials Center (CTC)
for accuracy and appropriateness. When a discrepancy or
ambiguity was found, the CTC sent a written query to the
Principal Investigator, who retained the final word
concerning the diagnosis or cause of death. A random 10%
sample of strokes, nonfatal MIs and CHD deaths was
selected for blinded quality control evaluation by the
ALLHAT Endpoints Subcommittee; for these cases additional
documentation was requested.
No such routine Endpoints Subcommittee quality control
was initially planned for reported HF. However, the
Subcommittee was subsequently called upon to evaluate a
random sample of reported fatal and hospitalized nonfatal
HF events. As this occurred prior to the termination of
the doxazosin arm, neither the chair nor the members of
the Subcommittee was informed of the major reason for
this review, namely, the trend toward a higher HF event
rate in the doxazosin group compared to the
chlorthalidone group. The Subcommittee was told that the
review was undertaken at the request of the DSMB to
address the reliability and validity of reported HF
events. This evaluation consisted of fifty events, evenly
distributed across the four treatment groups, reported as
fatal or hospitalized nonfatal HF and with
protocol-required documentation (discharge summary for
hospitalized events, death certificates for deaths).
Additional material was not requested, since this would
have posed an undue burden on the clinical site staff and
would have risked raising questions about emerging
differences among treatment groups.
The ALLHAT definition of HF, used previously in the
Systolic Hypertension in the Elderly Program (SHEP) [ 5 ]
, includes "patients with clear-cut signs or symptoms of
left or right ventricular dysfunction that cannot be
attributed to other causes..." The diagnosis of HF must
include at least one of four stated symptoms [paroxysmal
nocturnal dyspnea, dyspnea at rest, New York Heart
Classification functional class III (for definition see
Additional Information, Item 1), or orthopnea], and one
of seven stated signs (rales, 2+ or greater ankle edema,
tachycardia of 120 beats/minute or more after five
minutes at rest, cardiomegaly by chest x-ray, chest x-ray
characteristic of HF, S
3 gallop, or jugular venous
distention). Since lower extremity edema or exertional
dyspnea may be due to non-cardiac causes, the presence of
either of these alone, without other indications of heart
failure, is not sufficient for a diagnosis of HF. Study
guidelines caution against a hasty HF diagnosis in
patients with severe pulmonary disease, including chronic
obstructive pulmonary disease (COPD), pneumonia, or other
severe, documented lung disease.
Baseline Characteristics and Medical
Management
Baseline characteristics of chlorthalidone and
doxazosin participants were compared. These analyses were
stratified by HF outcome: 1) fatal and hospitalized HF;
2) treated, non-hospitalized HF; and, 3) no HF.
Post-HF event medical management may provide
additional evidence of the physicians' confidence in the
HF diagnosis. The post-event use of open-label diuretics,
ACE-inhibitors, and beta-blockers, i.e., accepted
treatments for HF [ 6 7 8 9 ] , was compared between
doxazosin and chlorthalidone groups, as was the
proportion in each group of those who remained on
assigned blinded medication after the event. (For study
guidelines regarding the use and reporting of open-label
medicines of the same class as the blinded drugs, see
Additional Information, Items 2 and 3.)
Ejection Fraction Review
A CTC physician plus non-medical staff reviewed in a
blinded fashion 361 hospitalized HF events (representing
278 participants) for ejection fraction data: looking for
whether an ejection fraction was measured, the method
utilized, and the measurement. Results, tabulated by
randomization groups, reflected data that had been
collected up to July, 1999, the time of the review.
Case-Fatality Rates and Causes of Death
As a measure of the diagnostic validity and severity
of HF and comparability between drug groups,
time-from-event-to-death analyses of participants with
hospitalized or treated HF were compared between the two
groups. Causes of death of such participants were also
compared in the doxazosin and chlorthalidone groups.
Statistical Analyses
Data were analyzed according to participants'
randomization assignments and HF outcome status,
regardless of subsequent medication adherence. The
Kaplan-Meier method was utilized in calculating
cumulative event rates. Descriptive statistics by
treatment groups were presented for baseline
characteristics, HF ascertainment, ejection fractions and
use of HF medications. Comparability of baseline
characteristics of the treatment and HF outcome groups
was ascertained by the χ 2test for categorical variables
and standard normal (z) test for continuous
variables.
Results
Heart Failure Diagnostic Criteria
The blinded review by the Endpoints Subcommittee of 50
fatal or hospitalized HF events from the 4 drug groups
determined 11 (22%) to have incomplete data for a
definitive review. Of the remaining 39, 33 (85%) were
confirmed to have HF by one or both reviewers. For both
the chlorthalidone and doxazosin groups, the diagnosis of
HF was confirmed in 90% (18/20).
Baseline Characteristics
Baseline characteristics for the doxazosin and
chlorthalidone treatment groups, stratified for HF
status, are described in Table 1.
Baseline characteristics of doxazosin and
chlorthalidone participants with subsequent hospitalized
or fatal HF were compared. Doxazosin participants with
hospitalized or fatal HF had a higher baseline SBP than
the chlorthalidone participants (150.1 vs. 147.8 mm Hg at
the randomization visit). More doxazosin participants had
LVH by ECG (22.3% vs. 20.5% of chlorthalidone
participants); slightly more chlorthalidone than
doxazosin participants had LVH by echocardiogram. Several
eligibility risk factors, including previous MIs or
strokes, coronary revascularization procedures, other
atherosclerotic cardiovascular disease (ASCVD), and ST-T
wave changes, were reported more often in chlorthalidone
than in doxazosin participants, though the differences
were not significant. Chlorthalidone and doxazosin
participants with hospitalized or fatal HF had similar
pre-trial antihypertensive treatment durations. None of
these differences was significant at
P < .05.
Participants with HF events displayed higher rates of
most cardiovascular risk factors compared to those
without HF events. Approximately 35-36% of chlorthalidone
and doxazosin participants with fatal or hospitalized HF
had reported prior MI or stroke as baseline eligibility
risk factors, compared to 22-23% of those without HF (
P < .001). Participants with
hospitalized/fatal HF had significantly higher rates of
pre-randomization coronary artery bypass grafts (CABGs)
and coronary angioplasties (19-23% of those with HF vs.
13% of those without;
P < .001) and other
atherosclerotic cardiovascular disease (ASCVD) (29-33% of
those with HF vs. 23-25% of those without;
P < .001). Diabetes as a
baseline risk factor occurred more frequently in those
with HF: 47-48% in those with HF, 35-36% in those without
(
P < .001). Left ventricular
hypertrophy (LVH) by ECG was a risk factor in 21-22% of
those who later developed HF, compared with 16% of those
in each group who did not develop HF (
P < .001).
Baseline pulse pressure (PP) showed some variation
between participants who did and did not develop HF. For
participants with subsequent hospitalization or death
from HF, PP was 67 and 68 mm Hg for the chlorthalidone
and doxazosin groups, respectively. Treated,
non-hospitalized participants showed a lower mean
baseline PP of 65 (chlorthalidone group) and 64 mm Hg
(doxazosin group), and an even lower mean PP in those
without HF (62 mm Hg in each group).
Medical Management
Table 2presents post-event pharmacologic treatment of
participants with HF and antihypertensive treatment of
participants without HF. Following hospitalization for
HF, 36% (83/232) of chlorthalidone participants and 45%
(126/281) of doxazosin participants remained on their
blinded medications. Percentages of participants on
open-label diuretics and ACE-inhibitors were similar
following the event: 58% (135/232) of chlorthalidone
participants and 64% (180/281) of doxazosin participants
were prescribed open-label diuretics; 39% (90/232) of
chlorthalidone participants and 41% (114/281) of
doxazosin participants were prescribed open-label
ACE-inhibitors. Beta-blockers were prescribed for 14% of
each group following the event, which was actually
somewhat less than for participants who did not develop
HF. Three-quarters of hospitalized HF participants in
each group (169/232 in chlorthalidone group, 210/281 in
doxazosin group) received at least one of the three
medications (diuretic, ACE-inhibitor, or beta-blocker)
post-hospitalization.
Among participants treated but not hospitalized for
HF, 58% (54/93) of the chlorthalidone group and 64%
(93/145) of the doxazosin group remained on their blinded
medication. Over 60% of participants in each group were
prescribed open-label diuretics and over 30% received
ACE-inhibitors. Open-label beta-blocker use post-event
occurred in 19% (18/93) of the chlorthalidone group and
22% (32/145) of the doxazosin group, approximately the
same frequency as in participants without HF. In both
treatment groups, a diuretic, ACE-inhibitor or
beta-blocker was prescribed for over 75% of these
participants (72/93 in chlorthalidone group, 119/145 in
doxazosin group).
Ejection Fraction Review
Table 3displays the ejection fraction data. About half
(178/361) of reviewed discharge summaries mentioned
ejection fractions measured during hospitalization,
two-thirds (116/169) of which had quantitative
measurements reported in the discharge summaries (data
not given). Considering only the earliest ejection
fraction information ascertained for each HF participant,
63% (29/46) of the chlorthalidone and 70% (41/59) of the
doxazosin participants had ejection fractions at or below
40%. Just under half (27/59) of the ejection fractions
reported in the doxazosin group were at or below 30%,
compared with one third (15/46) in the chlorthalidone
group. Two-thirds of ejection fractions were obtained by
echocardiograms, though catheterizations accounted for a
larger percentage of results in the doxazosin group than
in the chlorthalidone group (36% vs. 24%).
Causes of Death and 2-Year Case-Fatality
Causes of death of participants with previous HF
hospitalization were distributed similarly in the two
groups, with slight variations. HF accounted for 21.2%
(11/52) of the deaths among chlorthalidone participants
and 17.1% (12/70) of the deaths among doxazosin
participants. Over half of the deaths in each group
(29/52 in the chlorthalidone group; 43/70 in the
doxazosin group) were due to cardiovascular events.
Fifteen percent (8/52) of deaths in the chlorthalidone
group were attributed to cancer, compared to 9% (6/70) in
the doxazosin group (Table 4).
Case-fatality for participants with hospitalized HF
events showed no significant differences (RR 0.96, 95%
CI, 0.67-1.38,
P = 0.83) between the two treatment
groups (Figure 1). Among participants in the doxazosin
treatment group who had been previously hospitalized for
HF, 22.1% (70/317) subsequently died, compared to 18.6%
(52/280) of those in the chlorthalidone group (Table 4).
As previously reported, all-cause mortality did not
significantly differ in the two treatment groups (RR
1.03, 95% CI 0.90-1.15,
P = 0.56) [ 2 ] .
Discussion
The finding of significantly increased HF events in the
doxazosin group compared with the chlorthalidone group
created a dilemma for ALLHAT. Since the trial was not
designed to focus on HF, a component of a secondary
endpoint, the validity of reported HF events became an
issue. In this paper, we have described several analyses to
address this concern.
As previously reported, lost-to-follow-up and event
documentation were similar in the two treatment groups [ 2
] . Steps employed to validate the HF outcome in these
treatment groups confirmed the consistency of HF event
reporting. Participants in the two drug groups had similar
baseline characteristics when stratified by HF status. The
differences in eligibility risk factors between those
participants with HF and those without is not surprising:
larger percentages of those with HF had a history of MI,
stroke, CABG, angioplasty, other atherosclerotic
cardiovascular disease (ASCVD), diabetes, low HDL levels
and ECG abnormalities. Nonetheless, these eligibility
factors were not substantially different between
chlorthalidone and doxazosin participants with HF.
Post-diagnosis pharmacologic management of patients is
one measure of the strength of physicians' confidence in
the HF diagnoses. Open-label diuretics, ACE-inhibitors and
beta-blockers, all recognized treatments for HF, were
prescribed similarly for the chlorthalidone and doxazosin
groups, suggesting similar assessment of these events in
the two treatment groups.
ALLHAT criteria for HF were equivalently met in the two
groups. While the sample (n = 50) of hospitalized or fatal
HF reports reviewed by the ALLHAT Endpoints Subcommittee
was limited in number and in adequacy of corroborating
documentation, the review nonetheless showed adherence to
study criteria for the majority (85%) of the event reports.
The sometimes-discrepant results between reviewers
pertained more often to incomplete data than to rejection
of a HF diagnosis.
Clinical use of more objective measures, including
noninvasive and/or invasive tools for the measurement of
left ventricular function, offers a means of establishing
and quantifying systolic failure in cases clinically
suggestive of HF [ 7 10 ] . Among the ejection fractions
reported in the ALLHAT events that were reviewed, the
majority fell at or below 40%, indicating some degree of
systolic dysfunction. However, HF is a clinical diagnosis
that does not necessarily exclude those with intact left
ventricular systolic function [ 11 ] . Hypertension is a
major risk factor for diastolic HF; as many as 25% of
asymptomatic hypertensives with left ventricular
hypertrophy have diastolic dysfunction. Additionally, 90%
of patients with coronary artery disease may have some
degree of diastolic dysfunction [ 12 ] .
The two-fold increased relative risk of HF in the
doxazosin group compared to the chlorthalidone group
changed little when confined to hospitalized and fatal
events. Further, HF patients in both the doxazosin and
chlorthalidone treatment groups showed a rather high 20%
case-fatality rate over two years, as expected in HF
patients [ 11 13 14 ] , further supporting the validity of
the diagnoses in the two groups. Among participants
hospitalized for HF who subsequently died, over half of the
deaths in each drug group were attributed to cardiovascular
causes.
Treatment group differences in mortality attributed to
HF may take time to be recognized. Patients with HF are at
risk for other competing causes of death. Accordingly, it
may be too early to determine if a higher rate of HF in the
doxazosin group translates into a higher overall mortality
rate. A 20% 2-year case-fatality rate with a 4% difference
in HF incidence rate translates into a 0.8% potential
difference in total mortality without any competing causes
of death. With competing causes, the difference would be
smaller and difficult to detect even in a trial of ALLHAT's
size.
The diagnosis of HF is generally made on the basis of
signs and symptoms that may overlap with those of other
cardiovascular and pulmonary pathologies. Moreover, the
clinical picture may be further complicated for patients
taking doxazosin, side effects of which (edema, dyspnea,
and tachycardia) [ 15 ] may be misinterpreted as
manifestations of HF.
The capture of events in a "large and simple trial" such
as ALLHAT has potential limitations. Built into a structure
composed largely of community-based physicians is the
assumption that their characterization of clinical events
reflects diagnostic standards of the medical community,
and, as such, meets study criteria. However, with its large
number of endpoints, resources available to ALLHAT
precluded more than modest confirmatory event
documentation. Resources were allocated for additional
documentation for quality control validation only for a
sample of the primary endpoint (MIs and fatal CHD) and for
strokes. While all reported events are reviewed at the CTC,
the sometimes incomplete supporting details in
documentation may not allow for validation of all events
according to ALLHAT criteria. Some discharge summaries and
death certificates may lack sufficient descriptive
information needed to confirm the clinical diagnoses.
Clinic staff are unable to provide corroborating
documentation for 2% of ALLHAT event reports.
Efforts to authenticate the HF events in the doxazosin
and chlorthalidone treatment groups represented a desirable
step in the examination of the increased rate of HR in the
doxazosin group. All methods employed provided confirmatory
evidence that both the HF diagnosis and the difference in
HF rates noted between the doxazosin and chlorthalidone
groups were valid. Results of this exploratory
investigation support the event ascertainment methods
developed for ALLHAT, specifically for HF events. This
validation exercise further illustrates the ability of
large, simple trials to answer important public health
questions requiring large sample sizes and to grapple with
unexpected results in a responsible and meaningful
manner.
Competing Interests
The authors of this paper disclose their affiliations
with Aventis (A), Abbott (AB), AstraZeneca (AZ), Bayer (B),
Biovail (BV), Bristol-Myers Squibb (BMS), Forest (F),
Glaxo-SmithKline/SmithKline Beecham (GSK/SKB), King
Pharmaceuticals/Monarch (KM), Merck (M), Novartis (N),
Nu-Pharm (NP), Pharmacia/Upjohn (PHU), Pfizer, Inc. (P),
Sankyo (SY), Searle (SE), Solvay (SV), Takeda (T). These
relate to personal or institutional-affiliated receipt of
income in the areas of research grants, consultant fees, or
other compensation: BRD (AB,BMS,F,M,P,PHU,GSK/SKB), WCC
(AZ,BMS,F,M,P,PHU,SY,SE,SV,T), JTW (A,B,BMS,F,KM, M,N,P),
FHHL (AZ,B,BMS,M,NP,P,PHU), LJH (PHU); the other authors
report no competing interests.
Additional Information
1) New York Heart Classification functional class III:
"Patients with cardiac disease resulting in marked
limitation of physical activity. They are comfortable at
rest. Less than ordinary physical activity causes fatigue,
palpitation, dyspnea, or anginal pain." 1994 Revisions to
Classification of Functional Capacity and Objective
Assessment of Patients with Diseases of the Heart: AHA
Medical/Scientific Statement.
2) The ALLHAT Manual of Operations provides for
prescription of open-label medicines of the same class as
the blinded medications, when a compelling indication
exists, such that the total dose of the added open-label
drug should not exceed 1/2 of the maximum dose as
recommended in the Sixth Report of the Joint National
Committee on Detection, Evaluation and Treatment of High
Blood Pressure (JNC VI). If a compelling reason requires a
higher dose, it is permitted.
3) The ALLHAT follow-up form allows for reporting of
open-label ACE-inhibitors and diuretics; among
beta-blockers, only atenolol is reported. The use of other
beta-blockers cannot be ascertained from the data.
