Why Uncomplicated Hypertension -Blockers Should Not Be Used as First Choice in

Why ␤-Blockers Should Not Be Used as First Choice in
Uncomplicated Hypertension
Alberto Ranieri De Caterina, MD*, and Antonio Maria Leone, MD
In the past 4 decades, ␤ blockers (BBs) have been widely used in the treatment of
uncomplicated hypertension and are still recommended as first-line agents in national and
international guidelines. Their putative cardioprotective properties, however, derive from
the extrapolation into primary prevention of data relative to the reduction of mortality
observed in the 1970s in patients with previous myocardial infarctions. In the past 5 years,
a critical reanalysis of older trials, together with several meta-analyses, has shown that in
patients with uncomplicated hypertension BBs exert a relatively weak effect in reducing
stroke compared to placebo or no treatment, do not have any protective effect with regard
to coronary artery disease and, compared to other drugs, such as calcium channel blockers,
renin-angiotensin-aldosterone system inhibitors or thiazide diuretics, show evidence of
worse outcomes, particularly with regard to stroke. Several reasons can explain their
reduced cardioprotection: their suboptimal effect in lowering blood pressure compared to
other drugs; their “pseudoantihypertensive” efficacy (failure to lower central aortic pressure); their undesirable adverse effects, which reduce patients’ compliance; their unfavorable metabolic effects; their lack of an effect on regression of left ventricular
hypertrophy and endothelial dysfunction. In conclusion, the available evidence does
not support the use of BBs as first-line drugs in the treatment of hypertension. Whether
newer BBs, such as nebivolol and carvedilol, which show vasodilatory properties and a
more favorable hemodynamic and metabolic profile, will be more efficacious in reducing morbidity and mortality remains to be determined. © 2010 Elsevier Inc. All rights
reserved. (Am J Cardiol 2010;105:1433–1438)
Beta blockers (BBs) have been considered a cornerstone
in therapy for hypertension in the past 4 decades, especially
for their putative cardioprotective properties. The concept
of cardiovascular (CV) protection mediated by BBs was
born in the 1970s from several prospective randomized
trials in patients with previous myocardial infarctions, in
whom mortality of about 25% was observed.1 This observation was then uncritically translated from secondary to
primary prevention of the broad spectrum of CV diseases,
including uncomplicated hypertension. On the basis of this
extrapolation, and the common idea that reducing blood
pressure (BP) automatically reduces CV morbidity and mortality, even most recent international guidelines2,3 recommend BBs as first-line agents in uncomplicated hypertension. The concept of cardioprotection mediated by BBs
penetrated so deeply into clinical practice that in 2005, the
New York Times reported that BBs, in particular atenolol,
were the fourth most prescribed drug in the United States,
with 44 million prescriptions yearly.4 Nowadays, a large
number of physicians perceive BBs as the most protective
class of drugs for the heart and brain and consider them the
most effective therapy in reducing CV mortality among all
other drugs.5 However, the cardioprotective effect of BBs in
primary prevention is based on assumptions that are still far
Institute of Cardiology, Catholic University of the Sacred Heart, Rome,
Italy. Manuscript received October 25, 2009; revised manuscript received
and accepted December 20, 2009.
*Corresponding author: Tel: 39-06-30154444; fax: 39-06-3055535.
E-mail address: adecatro@yahoo.it (A.R. De Caterina).
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjcard.2009.12.068
from being scientifically proved. The recently updated National Institute for Health and Clinical Excellence guidelines in Great Britain reflected this concern, having changed
the indication for BBs from use as first-line agents for
hypertension treatment to fourth-line add-on therapy in patients requiring multiple drugs.6 In this review, we analyze
the current evidence supporting the use of BBs in hypertension in primary prevention.
Efficacy of ␤ Blockers in Lowering Blood Pressure
BBs are universally considered a cornerstone therapy in
heart failure, chronic stable angina, myocardial infarction,
and some forms of tachyarrhythmias. Their efficacy in these
settings relies mainly on the antagonism of catecholaminemediated cardiotoxic effects and of hyperactivity of the
sympathetic system. These mechanisms, however, play an
important role in a few patients with uncomplicated hypertension and, eventually, more often in young than in elderly
patients. In fact, the efficacy of BBs in lowering BP involves other mechanisms, such as a decrease in cardiac
output, the inhibition of renin release and angiotensin II
production, the blockade of presynaptic ␣-adrenoceptors
that increase the release of norepinephrine from sympathetic
nerve terminals, and a decrease in central vasomotor activity.7,8 In contrast, ␤ blockade is known to determine a
vasoconstrictive effect in arteries and veins through ␤2
receptor antagonism, thus antagonizing the antihypertensive
effect of BBs. Moreover, it should not be forgotten that BBs
are a complex class of drugs involving several compounds
that differ from one another in terms of pharmacologic
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Table 1
Main studies assessing the antihypertensive effect of ␤ blockers (BBs) from 1985 to 2000
Study
Year of
No. of
Follow-Up
Publication Patients in
(years)
BB Group
MRC9
Coope et al10
STOP11
1985
1986
1991
2,285
419
812
4.8
4.4
4
MRCOA12
Dutch TIA Trial13
TEST14
NORDIL15
1992
1993
1994
2000
1,099
732
720
5,471
5.8
2.6
2.6
5
Drug
Comparison Arm Mean Age
Baseline
Final
(years)
Systolic/Diastolic Systolic/Diastolic
BP (mm Hg)
BP (mm Hg)
Propranolol
Atenolol
Atenolol/metoprolol/
pindolol
Atenolol
Atenolol
Atenolol
Mixed BB and diuretic
Benfluorazide
Open control
Placebo
Placebo
Placebo
Placebo
Diltiazem
51
68.8
75.7
158/98
197/99
195/102
137/85
188/87
166/85
70.3
54% ⬎65
70.4
60.5
183/91
158/91
161/89
173/105
169/84
152/88
157/86
149/87
MRCOA ⫽ Medical Research Council Trial in Older Adults; NORDIL ⫽ Nordic Diltiazem Study; TEST ⫽ aTEnolol in the Secondary prevention after
Stroke; TIA ⫽ transient ischemic attack.
characteristics, such as ␤1/␤2-selectivity, intrinsic sympathomimetic activity, and vasodilatory capabilities. Thus, it is
clear that the effect of ␤ blockade in BP control is complex and
not yet completely understood. Irrespectively of their exact
mechanisms of action, it is a fact that a number clinical trials
have proved the efficacy of BBs in lowering BP compared to
no treatment or placebo9 –15 (Table 1). On the basis of these
data, the perception of the efficacy of BBs as hypertensive
agents has become stronger over the decades. Moreover, it
must be acknowledged that they have been used as reference
drugs in several randomized controlled trials of hypertension.
A Change of View After Losartan Intervention for
End Point Reduction in Hypertension (LIFE) and the
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOTBPLA)
The robustness of the evidence for use of BBs as firstline therapy for uncomplicated hypertension was first challenged by the results of 2 of the latest large hypertension
trials: the Losartan Intervention for End Point Reduction in
Hypertension (LIFE) study16 and the Anglo-Scandinavian
Cardiac Outcomes Trial (ASCOT)–Blood Pressure Lowering Arm (BPLA),17 which demonstrated the superiority of a
strategy based on newer antihypertensive drugs, losartan and
amlodipine, respectively, compared to atenolol. After LIFE
and ASCOT-BPLA, all the published research supporting the
use of BBs in primary hypertension was critically reanalyzed.
Carlberg et al18 first systematically collected all published data regarding atenolol, the most frequently prescribed BB worldwide. In 2005, the same group extended
these observations from atenolol to all BBs.19 The results of
these meta-analysis first revealed that despite a BP reduction compared to placebo, BBs did not reduce the risk for
myocardial infarction or CV mortality, although they did
reduce the risk for stroke by about half (19% vs 38%) of that
usually believed from previous hypertension trials and from
the meta-analysis by Collins et al,20 which is frequently
referenced in hypertension guidelines. Moreover, compared
to other drugs, although no difference were observed for
myocardial infarction, BB treatment resulted in a 16%
higher relative risk for stroke.19 Even a recent Cochrane
review,21 the most complete and comprehensive document
analyzing the available research regarding BBs in primary
hypertension, concluded that BBs (1) exert a relatively weak
effect in reducing stroke compared to placebo or no treatment, (2) do not have any protective effect with regard to
coronary artery disease, and (3) compared to other drugs,
such as calcium channel blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and thiazide diuretics,
show evidence of worse outcomes, particularly with regard
to stroke. The final message was categorical: “The available
evidence does not support the use of BB as first-line drugs
in the treatment of hypertension.”21
Because these data were obtained mainly in an elderly
population, one could argue that BB therapy might have a
better prognostic impact in younger patients. However,
Khan and McAlister,22 in their meta-analysis of a cohort of
younger patients (mean age ⬍60 years), found that compared to placebo, BB therapy showed no benefit with regard
to all-cause mortality, myocardial infarction, or stroke. Similarly, compared to other antihypertensive agents, although
there was no increased risk for stroke (as seen with the
elderly cohort), there was also no benefit for the end points
of all-cause mortality, myocardial infarction, and stroke.
A Critical Reanalysis of Older Trials
Given this evidence, one may ask why this suboptimal
effect of BBs has not been appropriately taken into account
in hypertension guidelines over the years and why the efficacy of ␤ blockade on “hard” end points, such as CV
morbidity or mortality, has never been appropriately encountered.
The main reason resides in the fact that BBs have often
been analyzed together with diuretics, assuming that for the
same BP decrease, treatment with the 2 classes of drugs was
associated with similar effects in terms of CV morbidity and
mortality. This extrapolation led to the wrong attribution to
BBs of the beneficial effect effectively conferred by diuretics. Messerli et al,23 for instance, first demonstrated that less
than one-third over more than 2,000 patients were controlled on BB monotherapy, whereas the adjunction of diuretic therapy appropriately controlled BP in two-thirds of
patients. Notwithstanding this evidence, no effort was made
to analyze their efficacy separately. To simplify this concept, the example of gin and tonic has been previously
used,24 whereby, on the basis of a study in which two-thirds
Review/Reasons for Suboptimal Cardioprotective Effect of ␤-blockers
of patients assume gin and tonic and one-third tonic water
alone, one would paradoxically affirm that the tonic water
causes hepatic cirrhosis without separately assessing their
specific effects. Conversely, some evidence exists that adding BBs to diuretics to reach appropriate BP control distinctly reduces the benefits of the antihypertensive therapy.
In fact, in the Medical Research Council (MRC) trial, patients who received the combination of BBs and diuretics
fared consistently worse than those taking diuretics alone,
but they did somewhat better than those receiving BBs
alone.9 Another potential explanation for the reduced efficacy of ␤ blockade is that most older trials used atenolol at
low doses, such as 50 mg, which are perhaps not effective
in allowing 24-hour BP control.11–13,15
Second, economic issues may have played a role. In the
1980s and 1990s, in fact, most of the trials with BBs were
sponsored by the pharmaceutical industry and often specifically designed to show a cardioprotective role of BBs over
the less remunerative generic thiazide diuretics. Moreover,
most of these studies were performed in an era when the
importance of the strict and accurate control of BP was not
perceived as it is today. In fact, the baseline BP values of the
study population were very high and, more important, BB
therapy resulted in a low and insufficient decrease in BP
values, at least considering the BP targets recommended by
most recent guidelines (see Table 1). For instance, in the
Swedish Trial on Old Patients (STOP), less than half of the
patients assigned to BB therapy had well-controlled BP
while receiving monotherapy, whereas almost two-thirds of
the patients assigned to diuretics reached the target BP.11
Hypertension guidelines then confirmed BBs as first-line
therapy on the basis of a few studies in which, concomitantly with BBs, thiazide diuretics were used in two-thirds
of patients.
Finally, the largest studies, consisting of large numbers
of patients (⬎50% of all ever studied patients), have been
published fairly recently (since 2002), and the interpretation
of their results was focused more on the superiority of
newer drugs rather than the less than optimal CV effect of
BB themselves.
The Reasons for the Lack of Cardiovascular
Protection
Why BBs do not confer similar CV protection to other
classes of agents despite their proved efficacy in lowering
BP? Several mechanisms, which we summarize here, could
be responsible for this reduced or lack of efficacy of BBs in
uncomplicated hypertension.
Reduced antihypertensive effect: Some evidence exists
that compared to other antihypertensive treatment, the BPlowering efficacy of BBs is suboptimal. This was first observed in older trials, in which BB therapy resulted in small
decreases in BP values, requiring the addition of second
drugs in most patients.9 Even in more recent trials, such as
LIFE, BP control was achieved in ⬍50% of patients assigned to the BB group, and only ⬍10% of patients continued receiving BB monotherapy.16 In ASCOT-BPLA,
compared to the atenolol-based arm, an amlodipine-based
regimen conferred a small but statistically significantly
higher effect in BP lowering (1.7 mm Hg mean lower
1435
systolic BP and 2.0 mm Hg mean lower diastolic BP).17
Because it is widely accepted that even a small adjunctive
decrease in BP confers prognostic relevance, the small difference between the 2 treatment arms in ASCOT-BPLA
might have played a role in the lower risk for coronary
events and stroke with amlodipine-based compared to
atenolol-based treatment.
Unfavorable hemodynamic effect and pseudoantihypertensive efficacy: In the elderly, the hemodynamic profile is typically characterized by low cardiac output and high
peripheral resistance. Focusing on their pure pharmacodynamic effects, most BBs lower BP by further decreasing
cardiac output and increasing systemic vascular resistance.
The difference pattern of hypertension, such as mainly systolic or diastolic, also might affect BBs efficacy. Because of
their negative chronotropic effect, BBs should not be prescribed to patients with predominantly systolic hypertension. In fact, the decrease in heart rate tends to be compensated
by a parallel increase in stroke volume, which will elevate
systolic BP and decrease diastolic BP, resulting in an unfavorable increase in pulse pressure. Moreover, even taking into
account the favorable independent prognostic impact conferred
by lowering heart rate,25 either by nonpharmacologic interventions or by heart rate–lowering drugs, a recent reanalysis from
Bangalore et al26 of nearly 65,000 patients with uncomplicated
hypertension showed that, in patients treated with BBs, lower
heart rates were associated with a significantly higher risk
for all-cause mortality, CV mortality, myocardial infarction,
stroke, and heart failure. The same concept can be also be
applied to hypertensive patients with higher heart rates at rest,
a group of patients in whom it is a widely accepted belief that
BB therapy would be indicated as the first choice. In contrast,
a recent reanalysis of a subgroup of ASCOT concluded that the
superiority of amlodipine-based over atenolol-based therapy
for patients with uncomplicated hypertension was independent
from heart rate and, more interestingly, was maintained in
those patients with higher baseline heart rates.27
Finally, although they reduce peripheral BP, which is
commonly measured and considered a reference in everyday clinical practice, BBs have been shown to be less
efficacious in reducing central aortic BP compared with
RAAS blockers, diuretics, and calcium channel blockers, a
phenomenon commonly called the pseudoantihypertensive
effect. Specifically, in the Conduit Artery Function Evaluation (CAFE) study,28 for the same peripheral BP, central
aortic systolic BP and central aortic pulse pressure were
significantly higher with atenolol-based compared to amlodipine-based treatment. The increase in central aortic systolic BP should be more predictive of CV events, such as
stroke and myocardial infarction, than the traditional peripheral (brachial) BP measurements. The pseudoantihypertensive effect thus might explain the increased risk for
stroke seen in clinical trials.19
Reduced compliance: BBs considered as a class have
many undesirable adverse effects, including drowsiness,
lethargy, sleep disturbance, visual hallucinations, depression, blurring of vision, dreams or nightmares, pulmonary
side effects such as increased airway resistance in asthmatics, and peripheral vascular side effects such as cold extremities, Raynaud’s phenomenon, and erectile and orgas-
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The American Journal of Cardiology (www.AJConline.org)
mic dysfunction. It is common experience that BBs are
often less tolerated in elderly patients than other drugs. For
instance, in MRC trial, twice as many patients withdrew
from the BB arm because of major adverse effects than from
the diuretic arm.9 Thus, BBs might expose elderly patients
to adverse effects and costs while conferring little if any true
benefit.
Reduced effect on left ventricular hypertrophy
(LVH) regression: It is now more clear that BP lowering
represents a surrogate end point that does not automatically
lead to a parallel decrease in CV morbidity and mortality.
Conversely, intermediate end points, such as LVH, have
been shown to be reliably linked to CV mortality and
morbidity. Specifically, the regression of LVH has been
shown to lower CV risk independently of other risk factors.29 In the LIFE study, antihypertensive treatment with
losartan-based therapy resulted in greater LVH regression
than conventional atenolol-based therapy.16 Moreover, a
meta-analysis of 109 studies of more than 2,000 patients
comparing the effects of various antihypertensive strategies
on LVH regression, BB-based therapy induced a significantly lower LVH regression compared to other drugs, especially RAAS blockers.30 A potential mechanism of the
reduced efficacy on LVH regression might reside in BBs
inability, as opposed to RAAS blockers, to decrease collagen content in the myocardium.31
Unfavorable metabolic effects: Metabolic side effects
induced by long-term BB treatment could have a particular
negative influence in younger patients. Traditional BBs, in
fact, have been shown to increase insulin resistance and
predispose patients to diabetes. In a meta-analysis including
almost 150,000 patients without diabetes, the risk for newonset diabetes was significantly increased with diuretics and
BBs than with placebo or other classes of antihypertensive
drugs.32 Possible mechanisms by which BBs may contribute
to the development of diabetes include weight gain, attenuation of the ␤-receptor-mediated release of insulin from
pancreatic ␤ cells and decreased blood flow through the
microcirculation in skeletal-muscle tissue, leading to decreased glucose uptake and increased insulin-resistance.33
Second, BBs can worsen the blood lipid profile. In fact, the
long-term administration of BBs has been shown to increase
triglyceride levels by 20% to 50% and decrease high-density lipoprotein cholesterol by 10% to 20%.33 BB therapy
also hampers exercise capacity. The mechanism of reduced
exercise tolerance in patients taking BBs may be attributed
to their hemodynamic effects, such as decrease in heart rate,
cardiac output, and mean BP, together with some of their
side effects, such as lethargy, sleep disturbance, or depression. As a consequence, BB use has been associated with
small but systematic weight gain. In the few hypertension studies that reported weight status, in fact, BB use
resulted in weight gains of as much as 1.2 kg.34 The weight
gain secondary to BBs can be attributed to their effect in
decreasing metabolic activity by as much as 10% and also to
other effects on energy metabolism. Given the negative
influence of obesity on global CV risk and new-onset diabetes, the effects of BBs in obese patients or patients with
risk factors for diabetes cannot be ignored.
Lack of vascular effects: Theoretically, the ideal antihypertensive agent should aim not only to control BP but
also to improve endothelial function. Traditional BBs have
no effect on endothelial function compared to other antihypertensive agents. In a small prospective study of 19 untreated hypertensive patients randomized to atenolol or amlodipine, after 1 year of treatment, whereas the amlodipine
group had correction of altered resistance artery structure
(on gluteal resistance vessels) and tended to have improved
endothelial function, patients treated with atenolol did not
show any vascular benefit given a similar BP control compared to amlodipine group.35 Similar results were obtained
with the RAAS blocker olmesartan.36 Furthermore, in another study, switching from a BB to irbesartan resulted in
the correction of previously persistently altered vascular
structure and endothelial dysfunction, suggesting a structural and endothelial protective effect of angiotensin-1 receptor antagonists.37 This effect on endothelial function is
thus independent of BP control and seems to be an intrinsic
property of these antihypertensive agents (calcium channel
blockers and RAAS blockers). Therefore, the lack of cardioprotective effects of BBs in patients with essential hypertension may be due partially to their failure in improving
endothelial function.
Newer ␤-Blocking Agents: Are They Different?
Most of data regarding the efficacy of BB therapy in
primary hypertension derive from studies conducted with
older agents, such as propranolol, atenolol, and metoprolol.
Newer BBs showing vasodilatory properties, such as carvedilol and nebivolol, show a much better hemodynamic and
metabolic profile than older compounds. Theoretically,
these properties may confer to these agents a cardioprotective effect similar to other class of antihypertensive agents.
Carvedilol is a third-generation vasodilating BB that
lacks intrinsic sympathomimetic activity and blocks ␣1-,
␤1-, and ␤2-adrenergic receptors without exhibiting high
levels of inverse agonist activity,38,39 thus being a much
better tolerated compound than the older BBs. Carvedilol
lowers BP by decreasing peripheral vascular resistance,
without affecting cardiac output. Because of the ␣1-adrenergic blocking effect, which accounts for its vasodilatory
effects, the hemodynamic effect of carvedilol is similar to
those of RAAS inhibitors and calcium channel blockers,
thus conferring to this agent a more beneficial effect on
LVH regression compared to conventional BBs.40 Moreover, carvedilol shows a significantly better metabolic profile than older compounds. In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in
Hypertensives (GEMINI) trial,41 as opposed to metoprolol,
patients taking carvedilol showed no significant weight
gain. Interestingly, in the same study, patients with diabetes
treated with metoprolol showed an increase in glycosylated
hemoglobin, whereas those treated with carvedilol did not.
This favorable metabolic profile was also confirmed in nondiabetic population. In the Carvedilol or Metoprolol European Trial (COMET),42 in fact, the risk for new-onset diabetes was 22% lower in patients receiving carvedilol than in
those receiving metoprolol. Finally, as opposed to older
BBs, carvedilol seems to have a neutral or beneficial effect
Review/Reasons for Suboptimal Cardioprotective Effect of ␤-blockers
on lipoprotein lipase activity and levels of triglycerides and
high-density lipoprotein.43 These findings suggest that in
the class of BBs, carvedilol should be the compound of
choice in subjects with metabolic syndrome, impaired glucose tolerance, or type 2 diabetes.
Nebivolol is a third-generation selective ␤-adrenergic
receptor antagonist. Its vasodilatory properties may be attributable to its ability to increase nitric oxide bioavailability, as demonstrated in animals, human volunteers, and
patients with hypertension.44,45 The mechanisms of nebivolol-mediated increases in nitric oxide bioavailability are still
debated. Nebivolol may decrease oxidative stress in essential hypertension and increase nitric oxide by reducing its
oxidative inactivation.46 In contrast, other investigators
have suggested the direct involvement of the ␤3-adrenoceptor as a possible nebivolol-mediated stimulation of endothelial nitric oxide synthase.47 Alternatively, nebivolol might
reduce circulating levels of asymmetric dimethylarginine, a
potent inhibitor of endothelial nitric oxide synthase.48 The
augmented nebivolol-mediated nitric oxide bioavailability
may partially explain its favorable hemodynamic effects
compared to older BBs. In fact, Mahmud and Feely49 showed,
in a small group of patients with untreated hypertension, that
given an equal reduction in brachial blood pressure, aortic
pulse pressure was reduced to a greater extent by nebivolol
compared to atenolol. Finally, similarly to carvedilol, nebivolol
has been shown to have a neutral or even favorable effect on
carbohydrate and lipid metabolism.50
Whether newer vasodilating agents such as carvedilol
and nebivolol, which show a more favorable hemodynamic
and metabolic profile, will be more efficacious in reducing
CV morbidity and mortality remains to be determined.
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