Context Few cardiovascular outcome data are available for blacks with hypertension
treated with angiotensin-converting enzyme (ACE) inhibitors or calcium channel
blockers (CCBs).
Objective To determine whether an ACE inhibitor or CCB is superior to a thiazide-type
diuretic in reducing cardiovascular disease (CVD) incidence in racial subgroups.
Design, Setting, and Participants Prespecified subgroup analysis of ALLHAT, a randomized, double-blind,
active-controlled, clinical outcome trial conducted between February 1994
and March 2002 in 33 357 hypertensive US and Canadian patients aged 55
years or older (35% black) with at least 1 other cardiovascular risk factor.
Interventions Antihypertensive regimens initiated with a CCB (amlodipine) or an ACE
inhibitor (lisinopril) vs a thiazide-type diuretic (chlorthalidone). Other
medications were added to achieve goal blood pressures (BPs) less than 140/90
mm Hg.
Main Outcome Measures The primary outcome was combined fatal coronary heart disease (CHD)
or nonfatal myocardial infarction (MI), analyzed by intention-to-treat. Secondary
outcomes included all-cause mortality, stroke, combined CVD (CHD death, nonfatal
MI, stroke, angina, coronary revascularization, heart failure [HF], or peripheral
vascular disease), and end-stage renal disease.
Results No significant difference was found between treatment groups for the
primary CHD outcome in either racial subgroup. For amlodipine vs chlorthalidone
only, HF was the only prespecified clinical outcome that differed significantly
(overall: relative risk [RR], 1.37; 95% confidence interval [CI], 1.24-1.51;
blacks: RR, 1.46; 95% CI, 1.24-1.73; nonblacks: RR, 1.32; 95% CI, 1.17-1.49; P<.001 for each comparison) with no difference in treatment
effects by race (P = .38 for interaction).
For lisinopril vs chlorthalidone, results differed by race for systolic BP
(greater decrease in blacks with chlorthalidone), stroke, and combined CVD
outcomes (P<.001, P = .01,
and P = .04, respectively, for interactions).
In blacks and nonblacks, respectively, the RRs for stroke were 1.40 (95% CI,
1.17-1.68) and 1.00 (95% CI, 0.85-1.17) and for combined CVD were 1.19 (95%
CI, 1.09-1.30) and 1.06 (95% CI, 1.00-1.13). For HF, the RRs were 1.30 (95%
CI, 1.10-1.54) and 1.13 (95% CI, 1.00-1.28), with no significant interaction
by race. Time-dependent BP adjustment did not significantly alter differences
in outcome for lisinopril vs chlorthalidone in blacks.
Conclusions In blacks and nonblack subgroups, rates were not lower in the amlodipine
or lisinopril groups than in the chlorthalidone group for either the primary
CHD or any other prespecified clinical outcome, and diuretic-based treatment
resulted in the lowest risk of heart failure. While the improved outcomes
with chlorthalidone were more pronounced for some outcomes in blacks than
in nonblacks, thiazide-type diuretics remain the drugs of choice for initial
therapy of hypertension in both black and nonblack hypertensive patients.
Cardiovascular disease (CVD) has become the leading cause of morbidity
and mortality worldwide, and elevated blood pressure (BP) is a leading contributor
to this phenomenon.1,2 The population
of blacks with hypertension has the highest morbidity and mortality from hypertension
of any population group in the United States and is among the highest in the
world.3,4 Mortality related to
hypertension and the risk of end-stage renal disease (ESRD), coronary heart
disease (CHD), heart failure (HF), and stroke are increased in the black compared
with the white population in the United States.4,5 While
the benefits of lowering elevated BP in reducing cardiovascular morbidity
and mortality are well established, until recently well-controlled studies
comparing different classes of antihypertensive agents for reducing cardiovascular
complications of hypertension were not available.
During the past decade the results of several clinical outcome trials
comparing the main first-line classes of antihypertensive agents have been
reported.6-12 The
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT) was a randomized, double-blind trial conducted in 42 418 participants
that determined that the regimen based on the thiazide-type diuretic was at
least as effective in preventing CHD as those based on the α-blocker,
the angiotensin-converting enzyme (ACE) inhibitor, or the calcium channel
blocker (CCB); more effective than these agents in preventing HF; and more
effective than the α-blocker and the ACE inhibitor in preventing stroke
and the composite of cardiovascular disease CVD outcomes.10,11,13 Results
analyzed by blacks vs nonblacks for the α-blocker group, which was terminated
early, were reported previously and are not included here.10,14,15
This report details the results of the ALLHAT antihypertensive trial
analyses by race. The subgroup results by race for the ALLHAT lipid trial
will be presented in a separate publication. While the limitations of examining
racial differences are appreciated, differences in BP lowering by race have
already been demonstrated for ACE inhibitors and to a lesser extent for α-blockers,3,16,17 and cardiovascular
outcome data for black patients with hypertension treated with ACE inhibitors
or CCBs have been lacking.6-8,18-20 For
this reason, race was a prespecified subgroup in the trial. This report expands
the results presented in the report of overall results by providing more detailed
analyses of treatment differences by race, including the influence of the
observed BP differences.
The rationale and design of ALLHAT have been presented elsewhere.13 Participants were men and women, aged 55 years or
older, who had untreated systolic (≥140 mm Hg) and/or diastolic (≥90
mm Hg) hypertension (but ≤180/110 mm Hg at 2 visits) or treated hypertension
(≤160/100 mm Hg while receiving 1-2 antihypertensive drugs at visit 1 and
≤180/110 mm Hg at visit 2 when medication may have been withdrawn) with
at least 1 additional risk factor for CHD events.13,21 The
risk factors included left ventricular hypertrophy (LVH) by electrocardiography
or echocardiography, history of type 2 diabetes, current cigarette smoking,
high-density lipoprotein cholesterol level less than 35 mg/dL (0.9 mmol/L),
previous (>6 months) myocardial infarction (MI) or stroke, and documentation
of other atherosclerotic CVD. Individuals with a history of hospitalized or
treated symptomatic HF, serum creatinine level less than 2.0 mg/dL (176.8 μmol/L),
and/or known left ventricular ejection fraction less than 35% were excluded.
Race was defined by self-report as black, white, Asian, Native American, and
other; the last 4 categories are combined for this report as nonblack (92%
white). All participants gave written informed consent, all centers obtained
institutional review board approval, and the trial was monitored by a National
Heart, Lung, and Blood Institute–appointed data and safety monitoring
board.
Enrollment and Study Organization
Unless the drug regimen required tapering for safety reasons, individuals
discontinued any prior antihypertensive medications only when they received
randomized study drug. Participants included in this report were randomized
to receive chlorthalidone, amlodipine, or lisinopril in a ratio of 1.7:1:1,
respectively (Figure 1). Since all groups
were compared with the diuretic, this ratio was chosen to maximize statistical
power for a 4-group trial. The concealed randomization scheme was generated
by computer at the clinical trials center, stratified by center, and blocked
in randomly ordered 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
1998.11 The closeout phase began October 1,
2001, and ended March 31, 2002. The range of follow-up was 3 years 8 months
to 8 years 1 month. Mean follow-up was 4.9 years.
Intervention and Follow-up
Trained observers using standardized techniques measured BPs during
the trial.22 Visit BP was the average of 2
seated measurements separated by 30 seconds. Goal BP for all participants
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. Step 1
drugs were identically encapsulated so that 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. The study supplied open-label atenolol, reserpine, and clonidine
at step 2, and hydralazine for step 3, if needed for BP control. The choice
of step 2 and 3 medications was at the investigator’s discretion. Slow-release
potassium chloride was provided for serum potassium levels consistently less
than 3.5 mEq/L. After initial monthly titration visits, participants were
seen every 3 months during the first year and every 4 months thereafter. Visit
adherence was determined by the percentage of participants appearing for their
protocol visit within the visit window.
The primary outcome was the combination of fatal CHD and nonfatal MI.13 Four major prespecified secondary outcomes were (1)
all-cause mortality, (2) fatal and nonfatal stroke, (3) combined CHD (≥1
of the primary outcome, coronary revascularization, or hospitalized angina),
and (4) combined CVD (≥1 of combined CHD, fatal or nonfatal stroke, nonhospitalized
treated angina, HF [fatal, hospitalized, or treated nonhospitalized], and
treated peripheral arterial disease). Individual components of combined outcomes
were also examined. Other prespecified secondary outcomes included incident
cancer, first hospitalization for gastrointestinal bleeding, incident electrocardiographic
LVH, and ESRD (dialysis, renal transplant, or renal death). Change in estimated
glomerular filtration rate23 was examined post
hoc, and results for incident LVH will be reported separately.
Study end points were assessed at follow-up visits and reported to the
clinical trials center.13 Hospitalized outcomes
were primarily based on clinic investigator reports, with copies of death
certificates and hospital discharge summaries requested for central review.
Among all combined CVD events that resulted in deaths and/or hospitalizations,
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 & Medicaid Services,
the Department of Veterans Affairs, the National Death Index, and the Social
Security Administration databases. Clinical trials center medical reviewers
verified the clinician-assigned diagnoses of outcomes using death certificates
and hospital discharge summaries. More detailed information was collected
on random (10% subset) CHD and stroke events to validate the procedure of
using clinician diagnoses.13 When a large excess
of HF became evident in the doxazosin group, 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
end point, 84% (129/153) for stroke, and 85% (33/39) for HF hospitalizations14 and were similar in all treatment groups. Subsequent
blinded review of 98% of the HF hospitalizations in 97% of the participants
with HF has confirmed the validity of this outcome.14,24
ALLHAT was designed as a superiority trial. Based on its anticipated
sample size, assumptions of 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 the chlorthalidone group and each other group
at a 2-sided α of .05/3, or .0178 (z = 2.37)
to account for the 3 original comparisons.11,13 Baseline
characteristics and intermediate outcomes were compared across treatment within
baseline racial classification using analysis of variance for continuous covariates
and contingency table analyses for categorical data. Data were analyzed according
to participants’ randomized treatment assignments regardless of their
subsequent medications (ie, intention-to-treat analysis). Six-year cumulative
event rates were calculated using the Kaplan-Meier procedure. Cox proportional
hazards models were used to obtain hazard ratios (hereafter termed relative
risks [RRs]) and 95% confidence intervals (CIs) for time-to-event outcomes
and included the participant’s entire trial experience. The proportional
hazards assumption was examined by using log-log plots and testing a treatment × time
(time-dependent) interaction term; if the assumption was violated, the RR
estimate from a cumulative incidence analysis of a 2 × 2 table
(ie, event/no event vs amlodipine/chlorthalidone or lisinopril/chlorthalidone)25 or an alternative Cox regression model that included
a treatment × time interaction term was used. In the case
of HF, the model used a treatment × time indicator variable
(≤1 year vs >1 year).
For the published main ALLHAT results,11 the
HF outcomes for the total group were obtained using 2 × 2
tables, but the results for the subgroups used the results from the Cox regression
analyses. For this analysis, the proportional hazards assumption was also
violated within the black and nonblack subgroups, so the subgroup results
obtained using 2 × 2 tables are reported. Heterogeneity of
treatment effects across racial subgroups was examined by testing for treatment × race
interaction with the proportional hazards model (or in a logistic model if
the proportional hazards assumption was violated) using P<.05. Where there were significant differences in baseline characteristics
by race, these were included as covariates in adjusted models. Given the many
multivariate, subgroup, and interaction analyses performed, statistical significance
at the .05 level should be interpreted with caution.
To adjust for observed BP differences over time between treatment groups,
Cox proportional hazards models with systolic BPs (SBPs) and diastolic BPs
(DBPs) as time-varying covariates were used.26 The
time-dependent analyses were performed both with no imputation for missing
values and with multiple imputation for the missing SBP and DBP observations.22,27 Since the results with and without
imputation were similar, the results without imputation for missing values
are presented. Stata version 8 (Stata Corp, College Station, Tex) was used
for all analyses.
The baseline characteristics of the ALLHAT study population by race
and treatment group are shown in Table 1.
Compared with nonblacks, black participants were more likely to be women (55%
vs 43%), have diabetes (46% vs 39%), smoke cigarettes (25% vs 20%), and have
electrocardiographic LVH (24% vs 12%). Black participants were also slightly
younger, had higher levels of high-density lipoprotein cholesterol, and were
less likely to have a history of CHD, atherosclerotic disease, or both. Baseline
BP levels were similar in the black and nonblack subgroups (146/85 and 146/84
mm Hg, respectively), and within subgroups no differences were noted across
the 3 treatment groups in baseline BP or in distribution by age, risk factor
levels, and history of CVD.
Visit and Medication Adherence by Race
Visit adherence was slightly lower for blacks than nonblacks. For nonblacks,
93% of expected follow-up visits were completed in each of the 3 treatment
groups at 1 year, while the corresponding rates were 89% to 91% for blacks.
At year 5, 86% to 89% (across treatment groups) of expected visits were completed
for nonblacks, while the rates for blacks were 80% to 84%. Of those seen,
83% to 84% of both racial subgroups randomized to receive chlorthalidone or
amlodipine were still receiving the blinded drug at year 1 (87%-89% for each
treatment group if drugs of the same class are included). At year 5, 71% to
73% were still receiving the blinded study drug (80%-81% were receiving drugs
of the same class as the blinded study drug). Among those randomized to receive
lisinopril, for nonblacks and blacks respectively, 78% vs 76% were still receiving
blinded study drug at year 1 and 63% vs 57% at year 5. Including any ACE inhibitor,
the rates were 83% vs 81% at year 1 and 74% vs 69% at year 5 for nonblacks
and blacks, respectively.
Nonblacks assigned to receive chlorthalidone or amlodipine had progressive
BP declines to approximately 134/76 mm Hg by the end of 4 years of follow-up
(Table 2). In black participants, amlodipine
produced a decline in DBP similar to that produced by chlorthalidone, although
SBP decline with amlodipine was approximately 2 mm Hg less. The BP decline
in nonblacks randomized to receive lisinopril was also similar to that for
those receiving chlorthalidone, with less than 1 mm Hg separating the treatment
groups at 4 years. Blood pressure decline while receiving lisinopril was significantly
less in blacks compared with nonblacks and less than in blacks randomized
to receive chlorthalidone, especially during the early time periods. At 2
years, blacks experienced a 5/2-mm Hg greater BP reduction on average with
chlorthalidone than with lisinopril; this difference decreased to 4/1 mm Hg
at 4 years. Among nonblacks, BPs averaged over 5 years of follow-up were 137/78
mm Hg in the chlorthalidone and amlodipine groups, respectively, and 138/78
mm Hg in the lisinopril group; equivalent measures in blacks were 138/80 mm
Hg, 140/80 mm Hg, and 143/82 mm Hg, respectively.
The percentages of nonblacks achieving a BP less than 140/90 mm Hg at
4 years were 69%, 69%, and 67% in the chlorthalidone, amlodipine, and lisinopril
groups, respectively. The corresponding percentages among blacks were 63%
for chlorthalidone, 60% for amlodipine, and 54% for lisinopril. By 5 years
of follow-up, 56% to 70% of black participants and 61% to 63% of nonblack
participants were prescribed 2 or more antihypertensive drugs, depending on
the treatment group. The most common step 2 agent for both racial subgroups
and for all treatment groups was atenolol (24%-33%) followed in frequency
by clonidine (8%-24%). Three or more antihypertensive drugs were prescribed
to 24% of blacks and nonblacks randomized to receive chlorthalidone, compared
with 41% and 31%, respectively, randomized to receive lisinopril and with
28% and 25%, respectively, randomized to receive amlodipine.
Fasting glucose levels increased significantly and potassium levels
decreased in participants randomized to receive chlorthalidone compared with
those in the lisinopril and amlodipine groups at 4 years (Table 2 and Table 3). These
metabolic changes were similar in both racial subgroups. In addition, the
previously reported higher incidence of participants exceeding a fasting glucose
level of 126 mg/dL (7.0 mmol/L) was 3% to 4% higher in nonblacks and 1% to
5% higher in blacks receiving chlorthalidone compared with the other 2 treatment
groups.11 For lisinopril, by 4 years cholesterol
levels declined less in blacks than in nonblacks and also declined less for
blacks receiving chlorthalidone (P = .02)
(Table 3). The change in the cholesterol
levels at 4 years for chlorthalidone vs amlodipine did not differ between
blacks and nonblacks.
Table 4 presents the serious adverse
events collected in the trial. Due to the large simple trial design and since
the drugs were all approved and widely used, more detailed information on
these events and information on less-severe events was not collected. Except
for the previously reported increased incidence of angioedema in the group
treated with ACE inhibitors, especially in blacks,11 the
incidence of serious adverse events was small and did not differ across treatment
groups.
Overall, 6-year event rates were significantly lower in black vs nonblack
participants for the primary outcome, nonfatal MI plus fatal CHD (9.7% vs
12.3%, P<.001), combined CHD (15.9% vs 22.5%, P<.001), and combined CVD (28.4% vs 33.7%, P<.001). Black participants had significantly higher rates of stroke
(6.5% vs 5.3%, P<.001) and ESRD (2.6% vs 1.5%, P<.001) and higher overall mortality (17.7% vs 16.8%, P = .003). These differences are unadjusted for
the numerous baseline differences between blacks and nonblacks.
The treatment comparisons by racial subgroup for the prespecified clinical
outcomes are shown in Table 5, Table 6, and Figure
2. As previously reported, no difference was noted between treatment
groups in the primary outcome of MI and fatal CHD in either racial subgroup.11 For amlodipine compared with chlorthalidone, a higher
rate of HF (RR, 1.46 and 1.32 in blacks and nonblacks, respectively; 1.37
[95% CI, 1.24-1.51] overall) was the only prespecified clinical outcome that
differed significantly in either subgroup. There was no evidence of treatment × race
interaction for the amlodipine vs chlorthalidone HF comparison (P = .38).
Comparing lisinopril vs chlorthalidone, different treatment effects
by race were seen for BP reduction (P<.001 for
interaction) (Table 2), stroke (P = .01), and combined CVD outcomes (P = .04). In blacks, compared with randomization to chlorthalidone,
randomization to lisinopril significantly increased risk of stroke (RR, 1.40;
95% CI, 1.17-1.68). No such effect was seen in nonblacks (RR, 1.00; 95% CI,
0.85-1.17). The RR for combined CVD was 1.19 (95% CI, 1.09-1.30) for blacks
vs 1.06 (95% CI, 1.00-1.13) for nonblacks. For HF, although the effect estimate
was somewhat larger in blacks (1.30; 95% CI, 1.10-1.54) than in nonblacks
(1.13; 95% CI, 1.00-1.28), there was no significant interaction, so the previously
reported overall RR (1.19; 95% CI, 1.07-1.31) is the best estimate for both
racial subgroups.11
The relative differences in HF event rates between treatment groups
in both racial categories occurred early (during the first year) and decreased
over time (Figure 3). For example, in
blacks, the RRs for HF at 1 year were 2.26 (95% CI, 1.56-3.27) for amlodipine
vs chlorthalidone and 2.17 (95% CI, 1.49-3.15) for lisinopril vs chlorthalidone.
In nonblacks, the RRs for HF at 1 year were 2.37 (95% CI, 1.75-3.22) for amlodipine
vs chlorthalidone and 2.26 (95% CI, 1.66-3.07) for lisinopril vs chlorthalidone.
The RRs declined after 1 year, with larger declines in nonblacks.
When time-dependent adjustment for BP was applied to the data presented
above, these findings did not change significantly in either racial subgroup
(Table 7). For example, for lisinopril
vs chlorthalidone in blacks, time-dependent BP adjustment reduced the RR from
1.40 to 1.36 for stroke, from 1.30 to 1.26 for HF,11 and
from 1.19 to 1.17 for combined CVD. Finally, adjusting for baseline differences
in age, sex, history of CHD, diabetic status, treatment for hypertension,
aspirin use, SBP, DBP, glucose levels, and years of education in both racial
subgroups had no effect on the stroke outcome, whether or not results also
were adjusted for time-dependent BP.
ALLHAT is the first large-scale trial with a substantial number of black
participants to evaluate the effect of dihydropyridine CCBs and ACE inhibitors
on preventing cardiovascular outcomes. The findings by race mostly parallel
those in the whole cohort and in nonblacks, who comprised two thirds of the
participants. The major exception was the outcome for stroke (as discussed
below); effects on SBP also differed in blacks and nonblacks. In both racial
subgroups as in the whole cohort, neither the ACE inhibitor nor the CCB was
more effective than the thiazide-type diuretic in preventing the primary outcome
of MI or fatal CHD or any other major cardiovascular or renal outcome, and
diuretic-based treatment was superior to ACE inhibitors and CCBs in reducing
HF incidence.
While the CCB conferred a higher rate of HF compared with the diuretic
in both blacks and nonblacks (37% overall), the other prespecified outcomes
did not differ in either subgroup. The small BP difference in both subgroups
between the CCB and diuretic treatment groups is unlikely to account for the
higher HF incidence with the CCB. This finding confirms and specifically establishes
in both blacks and nonblacks previous findings that suggested that CCBs are
less effective than diuretics in preventing or treating HF.7,18,28-31
As previously reported,11 stroke was
significantly less likely with the diuretic than with the ACE inhibitor in
blacks but not in nonblacks, and the difference in the composite CVD outcome
was greater in blacks. The diuretic also was more effective in lowering and
controlling BP in blacks, and the difference in effect on stroke in blacks
and nonblacks is likely explained in part by the BP differences. In considering
the race-specific differences between treatment groups, BP correlated less
with HF than with stroke, a finding confirmed by the recent prospective meta-analysis
of hypertension outcome trials.28 Importantly,
the overall improved HF outcomes with diuretics did not differ in blacks and
nonblacks.
The BP findings in ALLHAT are consistent with previous studies reporting
lesser BP lowering in blacks receiving monotherapy with ACE inhibitors and
other agents whose mechanism of BP lowering is related to inhibiting the renin-angiotensin
system (RAS), eg, angiotensin receptor blockers and β-blockers.3,4,16,32 In
ALLHAT, this smaller degree of BP reduction was associated with a 19% higher
risk of the composite CVD outcome, 40% higher risk of stroke, and 30% higher
risk of HF in blacks randomized to receive the ACE inhibitor compared with
the diuretic.
Previous studies suggest that the smaller degree of BP reduction could
explain the difference in outcomes at least in part. Based on results from
the placebo-controlled Systolic Hypertension in the Elderly Program (SHEP)33 and the Systolic Hypertension in Europe Trial (Syst-Eur),18 in which the respective 12- and 10-mm Hg SBP differences
were associated with 49% and 29% decreases in HF, respectively, a 5-mm Hg
difference could explain a 15% to 20% decrease in this outcome. A meta-analysis
of prospective studies suggests that this SBP difference could account for
an approximately 18% decrease in stroke.34 ALLHAT
demonstrated a 26% decrease in stroke using a time-dependent analysis to adjust
for change in BP and a 29% decrease without adjusting for BP. Therefore, approximately
two thirds (18%/29%) of the stroke reduction can be explained by the change
in BP. A report of more detailed analyses of the effects of differences in
BP on the results in ALLHAT is forthcoming, but it is worth noting that at
4 years of follow-up, the average BP for blacks in the ACE inhibitors group
was 138/79 mm Hg and that more than 54% of blacks in this treatment group
had BPs less than 140/90 mm Hg. Thus, the differences in stroke outcomes occurred
despite more than half of the participants achieving the target BP.
ACE inhibitors and angiotensin receptor blockers have slowed decline
of renal function in trials of patients with reduced baseline renal function.35-37 In the African American
Study of Kidney Disease and Hypertension (AASK), an ACE inhibitor–based
regimen slowed progression of renal disease in black participants with hypertension
more than a regimen based on a β-blocker or a dihydropyridine CCB.35 However, ALLHAT is the first trial to compare renal
outcomes by race and the first in which a diuretic was compared with an ACE
inhibitor or CCB for renal outcomes. A diuretic was often used as the first
add-on drug in the previous trials of renal outcomes. Participants in both
racial subgroups who were randomized to receive the diuretic had rates of
ESRD that were not significantly different than the rates for those receiving
an ACE inhibitor. More detailed analyses of the renal outcomes in ALLHAT are
forthcoming in a separate manuscript.38
The choice of available step 2 or step 3 agents in ALLHAT may have contributed
to the poorer BP control in the ACE inhibitor group, especially in the black
subgroup. β-Blockers (followed by clonidine) were the most frequently
prescribed add-on agents in all treatment groups. ACE inhibitors and β-blockers
are both less effective in lowering BP in blacks in the absence of a diuretic
(or CCB),3,39-43 and
the combination of a sympatholytic and RAS inhibitor may be less effective
than the combination of either class with an agent not affecting the RAS.39,44,45
Since ACE inhibitors, CCBs, and thiazide-type diuretics were being compared
as first-line agents, unless a specific clinical indication (including uncontrolled
BP) developed, participants randomized to receive ACE inhibitors who required
multiple antihypertensive agents to control BP could not receive either diuretics
or CCBs. These antihypertensive agents have been shown to be the most effective
add-on agents for reducing BP in blacks with hypertension when combined with
ACE inhibitors.3,39,41-43 This
study design was necessary, since a primary objective of ALLHAT was to determine
the optimal antihypertensive agent when selected as the initial agent. For
an agent that is less effective in lowering BP to be recommended as initial
therapy over a more effective agent, it must exhibit beneficial properties
independent of BP lowering. The results of ALLHAT suggest that any non–BP-related
benefit of ACE inhibition is insufficient to overcome the 5-mm Hg less BP
reduction it conferred in black participants (or even the 1-mm Hg SBP disadvantage
noted in nonblacks). This implication for RAS inhibition as first-line approach
was also seen in a recent study comparing the angiotensin receptor blocker
valsartan with the CCB amlodipine in a predominantly nonblack cohort.46 The higher risk of ACE inhibitor–associated
angioedema that was noted in the black ALLHAT subgroup, previously reported,11,47 provides another disadvantage for
selecting ACE inhibition as initial therapy in this subgroup. Based on other
studies, ACE inhibitors are recommended as part of treatment regimens for
black patients with hypertension and renal disease or HF.35,48,49 Normally,
such patients would also receive a diuretic for control of BP, fluid retention,
or both.
Thus, the overall ALLHAT conclusions that thiazide-type diuretics are
indicated as the drug of choice for initial therapy of hypertension apply
to both black and nonblack patient populations. Despite more favorable metabolic
profiles in the 3 newer classes of drugs, diuretics were either similar or
superior in lowering BP, in tolerability, and in preventing the major clinical
complications of hypertension. We previously recommended that for patients
unable to take a diuretic, a CCB or an ACE inhibitor may be appropriate first-line
therapy.11 In this analysis, nonblacks had
a higher risk of HF with the CCB than with the ACE inhibitor when compared
with the diuretic. However, the increase in HF in the ACE inhibitor group
compared with the diuretic group was large initially and remained so over
the course of the trial. Analyses directly comparing outcomes for CCBs vs
ACE inhibitors are currently under way. The Blood Pressure Lowering Treatment
Trialists’ Collaboration second-cycle meta-analysis reported no significant
difference between these classes for aggregated major cardiovascular events,
though there were trends favoring CCBs for stroke outcomes and ACE inhibitors
for HF outcomes.28
In conclusion, in blacks with hypertension and without renal disease
or HF, these results indicate that thiazide-type diuretics, and CCBs in patients
who cannot take a diuretic (eg, those with allergy or confirmed intolerance),
are preferred to ACE inhibitors as initial single-drug therapy. The recommended
preference for a CCB over an ACE inhibitor as the first alternative to a diuretic
in blacks is based on the greater risk for stroke, combined CHD, combined
CVD, and angioedema seen with ACE inhibitors, overriding the greater risk
for HF with a CCB. This conflicts with the recommendation of one panel that
continued to advocate inclusion of a RAS inhibitor as first-line antihypertensive
therapy50 but is consistent with the recommendations
from more recent guideline panels.36,51,52
Corresponding Author: Jackson T. Wright,
Jr, MD, PhD, General Clinical Research Center, Case Western Reserve University,
11000 Euclid Ave, Bowell Bldg, Fifth Floor, Cleveland, OH 44106 (jackson.wright@case.edu).
Author Contributions: Dr Davis had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Wright, Cutler, Davis,
Cushman, Haywood, Papademetriou, Probstfield, Whelton.
Acquisition of data: Wright, Davis, Cushman,
Ford, Haywood, Leenen, Margolis, Papademetriou, Probstfield.
Analysis and interpretation of data: Wright,
Dunn, Cutler, Davis, Cushman, Ford, Haywood, Leenen, Margolis, Papademetriou,
Probstfield, Whelton, Habib.
Drafting of the manuscript: Wright, Dunn, Cutler,
Cushman, Ford, Haywood, Papademetriou, Probstfield.
Critical revision of the manuscript for important
intellectual content: Wright, Cutler, Davis, Cushman, Haywood, Leenen,
Margolis, Papademetriou, Probstfield, Whelton, Habib.
Statistical analysis: Dunn, Davis, Cushman,
Ford, Whelton.
Obtained funding: Wright, Cutler, Davis, Papademetriou,
Probstfield.
Administrative, technical, or material support:
Wright, Cutler, Davis, Cushman, Leenen, Margolis, Probstfield.
Study supervision: Wright, Cutler, Davis, Cushman,
Leenen, Margolis, Papademetriou, Probstfield.
Financial Disclosures: Dr Wright has received
research grants, honoraria, and/or consulting fees from AstraZeneca, Aventis,
Bayer, Bristol-Myers Squibb, Eli Lilly & Co, Merck & Co, Novartis
Pharma AG, Pfizer Inc, Phoenix Pharmaceuticals, Searle & Co, SmithKline
Beecham, and Solvay/Unimed. Dr Davis has received consulting fees from Merck,
Pfizer, SmithKline Beecham/GlaxoWellcome, and Takeda. Dr Cushman has received
grants/research support and/or consulting fees/honoraria from Abbott, AstraZeneca,
Aventis, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Forest, King,
Kos, Novartis, Pfizer, Reddy, Sankyo, and Sanofi. Dr Whelton has received
honoraria from Pfizer. No other authors reported financial disclosures.
Funding/Support: This study was supported by
contract NO1-HC-35130 from the National Heart, Lung, and Blood Institute.
The ALLHAT investigators acknowledge contributions of study medications supplied
by Pfizer Inc (amlodipine), AstraZeneca (atenolol and lisinopril), and Bristol-Myers
Squibb (pravastatin) and financial support provided by Pfizer Inc.
Role of the Sponsors: 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. Pfizer Inc, AstaZeneca, and Bristol-Myers Squibb had no role
in the design and conduct of the study; the collection, analysis, and interpretation
of the data; or the preparation or approval of the manuscript.
A list of the ALLHAT Collaborative Research Group members has been published previously.11
1.World Health Organization. World Health Report 2002; Reducing Risk, Promoting
Healthy Life. Geneva, Switzerland: World Health Organization; 2002
2.Chobanian AV, Bakris GL, Black HR.
et al. The Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.
JAMA. 2003;289:2560-257212748199
Google ScholarCrossref 3.Rahman M, Douglas JG, Wright JT. Pathophysiology and treatment implications of hypertension in the African-American
population.
Endocrinol Metab Clin North Am. 1997;26:125-1449074856
Google ScholarCrossref 4.Johnson EF, Wright JT Jr. Management of hypertension in black populations. In: Weber MA, Oparil S, eds. Hypertension.
Philadelphia, Pa: Elsevier; 2005:587-595
5.Gillum RF. Cardiovascular disease in the United States: an epidemiologic overview. In: Brest AN, ed. Cardiovascular Diseases in Blacks. Philadelphia, Pa: FA Davis Co; 1991:3-16
6.Hansson L, Hedner T, Lund-Johansen P.
et al. Randomised trial of effects of calcium antagonists compared with diuretics
and beta-blockers on cardiovascular morbidity and mortality in hypertension:
the Nordic Diltiazem (NORDIL) study.
Lancet. 2000;356:359-36510972367
Google ScholarCrossref 7.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;356:366-37210972368
Google ScholarCrossref 8.Hansson L, Lindholm LH, Niskanen L.
et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional
therapy on cardiovascular morbidity and mortality in hypertension: the Captopril
Prevention Project (CAPPP) randomised trial.
Lancet. 1999;353:611-61610030325
Google ScholarCrossref 9.UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular
and microvascular complications in type 2 diabetes: UKPDS 39.
BMJ. 1998;317:713-7209732338
Google ScholarCrossref 10.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;283:1967-197510789664
Google ScholarCrossref 11.ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
Group. 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).
JAMA. 2002;288:2981-299712479763
Google ScholarCrossref 12.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;354:1751-175610577635
Google ScholarCrossref 13.Davis BR, Cutler JA, Gordon DJ.
et al. ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid Lowering Treatment
to Prevent Heart Attack Trial (ALLHAT).
Am J Hypertens. 1996;9:342-3608722437
Google ScholarCrossref 14.Piller LB, Davis BR, Cutler JA.
et al. Validation of heart failure events in the Antihypertensive and Lipid
Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants assigned
to doxazosin and chlorthalidone.
Curr Control Trials Cardiovasc Med. 2002;3:1012459039
Google ScholarCrossref 15.Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial Collaborative Research Group. Diuretic versus alpha-blocker as first-step antihypertensive therapy:
final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT).
Hypertension. 2003;42:239-24612925554
Google ScholarCrossref 16.Materson BJ, Reda DJ, Cushman WC.
et al. Department of Veterans Affairs Cooperative Study Group on Antihypertensive
Agents. Single-drug therapy for hypertension in men: a comparison of six antihypertensive
agents with placebo.
N Engl J Med. 1993;328:914-9218446138
Google ScholarCrossref 17.Luther RR, Glassman HN, Jordan DC, Sperzel WD. Efficacy of terazosin as an antihypertensive agent.
Am J Med. 1986;80:73-762872811
Google ScholarCrossref 18.Staessen JA, Fagard R, Thijs L.
et al. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised
double-blind comparison of placebo and active treatment for older patients
with isolated systolic hypertension.
Lancet. 1997;350:757-7649297994
Google ScholarCrossref 19.Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients.
N Engl J Med. 2000;342:145-15310639539
Google ScholarCrossref 20.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;358:1033-104111589932
Google ScholarCrossref 21.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;37:19-2711208751
Google ScholarCrossref 22.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;137:313-32012204014
Google ScholarCrossref 23.Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D.Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from
serum creatinine: a new prediction equation.
Ann Intern Med. 1999;130:461-47010075613
Google ScholarCrossref 24.Einhorn P, Davis BR, Pillar LB.
et al. Review of heart failure events in the Antihypertensive and Lipid Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT): ALLHAT Validation Study
[abstract].
Circulation. 2003;108:(suppl IV)
399
Google ScholarCrossref 25.Klein JP, Moeschberger ML. Survival Analysis: Techniques for Censored and Truncated
Regression. New York, NY: Springer-Verlag; 1997
26.Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. 2nd ed. New York, NY: John Wiley & Sons; 2002
27.Mander A, Clayton D. Hotdeck Imputation. College Station, Tex: Stata Corp; 2000:196-199
28.Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular
events: results of prospectively-designed overviews of randomised trials.
Lancet. 2003;362:1527-153514615107
Google ScholarCrossref 29.Black HR, Elliott WJ, Grandits G.
et al. Principal results of the Controlled Onset Verapamil Investigation of
Cardiovascular End Points (CONVINCE) trial.
JAMA. 2003;289:2073-208212709465
Google ScholarCrossref 30.Packer M, O'Connor CM, Ghali JK.
et al. Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of amlodipine on morbidity and mortality in severe chronic heart
failure.
N Engl J Med. 1996;335:1107-11148813041
Google ScholarCrossref 31.Psaty BM, Lumley T, Furberg CD.
et al. Health outcomes associated with various antihypertensive therapies
used as first-line agents: a network meta-analysis.
JAMA. 2003;289:2534-254412759325
Google ScholarCrossref 32.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;150:1707-17132200382
Google ScholarCrossref 33.Kostis JB, Davis BR, Cutler J.
et al. SHEP Cooperative Research Group. Prevention of heart failure by antihypertensive drug treatment in older
persons with isolated systolic hypertension.
JAMA. 1997;278:212-2169218667
Google ScholarCrossref 34.Lewington S, Clarke R, Qizilbash N, Peto R, Collins R.Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality:
a meta-analysis of individual data for one million adults in 61 prospective
studies [published correction appears in Lancet . 2003;361:1060].
Lancet. 2002;360:1903-19131969567
Google ScholarCrossref 35.Wright JT Jr, Bakris G, Greene T.
et al. Effect of blood pressure lowering and antihypertensive drug class on
progression of hypertensive kidney disease: results from the AASK trial.
JAMA. 2002;288:2421-243112435255
Google ScholarCrossref 36.Chobanian AV, Bakris GL, Black HR.
et al. Seventh report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure.
Hypertension. 2003;42:1206-125214656957
Google ScholarCrossref 37.National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation,
classification, and stratification.
Am J Kidney Dis. 2002;39:(2 suppl 1)
S1-S26611904577
Google ScholarCrossref 38.Rahman M, Cutler JA, Davis BR, Pressel S, Whelton PK.ALLHAT Collaborative Research Group. Renal outcomes in hypertensive patients with impaired renal function.
Arch Intern MedIn pressGoogle Scholar 39.Williams GH. Converting-enzyme inhibitors in the treatment of hypertension.
N Engl J Med. 1988;319:1517-15253054561
Google ScholarCrossref 40.Cushman WC, Reda DJ, Perry HM, Williams D, Abdellatif M, Materson BJ.Department of Veterans Affairs Cooperative Study Group on Antihypertensive
Agents. 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;160:825-83110737282
Google ScholarCrossref 41.Messerli FH, Oparil S, Feng Z. Comparison of efficacy and side effects of combination therapy of angiotensin-converting
enzyme inhibitor (benazepril) with calcium antagonist (either nifedipine or
amlodipine) versus high-dose calcium antagonist monotherapy for systemic hypertension.
Am J Cardiol. 2000;86:1182-118711090788
Google ScholarCrossref 42.Roca-Cusachs A, Torres F, Horas M.
et al. Nitrendipine and enalapril combination therapy in mild to moderate
hypertension: assessment of dose-response relationship by a clinical trial
of factorial design.
J Cardiovasc Pharmacol. 2001;38:840-84911707687
Google ScholarCrossref 43.Materson BJ, Reda DJ, Williams D.Department of Veterans Affairs Cooperative Study Group on Antihypertensive
Agents. Lessons from combination therapy in Veterans Affairs Studies.
Am J Hypertens. 1996;9:(12 pt 2)
187S-191S8968432
Google ScholarCrossref 44.MacGregor GA, Markandu ND, Smith SJ, Sagnella GA. Captopril: contrasting effects of adding hydrochlorothiazide, propranolol,
or nifedipine.
J Cardiovasc Pharmacol. 1985;7:(suppl 1)
S82-S872580182
Google ScholarCrossref 45.Bolzano K, Arriaga J, Bernal R.
et al. The antihypertensive effect of lisinopril compared to atenolol in patients
with mild to moderate hypertension.
J Cardiovasc Pharmacol. 1987;9:(suppl 3)
S43-S472442551
Google ScholarCrossref 46.Julius S, Kjeldsen SE, Weber M.
et al. Outcomes in hypertensive patients at high cardiovascular risk treated
with regimens based on valsartan or amlodipine: the VALUE randomised trial.
Lancet. 2004;363:2022-203115207952
Google ScholarCrossref 47.Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme
inhibitor-associated angioedema.
Clin Pharmacol Ther. 1996;60:8-138689816
Google ScholarCrossref 48.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;344:1351-135711333991
Google ScholarCrossref 49.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;40:311-31712106937
Google ScholarCrossref 50.Douglas JG, Bakris GL, Epstein M.
et al. Management of high blood pressure in African Americans: consensus statement
of the Hypertension in African Americans Working Group of the International
Society on Hypertension in Blacks.
Arch Intern Med. 2003;163:525-54112622600
Google ScholarCrossref 51.Williams B, Poulter NR, Brown MJ.
et al. British Hypertension Society guidelines for hypertension management
2004 (BHS-IV): summary.
BMJ. 2004;328:634-64015016698
Google ScholarCrossref 52.Khan NA, McAlister FA, Campbell NR.
et al. The 2004 Canadian recommendations for the management of hypertension:
part II—therapy.
Can J Cardiol. 2004;20:41-5414968142
Google Scholar