Nephrology Dialysis Transplantation 2006 21(6):1469-1473; doi:10.1093/ndt/gfk064
© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Editorial Comment
The role of combination therapy in the management of hypertension
Joel M. Neutel
Orange County Research Center, Tustin, CA, USA
Correspondence and offprint requests to: Joel M. Neutel, Orange County Research Center, Tustin, CA, USA. Email: JMNeutel{at}aol.com
Keywords: angiotensin receptor blockers; combination therapy; goal blood pressure
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The relationship of blood pressure and cardiovascular risk
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Data from the largest meta-analysis of hypertensive patients
clearly demonstrate that increasing systolic blood pressure
(BP) in any age group is associated with very significant increases
in cardiovascular disease [
1]. It has been shown that for every
20 mmHg increase in systolic BP, or for every 10 mmHg increase
in diastolic BP, there is a doubling in the risk of cardiovascular
disease. Conversely, a meta-analysis of outcome studies in the
treatment of systolic hypertension demonstrated that for every
20 mmHg reduction in systolic BP there is an
40–45% reduction
in cardiovascular disease [
2]. These studies have confirmed
the very significant cardiovascular risk associated with hypertension
and the impressive benefits that can be derived from the treatment
of this disease process. Despite these findings, worldwide epidemiological
data have shown that fewer than one-third of hypertensive patients
achieve a BP of <140/90 mmHg [
3].
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The blood pressure values achieved in clinical practice
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Perhaps of even more concern is the fact that <50% of treated
hypertensive patients (patients on antihypertensive medication
and being followed by a physician) have a BP of <140/90 mmHg
[
4,
5]. These are patients who have been diagnosed and treated
for hypertension and for some reason inadequate BP control has
been accepted. There are now several studies that clearly show
that these patients remain at significant risk for cardiovascular
disease. In the UKPDS study, two groups of diabetic patients
were differentiated; those with ‘tight’ BP control
and those with ‘less tight’ BP control [
6]. Since
all patients in the study were being treated with antihypertensive
drugs, the comparison was really one of treated hypertensive
patients with inadequate BP control compared with treated hypertensive
patients with what was considered by the authors as adequate
control. The difference in BP between the two groups was only
10/5 mmHg. However, patients with tight control had 44% fewer
strokes and 21% fewer myocardial infarctions than those with
less tight control (
Figure 1). Thus, more aggressive treatment
in patients already on antihypertensive treatment, but with
inadequate BP control, has a significant impact on the risk
of cardiovascular disease [
6]. The HOT study was performed to
assess whether lower BP is better: each 5 mmHg decrease in diastolic
BP resulted in further decreases in cardiovascular disease—again
in a group of patients in which everyone was being treated for
hypertension (
Figure 2) [
6]. In the diabetic cohort from the
HOT study, for every 2 mmHg reduction in diastolic BP, there
was a significant further reduction in cardiovascular disease
(
Figure 3) [
6]. Data from these studies have now been analysed
to show that for every 2 mmHg reduction in systolic BP there
is a 7% reduction in coronary artery disease and an 10% reduction
in stroke [
6].
It is clear from these studies that treated but inadequately
controlled hypertensive patients remain at risk for cardiovascular
disease and it is critical that clinicians around the world
focus on achieving recommended goal BP values in these patients.
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Reasons for inadequate blood pressure control
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There are currently >125 antihypertensive agents available
for the treatment of hypertension; many of them are very effective
drugs. Despite this, we struggle to control BP. The question
must be asked, why are we doing so poorly in the management
of hypertension, and what can we do differently to improve control
rates? The answer may be that the stepped care approach is failing
in the management of hypertension. Over the past 30 years, the
Joint National Committee has advocated the stepped care approach
for the management of hypertension. During this time, control
rates in the USA, as reported by the NHANES group, have improved
by only 5%. This clearly demonstrates that this approach is
failing. The principle of the stepped care approach is sound
in that it advocates treating people with a chronic illness
with as few drugs as possible at the lowest doses possible.
Why then is this not working in the management of hypertension?
Surveys performed on clinicians to determine which qualities
of antihypertensive agents are most important in the selection
of initial drugs for the treatment of hypertension repeatedly
show that efficacy and safety are most important. It is here
that the problem lies. If you consider the stepped care approach,
the logic is that as you increase the dose of a particular agent,
the efficacy increases along the dose–response curve.
However, as you increase the dose of that same agent, there
is a simultaneous increase in dose-dependent side effects. Thus
the two criteria most important to clinicians in the management
of hypertension move in opposite directions as we follow the
stepped care approach [
7]. This creates a clinical conundrum,
since in many cases we cannot have all that we want in the treatment
of our patients. The result is that we accept inadequate BP
control, are ready to accept a little less efficacy in order
to have tolerable side effects, and depend on non-pharmacological
methods to achieve greater BP reduction. This contributes significantly
to the poor control rates around the world.
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The solution: combination therapy—greater efficacy
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The solution to this problem is the use of combination therapy.
In terms of efficacy, using two complementary antihypertensive
agents in combination will always result in greater efficacy
than high-dose monotherapy.
Figure 4 demonstrates that small
doses of hydrochlorothiazide (HCTZ) (6.25 mg) added to small
doses of bisoprolol (10 mg) are more effective than high-dose
HCTZ monotherapy (25 mg) and more effective than high-dose bisoprolol
(40 mg) [
8]. Similarly, as shown in
Figure 5, uptitration of
any of the angiotensin receptor blockers (ARBs) from low dose
to high doses results in significantly less impact on BP than
the addition of a small dose of HCTZ (12.5 mg) to the lower
dose ARB [
9–11]. It is clear from these data that if efficacy
is important to a clinician, you will always do better, by
3-fold,
when using complementary drugs in combination than you could
do by uptitration.
Table 1 shows control rates from a large
PROBE design study using ambulatory blood pressure measurement
to demonstrate that the vast majority of patients can be controlled
by simply using a combination agent [
12].
View this table:
[in this window]
[in a new window]
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Table 1. Adverse event rate in patients treated with a low dose combinations of a beta blockers and a diwetic compared to those treated on placebo
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Combination therapy—fewer side effects
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As far as side effects are concerned, you will get similar or
fewer side effects with complementary drugs used in combination
than with high-dose monotherapy. As is shown in
Table 1, despite
ß-blockers and diuretics having many dose-dependent
side effects, particularly at higher doses, when given in low-dose
combinations there are very impressive reductions in BP with
placebo-like adverse events [
8]. Similarly, as shown in
Figure 5,
an ARB given in combination with a low-dose diuretic results
in substantially greater BP reduction than with monotherapy,
and the side effect profile for the combination, despite greater
BP reductions, is no different from that for the monotherapy
(
Table 1) [
11]. The addition of an angiotensin-converting enzyme
(ACE) inhibitor to a dihydropyridine calcium channel blocker
(CCB) results in less oedema using the combination, despite
greater BP reduction, than the CCB given at the same dose as
monotherapy. This is because of the complementary effect of
the combination decreasing capillary pressure and thus decreasing
oedema [
13]. Similarly, the metabolic effects of diuretics are
significantly attenuated when given with an ACE inhibitor or
an ARB. Thus, by using combination therapy, we can have efficacy
and safety both going in the same direction (
Figure 6), providing
us with the two most important criteria in the management of
hypertension.
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The role of fixed combinations
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This concept has enabled us to use higher dose fixed combinations.
It is well known that it is predominantly the inadequate control
of systolic BP that has contributed to poor BP control rates.
Due to the adverse events and metabolic side effects associated
with high-dose use of diuretics, there is a general consensus
that HCTZ should not be used at doses greater than 12.5 mg.
However, many of the new combinations have included HCTZ at
a 25 mg dose. The reason for this is shown in
Figure 7. Uptitration
of an ARB from low dose to high dose results in a small further
reduction in BP along with a dose–response curve which
is relatively flat for the class. The addition of 12.5 mg of
HCTZ to the high-dose ARB results in a further very impressive
reduction in systolic BP [
14]. One may think that the addition
of a further 12.5 mg of HCTZ (to 25 mg) would also result in
a flat dose–response curve. However, as shown, the addition
of the second 12.5 mg of HCTZ results in at least as much further
reduction in systolic BP as did the first 12.5 mg [
11]. This
is not surprising since systolic hypertension is volume dependent
and very responsive to diuretics. When considering the adverse
events, the fact that HCTZ is given with high-dose ARBs results
in a side effect profile which is not significantly different
from that seen with HCTZ 25 mg given as monotherapy [
14]. Thus,
the complementary nature of these agents allows us to achieve
much greater reductions in systolic BP without significantly
impacting side effects.
Another important benefit of fixed dose combination therapy
is improved compliance rates. It has been shown that the addition
of antihypertensive agents to a treatment regimen has a very
significant inverse effect on compliance, even if the drugs
are given once daily [
15]. The simplification of regimen of
the antihypertensive agents is critical in the management of
hypertension. Wherever possible, a fixed dose combination should
be used by clinicians to simplify the dosing regimen. It has
been shown that more rapid control of BP results in fewer cardiovascular
events than BP controlled over longer periods of time. This
improves patient compliance and decreases cardiovascular disease,
resulting in fewer events. More rapid control is always achieved
by using combination therapy than can be achieved by monotherapy,
even at higher doses.
Another advantage of combination therapy is its ability to control BP similarly across all subgroups of hypertensive patients. For example, it is well known that African American patients are less responsive to ACE inhibitors, ARBs and ß-blockers than Caucasian patients. However, if given in combination with HCTZ, each of these drug classes is equally effective in African American and Caucasian patients [9]. Seeing as it has also been shown that the cardioprotective effects of blockade of the renin–angiotensin system are largely independent of BP, this approach offers African American patients the benefit of the vascular protection of these agents without compromising efficacy. This increased response rate simplifies the management of hypertension.
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‘Overtreatment’—a legitimate concern?
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There appears to be a major concern by physicians regarding
‘overtreatment’ of hypertension. Our goal in managing
this disease seems to be simply to dip our patients into the
normotensive range. For example, if we have a patient with a
diastolic BP of 100 mmHg, the patient is started on monotherapy
and the resulting diastolic BP is 88 mmHg. Most physicians would
be very pleased with this result, believing that they had taken
a sick patient and made them better and they would probably
stop at this point. However, a more aggressive physician would
say that this same patient has grade II hypertension and start
them on combination therapy. If the resulting diastolic BP was
now 80 mmHg without adverse events, this physician has taken
a sick patient and made them even better. This has been shown
in the HOT study—the lower the BP, the lower the risk
of cardiovascular disease [
6]. It could be argued that this
is an overtreated patient, in that they could have been controlled
on one drug; however, the use of two agents to lower BP further,
provided there are no side effects, would be a much better approach.
Thus, overtreatment is determined by adverse events rather than
by BP and should be less of a concern to physicians, particularly
if they are using complementary agents in combination.
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Conclusion
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In conclusion, our current approach to the management of hypertension
has not provided us with the desired results. The use of combination
therapy as first-line treatment, or treatment much earlier in
the course of treating hypertension, appears to be much more
efficient than the stepped care approach. The use of combination
therapy will provide greater efficacy, fewer side effects and
greater convenience than can be achieved with monotherapy and,
most importantly, will significantly increase control rates.
It would appear that a change in paradigm in the treatment of
hypertension may be the most significant change that we can
make in order to improve worldwide control rates, which will
ultimately impact cardiovascular disease.
Conflict of interest statement. None declared.
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Received for publication: 7.12.05
Accepted in revised form: 21.12.05
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The relationship of blood...
The blood pressure values...
