Are there meaningful differences in blood pressure control with current antihypertensive agents?
© 2002 by the American Journal of Hypertension
Are There Meaningful Differences in Blood Pressure Control With Current Antihypertensive Agents?
Suzanne Oparil 0 1
0 Professor of Medicine, Physiology , and Biophysics, Director , Vascular Biology and Hypertensive Program, Division of Cardiovascular Disease, University of Alabama at Birmingham , 1034 Zeigler Research Building, 933 South 19th Street, Birmingham, Alabama 35294 , USA
1 From the Division of Cardiovascular Disease, University of Alabama at Birmingham , Birmingham, Alabama , USA
Hypertension is a major risk factor for cardiovascular disease, and small reductions in blood pressure can have a substantial impact on outcome. Effective control of hypertension per se is important in reducing morbidity and mortality, but there is growing evidence that the class of drug used in treatment may affect patient outcomes. The Heart Outcomes Prevention Evaluation (HOPE) trial provided evidence that angiotensin converting enzyme inhibitors (ACEI), agents that inhibit the renin-angiotensin system (RAS), are particularly effective in reducing the risk of cardiovascular events in a wide range of patients. These beneficial effects of ACEI may be independent of antihypertensive effect. Angiotensin receptor blockers (ARB) are the newest class of antihypertensive drug to enter clinical
Hypertension; angiotensin-converting enzyme inhibitors; angiotensin II receptor blockers
H able risk factors for cardiovascular disease.1,2
ypertension is one of the most prevalent
modifiThe risks of stroke, myocardial infarction,
cardiac failure, coronary heart disease, peripheral artery
disease, cardiovascular mortality, and all-cause mortality are
all substantially elevated in individuals with
hypertension.1–5 Compared with normotensive individuals, men
with hypertension have risk ratios for cardiac failure and
stroke of 4.0 and 3.8, respectively (Fig. 1). The increase in
risk is of similar magnitude in women.3 Hypertension also
doubles the risk of coronary disease (risk ratios are 2.0 and
2.2 in men and women, respectively), and this remains the
most common and lethal consequence of hypertension.3
The relationship between blood pressure (BP) and
cardiovascular disease is positive and continuous2 and has
been established independently for systolic blood
pressure (SBP), diastolic blood pressure (DBP), and pulse
pressure.1,4,6 –11 For example, in the Multiple Risk Factor
Intervention Trial (MRFIT), baseline BP measurements
were obtained from approximately 348,000 middle-aged
men.11 Data collected during 11.6 years of follow-up
showed that both SBP and DBP were related to the
incidence of death from coronary heart disease.11 For both
use. By blocking the angiotensin II type 1 receptor, ARB
achieve more complete blockade of the RAS than ACEI.
The ARB also have a substantially better side effect profile
than ACEI, and early evidence suggests that ARB are
beneficial in combating hypertension-related target organ
damage. These favorable characteristics suggest that ARB
should be considered as first-line treatment for
hypertension. Based on comparative antihypertensive efficacy,
olmesartan, a new ARB, may represent a significant
addition to this drug class. Am J Hypertens 2002;15:
14S–21S © 2002 American Journal of Hypertension, Ltd.
indices, the relationship was statistically significant and
was continuous, graded, strong, and independent of other
major risk factors.11
Control of Hypertension
Reduces Morbidity and Mortality
Reduction of elevated BP is highly effective for reducing
the risk of cardiovascular morbidity and mortality.12–15 In
the Hypertension Optimal Treatment (HOT) trial, patients
with an initial DBP between 100 and 115 mm Hg were
randomized to one of three DBP target groups (90, 85, and
80 mm Hg).16 Achieved differences in mean DBP and SBP
between the highest and lowest target groups were 4.1 and
4.0 mm Hg, respectively. These relatively small
differences were associated with a 28% reduction in the risk of
myocardial infarction.16 Similarly strong data have come
from observational studies. In a combined analysis of nine
such studies involving 420,000 individuals, MacMahon
et al concluded that a prolonged difference in DBP of
5 mm Hg was associated with a 34% difference in the risk
of stroke and a 21% difference in the risk of coronary heart
disease.10 These studies thus show that relatively minor
decreases in DBP are associated with substantial
reductions in morbidity.
Among elderly hypertensive patients, many of whom
have isolated systolic hypertension, randomized controlled
trials have shown that antihypertensive treatment is
associated with reductions of 17% to 40% in the overall risk
of cardiovascular disease.12–15 Table 1 shows the
reductions in risk of specific cardiovascular end points achieved
in the Systolic Hypertension in the Elderly Program
(SHEP), the Swedish Trial in Old Patients with
Hypertension (STOP-Hypertension), the Medical Research Council
(MRC) trial of treatment of hypertension in older adults,
and the Systolic Hypertension in Europe (Syst-Eur)
trial.12–15 MacMahon and Rodgers combined the results
of three of these trials (SHEP, STOP-Hypertension, and
MRC) with those from the European Working Party on
High Blood Pressure in the Elderly (EWPHE) trial and
those published by Coope and Warrender.17–19 In this
population of 12,483 elderly patients, a difference in SBP
of 12 to 14 mm Hg was associated with a 34% reduction
in the risk of stroke, a 19% reduction in the risk of
coronary heart disease, and a 23% reduction in the risk of
vascular death.19 Thus, as with diastolic pressure,
relatively modest reductions in systolic pressure are associated
with substantial reductions in risk.
Control of hypertension is particularly beneficial
among populations at very high risk for cardiovascular
events, such as individuals with diabetes or nephropathy.
In the HOT study, diabetic patients assigned to the
90 mm Hg DBP target group were twice as likely to
experience a major cardiovascular event and three times as
likely to die of cardiovascular disease than were those
assigned to the 80 mm Hg group.16 In the United Kingdom
Prospective Diabetes Study (UKPDS), patients with type
2 diabetes were assigned to one of two BP target groups;
the “tight control” group achieved a mean pressure of
144/82 mm Hg, and the “less tight control” group a mean
of 154/87 mm Hg.20 Tight control was associated with a
56% reduction in the risk of cardiac failure, a 44%
reduction in the risk of stroke, and a 32% reduction in the risk
of diabetes-related death.20 Interestingly, in this diabetic
population, tight control of BP appeared to be more
effective in reducing the risk of cardiovascular disease than
tight control of blood glucose.20 –22
Patients with renal disease also benefit from effective
control of BP. In a summary of data from nine trials
involving patients with nephropathy, Bakris et al found a
significant negative relationship between mean arterial
pressure and glomerular filtration rate.21 Studying patients
with chronic renal disease, Lazarus et al found that each 1
mm Hg increase in SBP was associated with a 1.35 times
greater risk of hospitalization for cardiovascular or
cerebrovascular disease.9 These data show that effective
control of BP is extremely beneficial in a wide range of patient
Current Status of
There have been substantial improvements in the levels of
awareness, treatment, and control of hypertension in the
Reduction of cardiovascular risk associated with antihypertensive therapy in elderly hypertensive
Between-Group Difference in Mean SBP (mm Hg)*
Data not published
United States over the past four decades, but the situation
is still far from optimal. Data from phase 2 of the National
Health and Nutrition Examination Survey (NHANES) III
show that 32% of hypertensive adults remain unaware of
their condition. A further 41% are aware that they are
hypertensive but are either untreated or receive treatment
that is not optimal. As a result, effective control of BP is
achieved in only 27% of hypertensive individuals.23 Poor
management is one factor that contributes to this statistic.
Berlowitz et al studied the care of 800 hypertensive men at
five Department of Veteran Affairs outpatient clinics over
a 2-year period. On average, patients made more than six
hypertension-related visits per year; in spite of this, 40%
of patients had a BP 160/90 mm Hg at the end of the
study.24 On 75% of occasions on which a BP 155/90
mm Hg was recorded, no increase in medication was
prescribed, nor was there an association between elevated
BP at a previous visit and a subsequent decision to change
the treatment regimen.24 These data show that lack of
aggressive treatment may be partly responsible for low
Unpleasant side effects of drugs are known to reduce
patient compliance and may also contribute to poor control
of BP.25 Agents that act on the renin-angiotensin system
have fewer adverse effects than diuretics, -blockers, or
calcium antagonists26 and may be preferred for this
reason. Angiotensin converting enzyme inhibitor (ACEI)
induced cough remains a problem, however. This adverse
effect may occur in up to 22% of patients27 and commonly
causes 3% to 4% of patients in clinical trials to discontinue
treatment.28 –30 In contrast to ACEI, angiotensin receptor
blockers (ARB) have a side effect profile similar to that of
placebo, and are not associated with an increased
incidence of cough.31
Inconvenient or complex dosing regimens may also
contribute to low control rates. Medications that are taken
once daily are associated with better compliance than
those taken twice daily, and are preferred for this reason.23
Leenen et al showed that the percentage of prescribed
doses taken on schedule was significantly higher with
once-daily dosing (amlodipine; 86%) than with
twicedaily dosing (diltiazem; 76%). In addition, once-daily
amlodipine remained effective in the face of poor compliance
(defined as patients who took 80% of their pills),
whereas twice-daily diltiazem showed reduced efficacy.32
Optimal control of BP is thus most likely to be achieved if
patients are prescribed a highly effective drug or drug
combination that requires once-daily administration and is
free of adverse effects.
How Do Medications Compare in Lowering Blood Pressure and Improving Outcome?
The BP-lowering efficacy of the older antihypertensive
drug classes appears to be comparable. The Treatment of
Mild Hypertension Research Group compared the efficacy
of acebutolol, amlodipine, chlorthalidone, doxazosin, and
enalapril in patients with mild hypertension (baseline
DBP, 90 to 99 mm Hg).33 Representative members of five
major drug classes were thus compared. With the
exception of a small difference in the ability of chlorthalidone
and doxazosin to reduce SBP ( 21.8 v 16.1 mm Hg,
respectively), there were no significant differences in
efficacy among these agents. If risk reduction depends solely
on the degree of BP control achieved, the results of the
Treatment of Mild Hypertension Study would suggest that
the class of antihypertensive drug used in treatment is
unimportant. There is mounting evidence, however, that
this assumption is wrong.34 Angiotensin converting
enzyme inhibitors, in particular, appear to be beneficial in
improving outcomes,34 and this is especially evident
among patients at very high risk for cardiovascular events.
In the Cooperative North Scandinavian Enalapril Survival
Study (CONSENSUS), the Survival and Ventricular
Enlargement Trial (SAVE), and the Studies of Left
Ventricular Dysfunction (SOLVD), ACEI led to substantial
reductions in cardiovascular morbidity and mortality.35–37
Patients enrolled in these trials had reduced left ventricular
ejection fractions or congestive heart failure at baseline,
and 19% to 44% were hypertensive.35–37 In the SAVE
trial, the beneficial effects of captopril were shown to be
independent of baseline BP.36
More recently, the results of the Heart Outcomes
Prevention Evaluation (HOPE) study demonstrated that the
beneficial effects of ACEI extend to a wider range of
patients. In this trial, patients with vascular disease or
diabetes plus one other cardiovascular risk factor
(hypertension, elevated total cholesterol, low levels of
highdensity cholesterol, cigarette smoking, or
microalbuminuria) were randomized to treatment with the ACEI,
ramipril, or placebo for 5 years.38 Patients with evidence
of left ventricular systolic dysfunction or cardiac failure
were excluded from the trial. Approximately 47% of
patients were hypertensive at baseline. Compared with
placebo, ramipril reduced the risks of myocardial infarction,
stroke, and cardiovascular mortality by 20%, 32%, and
26%, respectively,38 and these beneficial effects of
ramipril were independent of hypertensive status at
baseline. Over the course of the trial, mean BP changed from
139/79 mm Hg in both groups to 136/76 mm Hg in the
ramipril group and 139/77 mm Hg in the placebo group.
Although monitoring of BP was not as rigorous in the
HOPE study as in a trial primarily designed to evaluate
antihypertensive efficacy, the HOPE study investigators
concluded that only a small fraction of the beneficial
effects of ramipril could be attributed to the reduction in
BP. The investigators concluded that inhibition of the
renin-angiotensin system is of specific benefit in
preventing cardiovascular events.
Benefits of Specific Inhibition of the Renin-Angiotensin System
The clinical benefits of ACEI are well established.
However, these agents do not completely block the
reninangiotensin system. Angiotensin converting enzyme
cleaves bradykinin in addition to angiotensin I, and
nonACE pathways of angiotensin II generation exist and may
be clinically important. The use of ACEI thus results in
incomplete blockade of angiotensin II generation and
build-up of bradykinin.31 This latter effect may be
responsible for the most frequent side effects of ACEI, cough39
and may contribute to a more serious but rare side effect,
angioedema.40 Early attempts to block the
renin-angiotensin system concentrated on the development of peptide
angiotensin II receptor antagonists such as saralasin, and
this avenue has been re-explored more recently with the
development of the nonpeptide ARB. In contrast to ACEI,
ARB offer almost complete inhibition of angiotensin II
action via antagonism of its type 1 (AT1) receptor without
The antihypertensive efficacy of ARB has been
compared extensively with that of ACEI. Parallel-group
studies carried out using captopril, enalapril, or lisinopril and
all six of the older ARB (candesartan, eprosartan,
irbesartan, losartan, telmisartan, and valsartan) demonstrated
antihypertensive efficacy of the ARB that was similar or
slightly superior to that of the ACEI. The ARB were
markedly superior to the ACEI in terms of side
effects.41– 46 The ARB also compare favorably with calcium
channel blockers, particularly with respect to side-effect
Influence of ARB on
Morbidity and Mortality
Few published studies are powered and designed to
determine the effects of ARB treatment, without simultaneous
ACEI administration, on morbidity and mortality. One
such study is the Evaluation of Losartan in the Elderly
Study (ELITE), in which elderly patients with New York
Heart Association class II to IV heart failure were
randomized to treatment with losartan or captopril. The use of
other classes of cardiovascular drug was permitted. After
48 weeks there was no difference between treatment
groups in terms of improvement in serum creatinine (the
primary end point), but treatment with losartan was
associated with a 46% reduction in the risk of all-cause
mortality compared to captopril. Losartan was also better
tolerated than captopril, and was associated with
significantly fewer discontinuations.30 In a follow-up study
(ELITE II), the difference in tolerability between these two
drugs was confirmed, but the survival benefit associated
with losartan treatment was not.29 Overall, losartan was as
effective as captopril, which had been shown in previous
studies to have survival benefit in heart failure. Recent
preliminary data from the Valsartan Heart Failure Trial
(Val-HeFT) suggest that combining an ARB with an ACEI
in heart failure patients significantly reduces the combined
end point of all-cause mortality and morbidity, but has no
effect on all-cause mortality alone.52
In addition to these mortality data, there is widespread
evidence that ARB are effective in ameliorating much of
the target organ damage commonly associated with
hypertension. In hypertensive type 2 diabetic patients with
nephropathy, losartan was as effective as enalapril in
reducing urinary albumin excretion.53 In nondiabetic patients
with nephropathy and hypertension, losartan and
amlodipine effected almost identical reductions in BP, but only
losartan reduced proteinuria.54 The beneficial effects of
ARB on renal function may thus be independent of their
There is also evidence that ARB are effective in
controlling atherosclerosis. Irbesartan reduced serum levels of
tumor necrosis factor- receptor II, vascular cell adhesion
molecule–1, and superoxide in patients with premature
atherosclerosis and thus appears to retard the inflammatory
component of this condition.55 Losartan also attenuated
the increased expression of the endothelial receptor for
oxidized low-density lipoprotein (LOX-1) that occurs in
hypercholesterolemic rabbits.56 In a guinea pig model of
hypercholesterolemia, losartan was superior to enalapril in
reducing oxidant stress, normalizing cardiac eicosanoid
release, and improving myocardial dysfunction.57
Recent evidence has shown that ARB are capable of
normalizing the vascular remodeling and endothelial
dysfunction characteristic of hypertension and that this effect
is independent of their antihypertensive activity. Schiffrin
et al randomized patients with essential hypertension to 1
year of treatment with losartan or the -blocker, atenolol.
The two treatments resulted in almost identical reductions
in BP, but only losartan normalized
endothelium-dependent relaxation of resistance arteries. Treatment with
losartan also reduced the media:lumen ratio of these arteries
(a measure of pathological vascular remodeling), whereas
atenolol had no significant effect.58
Data from animal models suggest that olmesartan, the
newest ARB, are both renoprotective and
antiatherosclerotic. Olmesartan was administered at two doses to Zucker
diabetic rats.59 These animals develop progressive
hyperglycemia, hyperinsulinemia, hyperlipidemia,
glomerulosclerosis, and proteinuria,60,61 and are widely used as a
model of type 2 diabetes. Treatment with olmesartan
resulted in a rapid onset, dose-dependent reduction in
proteinuria that was maintained over the 19 weeks of the
experiment. This beneficial effect was independent of
changes in BP and blood glucose level.59 In the Watanabe
heritable hyperlipidemic rabbit model of atherosclerosis,
32 weeks of treatment with olmesartan (1 mg/kg) reduced
atherosclerotic lesion area by 40% compared with
vehicletreated controls. There was a minimal effect of treatment
on BP, and no effect on plasma cholesterol level. In
contrast, pravastatin (50 mg/kg) reduced plasma
cholesterol but had no effect on lesion area (Fig. 2).59 Olmesartan
with vascular remodeling, endothelial dysfunction,
atheroparator drugs in reducing SBP in the last 4 h of the
ment, the reduction in trough sitting cuff DBP (the primary
efficacy variable) was significantly greater in the
olmesartan group (11.5 mm Hg) than in the groups treated with
losartan (8.2 mm Hg), valsartan (7.9 mm Hg), or
irbesartan (9.9 mm Hg; Fig. 3). Substantial reductions in SBP
were also achieved (olmesartan, 11.3 mm Hg; losartan, 9.5
mm Hg; valsartan, 8.4 mm Hg; irbesartan, 11.0 mm Hg),
although the differences among groups were not
significant. Olmesartan was significantly more effective than
losartan and valsartan in reducing 24-h mean DBP and
SBP (Fig. 4), and was more effective than all three
cominterdosing period. The results of ambulatory BP
monitoring carried out in this study thus reinforced the data
obtained using cuff measurements. There were no
significant differences among treatment groups in the overall
incidence of clinical or laboratory adverse events. The
efficacy data from this study thus show that olmesartan
may have some advantages over older ARB in the
treatment of essential hypertension.
also reduced aortic plaque formation (64% reduction)
when administered to cynomolgus monkeys fed an
These data demonstrate that the beneficial effects of
ARB extend beyond treatment of hypertension. Patients
sclerosis, diabetes, cardiac failure, cardiac hypertrophy,
and nephropathy may all benefit from the unique
mechanism of action of this class of drugs. The excellent side
effect profile of ARB31 allows these benefits to be
achieved while maximizing patients’ quality of life.
Is There a Difference in the
Antihypertensive Efficacy of
Angiotensin Receptor Blockers?
Few studies allow direct comparison of more than two
ARB. Exceptions to this are a meta-analysis of
randomized controlled trials62 and a crossover study,63 both of
which compared the efficacy of losartan, valsartan,
irbesartan, and candesartan at low doses (50, 80, 150, and 8
mg, respectively) and after titration to double these doses.
The meta-analysis revealed no differences among these
drugs in their ability to reduce BP, either at the starting
dose or after forced or elective titration.62 In the crossover
study, valsartan and irbesartan reduced BP more
effectively than losartan when the drugs were used at their
starting doses, but the difference was not maintained after
elective dose titration.63
In a recent randomized, double-blind, parallel-group
study, the efficacy of the newest ARB (olmesartan, 20 mg)
was compared with that of losartan (50 mg), valsartan (80
mg), and irbesartan (150 mg) in patients with
mild-tomoderate essential hypertension.64 After 8 weeks of
treatFIG. 4. Least squares mean change from baseline in 24-h mean
ambulatory DBP and systolic blood pressure (SBP) after 8 weeks of
treatment with olmesartan (20 mg once daily), losartan (50 mg),
valsartan (80 mg), and irbesartan (150 mg) in patients with
essential hypertension. * P .05 compared with olmesartan. BP blood
pressure; other abbreviation as in Fig. 3.
Summary and Conclusions
Hypertension is widely recognized as a major risk factor
for cardiovascular events, and even small reductions in BP
have a substantial impact on patient outcome. Apparently
minor differences in the antihypertensive efficacy of drugs
may therefore have a significant effect on morbidity. It is
also becoming evident that the mechanism by which
elevated BP is controlled may have an effect on patient
outcome. In particular, ACEI appear to reduce the risk of
cardiovascular events, and this effect may be independent
of the antihypertensive actions of these drugs. The benefits
of ACEI are tempered by their side effects, however,
which may reduce patient compliance. The recent
introduction of ARB allows physicians to inhibit the
reninangiotensin system using a class of drugs with a
placebolike side effect profile. The antihypertensive efficacy of
ARB is similar to that of ACEI, and early evidence
suggests that ARB are effective in controlling
hypertensionassociated target organ disease. The newest ARB,
olmesartan, is not only a more effective antihypertensive agent
than some of the early drugs of this class but has also been
shown to protect against target organ disease. In the
absence of large-scale outcomes trials comparing different
ARB, differentiation among these agents should be made
on the basis of their antihypertensive efficacy.
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