Background
With the publication of the Antihypertensive and
Lipid-Lowering Treatment to prevent Heart Attack Trial
(ALLHAT), the role of peripheral alpha-1 antagonists in the
treatment of hypertension has become controversial. The
doxazosin arm of ALLHAT was stopped early, due to a
doubling of the incidence of congestive heart failure in
this group, as compared to the low-dose chlorthalidone arm
[ 1 ] . Prior to this publication, there had been no
obvious suggestion of a mechanism by which peripheral
alpha-1 antagonists in general or doxazosin in particular
would be inferior to chlorthalidone or would specifically
cause CHF. Because ALLHAT is an active-control trial, no
inferences can be made on whether this increased incidence
of CHF results from a harmful effect of doxazosin, a
beneficial effect of chlorthalidone, or both. Nonetheless,
there has been a large body of literature dedicated to the
positive effects of peripheral alpha-1 antagonists on
surrogate endpoints such as cholesterol levels and
tolerability. In light of the results of ALLHAT, we
performed a review of the literature on doxazosin,
terazosin, and prazosin.
Methods
Medline and the Cochrane databases were used to identify
English-language papers on peripheral alpha-1 antagonists
in studies targeting cardiovascular endpoints, background
physiologic literature, or any studies suggesting
mechanisms leading to an inferior performance in
cardiovascular endpoints. Medline was searched from 1966 to
the present with the key words "doxazosin," "prazosin,"
"terazosin," "adrenergic alpha-antagonists," or "alpha
blocker." The search was then limited to clinical trials
that had "hypertension" as a key word. Studies were
included in our review if they addressed either one or a
combination of the three agents as the main focus in the
context of hypertension therapy and if they in some way
addressed the outcomes of interest noted above. Relevant
data from these studies are reported descriptively. Other
relevant references were acquired from bibliographic
searches.
Results
Use in Hypertension and Prostatism
Evidence suggests that alpha-1 antagonists are
frequently prescribed for hypertension, but there are few
published data concerning the prevalence of the routine
use of peripheral alpha-1 antagonists, the prevalence
according to co-morbid conditions such as benign
prostatic hypertrophy and the usual duration of therapy.
In the sixth report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC VI), peripheral alpha-1 antagonists
are recommended not only as second-line anti-hypertensive
therapy after low-dose diuretics and beta blockers, but
also for specific indications such as therapy in men with
hypertension and prostatism [ 2 ] . Alpha-1 antagonists
represent effective therapy for prostatism, and fifty
percent of men have histologic evidence of BPH by 60
years of age [ 3 4 ] . The National Ambulatory Medical
Care Survey reported that the number of people on any
type of peripheral alpha-1 antagonist in 1995 was
approximately 6 to 7% of those with hypertension [ 5 ] .
About 80% of surveyed physicians would choose these drugs
as a first-line blood pressure agent for patients with
hypertension and symptoms of BPH [ 6 ] .
Weight and Fluid Status
Peripheral alpha-1 antagonists were consistently
associated with fluid retention. A 1984 study of prazosin
reported by Bauer revealed increases in plasma volume,
interstitial fluid volume, and extracellular fluid volume
following both short-term and long-term therapy [ 7 ] .
In this study of 14 hypertensive men, there was a
significant 1.4 L average increase in ECFV, with a 200 mL
average increase in plasma volume (measured with
radioisotopic assays) that occurred within 3-6 weeks of
initiation, lasted during 5 to 6 months of chronic
therapy, and was still present during a two-week washout
period. There was no weight change in that study, but two
other studies demonstrated both an increase in weight as
well as laboratory changes consistent with volume
expansion for prazosin [ 8 9 ] . Bauer and his colleagues
suggested that a net increase in total body sodium from
an acute renal effect of prazosin was offset by a
decrease in actual body weight. They also demonstrated
that the fractional excretion of sodium was unchanged
during treatment, and further suggested that the acute
changes were followed by chronic sodium homeostasis and
maintenance of the increased total body sodium.
The VA Cooperative Study on Antihypertensive agents
was a double-blind, randomized controlled trial comparing
atenolol, captopril, clonidine, diltiazem,
hydrochlorothiazide, prazosin, and placebo for
differences in antihypertensive efficacy in 1,105 men who
had mild diastolic hypertension [ 10 ] . A highly
significant weight gain of 1 kilogram was observed at 8
weeks with prazosin compared to baseline (p < .001),
and this gain was also statistically significant when
compared to the 8-week weight changes in all other groups
that had experienced either weight loss or no mean weight
change (p < 0.05). The prazosin arm had the highest
rate of adverse effects, leading to discontinuation of
treatment. The termination rate of 13.8% was higher than
the termination rate from adverse effects for clonidine
(10.1%), and significantly higher than the rates for
captopril (4.8%), atenolol (2.2%), or hydrochlorothiazide
(1.1%) [ 11 ] . The number of men treated with prazosin
decreased from 62 at the beginning of the trial to 28 by
the end. The average weight gain of 0.5 kilograms from
baseline was no longer statistically significant at one
year of therapy when compared to the original baseline
weight or the other therapies.
Safety and tolerability trials with terazosin have
shown similar results (Table 1). Patients treated with
terazosin tended to gain about 1 kilogram from baseline
on active therapy during these trials, and those on
placebo therapy lost weight. Two of the randomized trials
included a phase for withdrawal from active therapy, with
weight information reported by Ruoff [ 12 ] . Withdrawal
from active therapy was associated with a loss of 1.3
kilograms.
Doxazosin has also been associated with volume
expansion. A physiology study reported by Lund-Johansen
demonstrated a plasma volume fluid expansion of about 10%
when compared to baseline values [ 13 ] . Larger
randomized controlled trials have also consistently
demonstrated that patients treated with doxazosin gain
weight, as summarized in Table 2. While patients treated
with doxazosin tend to gain weight, patients on placebo
therapy lost weight. The Treatment of Mild Hypertension
Study (TOMHS) trial is a notable exception for the trend
towards weight gain [ 14 ] . All five treatment groups
and the placebo group received intensive dietary
counseling aimed at weight loss, and all groups lost
weight without significant differences between trial
arms.
Neurohormonal and Cellular Effects
Physiologic studies with small numbers of participants
are by nature underpowered to detect meaningful
population differences, but may provide a starting point
when such data are not available. Peripheral alpha-1
antagonists were associated with perturbations in
neurohormonal levels in various studies. In particular,
peripheral alpha-1 antagonists are associated with an
increase in plasma norepinephrine in diverse patient
populations, as summarized in Table 3. This table
reflects increases in norepinephrine in normotensive
patients, hypertensive patients, and patients with
chronic congestive heart failure from a variety of these
small studies.
Several lines of evidence suggest that elevated
catecholamine levels are cardiotoxic [ 15 ] . Elevated
plasma norepinephrine levels are hypothesized to cause
direct myocardial damage through many mechanisms, which
may be amplified by concomitant alpha-1 blockade. In
rats, norepinephrine stimulates apoptosis, which is
mediated through beta receptors [ 16 ] . In addition,
alpha-1 cardiac receptors inhibit this response in rat
myocytes [ 17 ] . The increased concentration of
norepinephrine leading to cardiac beta receptor
stimulation combined with alpha-1 receptor inhibition may
lead to increased apoptosis in myocytes.
Other hormones that are associated with cardiovascular
disease are affected by peripheral alpha-1 antagonists.
Endothelin-1 is a vascular hormone, which may play a role
in the generation and maintenance of heart failure [ 18 ]
. In hypertensive patients, doxazosin lowers von
Willebrand factor commensurate with blood pressure, but
it does not lower high levels of endothelin-1 while
atenolol does [ 19 ] .
Other mechanisms for cellular injury have been
suggested. Hooper proposed that peripheral alpha-1
antagonists alter cellular repair mechanisms, possibly
causing cardiac damage. He noted that prazosin blocks
heat shock protein expression in myocardium, and it has
been hypothesized that this may leave myocardium more
vulnerable to injury [ 20 ] .
Epidemiological and Clinical Trial Data
Between 1966 and 2001, there were 188 published
cardiovascular randomized controlled trials related to
the treatment of hypertension with the use of peripheral
alpha-1 antagonists. Among these, only ALLHAT
specifically assessed differences in cardiovascular
endpoints resulting from control of hypertension with a
peripheral alpha-1 antagonist. Most of these trials
focused on surrogate endpoints such as equivalence of
blood-pressure reduction and effects on cholesterol.
Other studies focused on tolerability and pharmacology.
There are no case control, cohort, or other studies that
analyzed the impact of these agents on cardiovascular
endpoints. Using data from other trials may offer a
partial framework for the interpretation of newer
findings.
ALLHAT demonstrated a highly statistically
significant, near doubling in the incidence of heart
failure in the doxazosin arm compared to heart failure
occurrences in the chlorthalidone arm. Although there was
no difference in the primary outcome of CHD or the
secondary outcome of total mortality, there were small
but statistically significant increases in the secondary
outcomes of angina (RR 1.16, 95% CI 1.05-1.27) and stroke
(RR 1.19, 95% CI 1.01-1.40). Since ALLHAT is a
comparative trial, we know that doxazosin is associated
with more adverse cardiovascular outcomes than low-dose
chlorthalidone, but we do not know how doxazosin might
compare with placebo. The SHEP trial, however, does
provide a comparison between chlorthalidone and placebo
therapy for a reference point of heart failure, although
the study populations have different demographic and
blood pressure distributions [ 21 ] . The SHEP trial
included 4,736 people aged 60 and older who had a
systolic blood pressure of 160 to 219 mmHg and a
diastolic blood pressure of less than 90 mmHg. Subjects
were randomized to low-dose diuretics or placebo, and
were followed for an average of 4.5 years for major CV
events. Comparisons between those randomized to active
therapy and those on placebo demonstrated nearly a 50%
reduction in fatal and nonfatal heart failure events (RR
0.51, 95% CI 0.37-0.71). The rates of CHF in SHEP
participants treated with diuretics and placebo were 5
and 10 per 1,000 person-years, respectively. In
comparison, the rates of CHF in ALLHAT participants
treated with diuretics and doxazosin were 10 and 20 per
1,000 person-years, respectively. If low-dose
chlorthalidone has a similar risk reduction in the ALLHAT
population, and halves the incidence of clinical heart
failure events compared to no therapy, the effect of
doxazosin would be comparable to that of the placebo arm
in the SHEP trial.
Conclusions
The report of the doxazosin arm termination in ALLHAT
was published in April, 2000. At that time, the results of
the ALLHAT trial were unexpected, given the potential
association between high dose diuretics and the risk of
sudden death [ 22 ] , and the favorable effect of
peripheral alpha-1 antagonists on lipid profiles [ 14 ] .
Comparing data from other studies suggests the possibility
that the beneficial effects of peripheral alpha-1
antagonists for lowering blood pressure may be nullified by
a negative effect, or that other antihypertensives have
positive actions beyond their antihypertensive effects.
Those treated with doxazosin in ALLHAT had a mean blood
pressure that was 2 to 3 mmHg higher than the mean blood
pressure of those treated with chlorthalidone. Based on
Framingham Heart Study logistic regression coefficients,
this 2 to 3 mmHg difference in systolic blood pressure is
associated with an increased relative risk of only 1.06 to
1.09 [ 23 ] . From available data, it appears that this
average difference in systolic blood pressure is not large
enough to double the average incidence of CHF.
The literature suggests several mechanisms by which
peripheral alpha-1 antagonists in general and doxazosin in
particular might prove inferior to other types of
antihypertensive therapy. They are associated with a mild
volume expansion, which may precipitate the clinical
presentation of heart failure in those with subclinical
disease. If this is the mechanism responsible for
increasing the incidence of CHF in the ALLHAT trial, it
would be consistent with the early divergence of the
Kaplan-Meier curves in that study.
Peripheral alpha-1 antagonists also cause neurohormonal
changes during chronic therapy. The long-term ramifications
of these changes for patients being treated for
hypertension are not known. These drugs appear to cause
increases in norepinephrine, and this increase may nullify
the beneficial effect of lowered blood pressure on the
occurrence of CHF. Not only are increased plasma
catecholamines a central feature in heart failure, they are
now a recommended target for effective life-prolonging
therapy [ 24 25 26 ] .
Given that doxazosin is not as effective as
chlorthalidone in reducing the cardiovascular complications
of hypertension, several questions remain. There is still a
paucity of information regarding the absolute risk
reduction for clinical heart failure or other
cardiovascular events afforded by peripheral alpha-1
antagonists in a variety of populations. Differentiation of
the mechanism for reduced protection compared to diuretics
would be interesting but difficult to accomplish. For heart
failure in particular, the increase in symptomatic episodes
of CHF may be due to hemodynamic effects of doxazosin
unmasking incipient heart failure, direct myocardial
injury, or both. Chronic volume loading may not only unmask
subclinical ventricular dysfunction, but may possibly
contribute to worsening ventricular function over time.
Whatever mechanisms were responsible for the heart
failure findings in ALLHAT, the results support the current
national recommendations to use low-dose diuretics or
beta-blockers as first line agents for the pharmacologic
treatment of uncomplicated hypertension.
Competing Interests
Dr. Psaty was a Merck/SER Clinical Epidemiology Fellow
(co-sponsored by the Merck Co. Foundation, Rahway, NJ, and
the Society for Epidemiologic Research, Baltimore, MD), and
a member of the Events Committee of the HERS trial funded
by Wyeth Ay erst.
