1. European Heart Journal (2011) 32, 2499–2506 REVIEW
doi:10.1093/eurheartj/ehr177
Novel therapeutic concepts
Hypertension management 2011: optimal
combination therapy
Peter S. Sever 1* and Franz H. Messerli 2
1
International Centre for Circulatory Health, Imperial College London, 59 North Wharf Road, London W2 1LA, UK; and 2Division of Cardiology, St Luke’s and Roosevelt Hospitals,
Columbia University College of Physicians and Surgeons, New York, NY, USA
Received 11 August 2010; revised 16 March 2011; accepted 13 May 2011; online publish-ahead-of-print 22 June 2011
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Raised levels of blood pressure result from the complex interplay of environmental and genetic factors. The complexity of blood pressure
control mechanisms has major implications for individual responsiveness to antihypertensive drugs. The underlying haemodynamic disorder
in the majority of cases is a rise in peripheral vascular resistance. This observation led to the discovery and development of increasingly
sophisticated and targeted vasodilators, although many of the earlier antihypertensive drugs, by virtue of their actions blocking the sympath-
etic nervous system, had a vasodilator component to their mode of action. A recent meta-analysis of placebo controlled trials of monother-
apy in unselected hypertensives, reports average (placebo-corrected) blood pressure responses to single agents of 9.1 mmHg systolic and
5.5 mmHg diastolic pressure. These average values disguise the extremely wide ranging responses in individuals across a fall of 20– 30 mmHg
systolic at one extreme, to no effect at all, or even a small rise in blood pressure at the other. The second factor determining individual
responses to monotherapy is the extent to which initial falls in pressure are opposed by reflex responses in counter regulatory mechanisms
that are activated following the blood pressure reduction. Thus, a satisfactory blood pressure response is rarely reached with monotherapy
alone. What then is the next step if blood pressure is not a goal after the patient has been treated with monotherapy for a few weeks? Should
you uptitrate, substitute or combine?
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Keywords Hypertension † Combination therapy
earlier antihypertensive drugs, by virtue of their actions blocking
Introduction the sympathetic nervous system, had a vasodilator component to
Raised levels of blood pressure result from the complex interplay their mode of action. The first non-specific vasodilator, hydrala-
of environmental and genetic factors leading to the activation or zine, was followed by vasodilatation which involved blockade
suppression of one or more of a host of physiological systems of calcium channels on vascular smooth muscle cells [the
involved in blood pressure regulation (Figure 1). The complexity calcium channel blockers (CCBs)], blockade of post-synaptic
of blood pressure control mechanisms, first hypothesized by alpha-adrenoceptors on peripheral sympathetic neurones (the
Irvine Page,1 has major implications for individual responsiveness alpha blockers) and, finally, vasodilatation achieved by
to antihypertensive drugs (Figure 2), because of the inevitable blockade of the renin–angiotensin –aldosterone system (RAAS)
variety of hypertensive phenotypes, the identification of which, [angiotensin-converting enzyme (ACE) inhibitors, angiotensin
with some notable exceptions, remains elusive to the practicing receptor blockers (ARBs), direct renin inhibitors (DRIs)] (Figure 3).
physician involved in making treatment decisions for individual The nature of these molecules, and in most cases their single site
patients.2 of action, dictates that when administered to a heterogeneous
Hypertension is, by definition, a haemodynamic disorder. The population, encompassing many hypertensive phenotypes, blood
major haemodynamic finding associated with higher levels of pressure responses will be largely unpredictable and wide
blood pressure is a rise in peripheral vascular resistance. This ranging (Figure 4). If, in a particular case, blood pressure levels
observation led to the discovery and development of increasingly are largely determined by activation of the RAAS, for example in
sophisticated and targeted vasodilators, although many of the renal artery stenosis, marked falls in blood pressure with
* Corresponding author. Tel: +44 207 594 1100, Fax: +44 207 594 1145, Email: p.sever@imperial.ac.uk
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: journals.permissions@oup.com

2. 2500 P.S. Sever and F.H. Messerli
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Figure 1 A schematic to demonstrate the interaction of environmental factors with underlying genetic predisposing factors to increase blood
pressure through the activation of a variety of pathogenetic mechanisms.
Figure 2 A modified and updated mosaic theory of blood pressure regulation derived from the original Paige mosaic.1
impairment of renal function may follow the administration of an systolic and 5.5 mmHg diastolic pressure. These average values dis-
ACE-Inhibitor.3 On the other hand, in the elderly and in those guise the extremely wide ranging responses in individuals across a
of African origins, where the activity of the RAAS is generally sup- fall of 20–30 mmHg systolic at one extreme, to no effect at all, or
pressed, blood pressure reductions4,5 with an ACE-Inhibitor may even a small rise in blood pressure at the other7 (Figure 4).
be small. In general, however, the phenotype is not known. The second factor determining individual responses to mono-
A recent meta-analysis of placebo-controlled trials of monother- therapy is the extent to which initial falls in pressure are
apy, in unselected hypertensives,6 reports average (placebo cor- opposed by reflex responses in counter regulatory mechanisms
rected) blood pressure responses to single agents of 9.1 mmHg that are activated following the blood pressure reduction. In

3. To uptitrate, to substitute, or to combine drugs 2501
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Figure 3 The history of development of antihypertensive drugs reproduced with kind permission of Thomas Unger.
Figure 4 The frequency distribution of changes in diastolic
blood pressure produced by three different antihypertensive Figure 5 Response to the vasodilator hydralazine followed by
drugs. Negative values represent placebo-corrected reductions the co-administration of the beta-blocker, atenolol.
in diastolic pressure. Modified from reference.7
antihypertensive drugs have a rather shallow dose–response
extreme cases, these reflex responses can nullify any fall in curve. In particular, with RAAS inhibitors doubling the dose has
pressure (Figure 5). minimal incremental effect on blood pressure. In contrast, with
Thus, a satisfactory blood pressure response is rarely reached CCBs, additional antihypertensive efficacy can be gained when, for
with monotherapy alone. What then is the next step if blood example, the starting dose of amlodipine is doubled from 5 to
pressure is not at goal after the patient has been treated with 10 mg. However, the incidence of pedal oedema also is dose depen-
monotherapy for a few weeks? Should you uptitrate, substitute, dent and increases with a higher dose of amlodipine. Importantly, the
or combine? additional blood pressure fall from combining drugs from two differ-
ent classes is 5 times greater than the one from doubling the dose
Uptitration of a single drug.8 Thus, the odds of getting blood pressure to goal are
Uptitration of the initial drug is reasonable only if definitive, several times greater with combining drugs than with up titration of
enhanced antihypertensive efficacy of the higher dose has been monotherapy. From a sheer efficacy point of view, combination
documented and the cost is not prohibitive. Regrettably, most therefore takes precedence over uptitration.

4. 2502 P.S. Sever and F.H. Messerli
Substitution Although there are some differences between guidelines, several
Substituting an antihypertensive drug from a different class should be now recommend the initiation of combination therapy as first line
considered only if there is no antihypertensive effect with a reason- in particular circumstances, in view of the associated risks of more
able dose, as is occasionally observed with beta-blockers or RAAS severe hypertension, the recognition that dual (or triple therapy) is
blockers in black patients, or if there are any intolerable adverse invariably needed to achieve target blood pressures of ,140/
effects such as angioedema. Fortunately, most modern antihyperten- 90 mmHg, and that there is a degree of urgency in reducing
sive drugs are generally well tolerated and serious adverse effects are blood pressure to more acceptable levels to combat this risk.
few. However, before resorting to drug substitution one may con- JNC-7 recommends initiating therapy with two drugs when
sider that the addition of another drug may unmask the antihyperten- blood pressure is .20 mmHg above systolic goal or 10 mmHg
sive efficacy of the initial agent. For instance, the addition of a thiazide above diastolic goal.10 The European Guidelines,12 including their
diuretic in a patient previously unresponsive to RAAS blockade is most recent update,13 confirm such a recommendation and also
prone to stimulate the renin–angiotensin system to the extent proposes the initiation of combination therapy in those with
that now both drugs, the RAAS inhibitor as well as the diuretic, milder degrees of blood pressure elevation in the presence of mul-
have an additive antihypertensive effect.9 tiple risk factors, subclinical organ damage, diabetes, renal, or
associated cardiovascular disease. Although combination therapy
is not specifically advocated as initial therapy in the 2004 British
Rationale for combination therapy Hypertension Society Guidelines14 (largely based on the fact that
there is a lack of randomized controlled trial evidence to
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The rationale for combination therapy in hypertension is therefore
support such practice), it is probable that the results of ongoing
straightforward. First, it is to combine drugs acting on different
trials will provide new evidence in favour of their early introduc-
physiological systems in a situation where the phenotype is not
tion into treatment strategies.
known and where a pharmacological ‘attack’ on two (or more)
Inevitably, there are concerns that initiating therapy with more
systems will have a greater impact on blood pressure reduction
than one drug could induce significant hypotension and increase
than blind monotherapy. Second, it is an attempt to block counter-
coronary risk. An analysis of intervention trials in hypertension15,16
regulatory responses that are activated by the perturbation of the
provides some evidence for a ‘J-curve’ relationship between the
blood pressure regulatory mechanisms when a physiological
magnitude of blood pressure lowering and coronary heart
system is blocked with single-drug therapy (Figure 6).
disease outcome, but this seems to be confined to high-risk indi-
Third, the hypertensive population includes many with levels of
viduals including those with established coronary artery disease,
blood pressure categorized as moderate or severe (stage 2 hyperten-
in whom excessive blood pressure lowering compromises coron-
sion).10 There is general consensus that those with systolic blood
ary perfusion. In uncomplicated hypertension, lower pressures are
pressures .160 mmHg and/or diastolic pressures .100 mmHg fall
well tolerated, for example, as seen in the Systolic Hypertension in
into this category. They constitute 10–15% of hypertensive popu-
the Elderly Study, in which diastolic pressures as low as 60 mmHg
lations and are at substantially greater risk of a future cardiovascular
were achieved in the active treatment group.17 Ongoing trials com-
event. For every 20 mmHg increase in systolic blood pressure,
paring initiation of dual therapy vs. sequential monotherapy in
there is an approximate doubling of cardiovascular risk.11
hypertension will aim to clarify the safety of the former.
Obviously the proportion of the population with hypertension
Fourth, blood pressure variability has been shown to decrease
increases with age and this also applies to those with stage 2 hyperten-
with combination therapy18 when compared with monotherapy.
sion. As age advances systolic hypertension predominates and is
In an extensive analysis of several randomized trials, visit-to-visit
largely accounted for by loss of elasticity and increasing rigidity of
variability of systolic blood pressure was documented to be a
large arteries.
strong predictor of both stroke and myocardial infarction and
this was independent of mean in-trial blood pressure.18 Interest-
ingly enough, CCBs and diuretics were most efficacious in reducing
visit-to-visit blood pressure variability and also were associated
with the most efficacious stroke prevention.19 In contrast, beta-
blockers were shown to increase variability of systolic pressure
in a dose-dependent way and also were the least efficacious in
stroke prevention. The addition of a CCB or to a lesser extent
of a diuretic to a RAAS inhibitor diminishes variability of systolic
pressure, which makes another strong argument for combination
therapy.
Trial evidence for and against
Figure 6 Renin– angiotensin– aldosterone system and sym- specific combinations
pathetic nervous system activation and suppression by different
classes of antihypertensive drugs. An extensive review of first-line drug choices has been published
by the Blood Pressure Lowering Treatment Trialists’

5. To uptitrate, to substitute, or to combine drugs 2503
Collaboration20,21 and is based upon prospective meta-analyses of cardiovascular outcome, and differentially affected by different
trials comparing different drug regimens. Similar analyses have been ´
treatment strategies. For example, in the CAFE substudy of
undertaken by the National Institute for Clinical Excellence (NICE) ASCOT, the amlodipine/perindopril regimen lowered central
in the UK.22 The difficulty in extending these analyses to evaluate aortic blood pressure to a greater extent than the atenolol/thia-
the comparative effects of different combinations of drugs is that in zide regimen (by 4 mmHg systolic), and the level of central
many trials it is not possible to establish which add-on drugs were pressure was related to cardiovascular and renal outcomes28. In
used and in what doses. The evidence base for making claims about another substudy, various measures of blood pressure variability
the comparable or superior efficacy of one regimen vs. another during the trial were strongly associated with both stroke and
comes from trials where the treatment algorithm was clearly coronary outcomes, in that the amlodipine-based treatment
defined and one could conclude with reasonable assuredness regimen reduced blood pressure variability compared with the
that a particular regimen was similar to, better than or worse atenolol-based regimen. These differences largely accounted for
than another. The best evidence, from which claims can be the observed differences in cardiovascular outcomes between
made of outcomes in favour of a particular regimen, comes from the two-drug regimens.29
four trials, the Losartan Intervention For Event Reduction Trial In the third trial, ACCOMPLISH,25 11 506 hypertensive patients
(the LIFE Trial,23 the Anglo-Scandinavian Cardiac Outcomes Trial were randomized to a combination of the ACE-Inhibitor, benaze-
(ASCOT).24 The Avoiding Cardiovascular Events through Combi- pril, with either hydrochlorothiazide, or the CCB, amlodipine.
nation Therapy in Patients Living with Systolic Hypertension Trial Patients were followed for 3 years. Blood pressure levels were
(ACCOMPLISH)25 and the Valsartan Antihypertensive Long-term reduced similarly in the two arms of the trial. Cardiovascular
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Use Evaluation Trial (VALUE).26 events were significantly reduced by 20% in benazepril/amlodipine
In the LIFE Trial,23 9193 hypertensive patients were random- arm compared with the benazepril/hydrochlorothiazide arm.
ized to initial treatment with either an ARB (losartan) or a beta- Myocardial infarction was reduced significantly (22%) and stroke
blocker (atenolol). Hydrochlorothiazide was added in the non-significantly (16%) by benazepril/amlodipine compared with
majority of patients to achieve blood pressure control, along benazepril/hydrochlorothiazide. The benefits of the benazepril/
with the further addition of common third-line agents in a min- amlodipine combination over benazepril/hydrochlorthiazide were
ority of patients. After an average follow-up of 5 years during seen in both diabetic and non-diabetic patients.30
which there was no discernable difference in blood pressure In the fourth study, VALUE,26 15 245 hypertensive patients
between the two regimens, the composite primary cardiovascu- were randomized to either the ARB, valsartan, or the CCB,
lar endpoint was reduced by 13% in the losartan-based group amlodipine. Hydrochlorothiazide was added to each limb in
compared with the atenolol-based group. The major benefit attempting to achieve goal blood pressures. Other add-on
was seen in the secondary stroke endpoint (a component of drugs were similar in the two treatment arms. Mean follow-up
the primary) which was reduced by 25% in the losartan-based was 4.2 years. Blood pressures were more effectively and more
group. rapidly reduced in the amlodipine-based treatment arm. Although
In the second trial, ASCOT,24 over 19 000 hypertensive patients the primary composite endpoint of cardiac morbidity and mor-
with no prior history of coronary heart disease were randomized tality was similar in the two arms of the trial, myocardial infarc-
to either a CCB, amlodipine, or a beta-blocker, atenolol. The tion occurred significantly less frequently (risk reduction 19%)
ACE-Inhibitor perindopril or the diuretic bendroflumethiazide and strokes non-significantly less often (risk reduction 15%) in
was added to each arm, respectively, in an attempt to achieve the amlodipine-based treatment arm compared with the
blood pressure targets. Again, common third-line drugs could be valsartan-based arm. The authors of the trial attributed early
added to each arm in a minority of patients. After an average differences in blood pressure as an explanation for the differential
follow-up of 5.5 years, the trial was stopped prematurely on the effects of the two treatments on myocardial infarction and
advice of the Data Safety Monitoring Committee, because of stroke.
highly significant outcome benefits in favour of the amlodipine- The cumulative evidence from these trials strongly supports the
based regimen. All cardiovascular events were reduced by 26%, view that, in hypertensive patients, combination therapy with CCB/
stroke by 23%, and all-cause mortality by 11% by the amlodipine- ACE-I or CCB/ARB is likely to be associated with better cardiovas-
based regimen compared with the atenolol-based regimen. The cular outcomes, including myocardial infarction and stroke, than
primary endpoint of non-fatal myocardial infarction and fatal cor- regimens containing beta-blockers and thiazide diuretics and that
onary disease was reduced non-significantly by 10% in favour of CCB/ACE-I combinations are preferable to diuretic/ACE-I combi-
the amlodipine-based regimen, best explained by the early termin- nations on major cardiovascular endpoints. Added to this should
ation of the trial before the required number of primary endpoints be the cost-effectiveness analysis from the NICE Guidelines
had been reached. In the event, a more comprehensive coronary which clearly demonstrates that CCBs and ACE-Is or ARBs are
endpoint which included coronary revascularizations was more cost-effective treatment choices than beta-blockers or
reduced significantly by 13%. thiazide diuretics.22
In several subsequent analyses, the small blood pressure differ- The above recommendations apply, in general, to those subjects
ences observed early in the trial did not explain the outcome with uncomplicated hypertension. In hypertensives with associated
benefits in favour of amlodipine-based treatment.27 In recent cardiovascular disease such as heart failure or coronary heart
reports, however, it has been shown that additional haemo- disease, the guidelines are consistent in recommending specific
dynamic measurements may be better determinants of drugs with compelling indications, based on randomized controlled

6. 2504 P.S. Sever and F.H. Messerli
trial evidence, that should be incorporated into treatment therefore be the preferred agent to be combined with a RAAS
strategies. blocker. Unfortunately most RAAS inhibitors are available only in
a fixed-dose combination (FDC) with hydrochlorthiazide.
In a recently reported study in a very elderly (.80 years) hyper-
Specific drug combinations tensive population, the Hypertension in the Very Elderly Study
Given that there are seven major classes of antihypertensive drugs (HYVET),34 a thiazide-like diuretic, indapamide, to which an
and numerous members of each class, the number of possible ACE-Inhibitor, perindopril, was added, was found to reduce
combinations is extensive. In the following, we subdivide combi- stroke incidence (30%) and the incidence of heart failure (64%),
nations as preferred, acceptable or unacceptable/ineffective combi- compared with placebo.
nations, based on outcome, antihypertensive efficacy, safety, and/or
tolerability. Acceptable combinations
Beta-blockers and diuretics
Preferred combinations The addition of diuretics has been shown to improve the antihy-
Renin–angiotensin –aldosterone system inhibitors pertensive efficacy of beta-blockers in African-American patients
and calcium channel blockers and other populations with low-renin hypertension. However,
Additive blood pressure reduction has been documented with the both of these drug classes have been shown to have similar
combination of an ACE-Inhibitor, ARB, or DRI with a CCB. The adverse effects in that they increase the risk of glucose intolerance,
common dose-dependent adverse effect of CCB monotherapy is the development of new-onset diabetes,22 fatigue, and sexual dys-
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peripheral oedema. The addition of a RAAS blocker has been function. Outcome studies have shown a morbidity and mortality
shown to mitigate this adverse effect. A recent meta-analysis has reduction with diuretics and beta-blockers in combination.22
shown that ACE-Inhibitors are somewhat more efficacious than
ARBs in decreasing peripheral oedema associated with CCB Calcium channel blockers and diuretics
therapy.31 As stated above, the ACCOMPLISH trial showed that Most physicians are somewhat reluctant to combine a CCB with a
fixed combination of an ACE-Inhibitor (benazapril) with a CCB diuretic. However, in the VALUE trial,26 hydrochlorthiazide was
(amlodipine) was more beneficial with regard to morbidity and added as a second step in patients randomized to amlodipine
mortality reduction than the fixed combination of the same and the diuretic/CCB combination was well tolerated, although
ACE-Inhibitor with hydrochlorthiazide.25 Generally, similar end- there was a higher risk of new onset diabetes and hyperkalaemia
point reductions have been demonstrated with ACE-Inhibitors when compared with the valsartan arm. Nevertheless, morbidity
and ARBs, although there is a suggestion that ACE-Inhibitors and mortality reductions were at least as good in the amlodipine
may be slightly more cardioprotective and that ARBs may confer as in the valsartan arm of the VALUE study.
some advantages in stroke prevention.32
The International Verapamil-Trandolapril Study (INVEST)33 was Calcium channel blockers and beta-blockers
a comparison of ‘new’ vs. ‘old’ drugs in that a regimen of the non- The combination of a beta-blocker with a dihydropyridine CCB
dihydropyridine, verapamil, to which trandolapril was added if has additive blood pressure reduction and, in general, is well toler-
necessary, was compared with atenolol to which hydrochlorthia- ated. In contrast, beta-blockers should not be combined with non-
zide was added if necessary to achieve blood pressure goals. A dihydropyridine calcium blockers such as verapamil or diltiazem.
total of 22 576 hypertensives with established coronary artery The negative chronotropic effect of both of these drugs may
disease were enrolled and followed up for a mean of 2.7 years. result in heart block or bradycardia.
The combined cardiovascular outcome was similar in the two
groups. Perhaps the most logical explanation for these findings is Dual calcium channel blockade
that the disadvantage of the beta-blocker regimen observed in The combination of a dihydropyridine CCB with either verapamil
hypertension trials in uncomplicated patients was offset by the or diltiazem has been shown in a recent meta-analysis 35 to have
known advantages of beta blockade in the context of established an additive effect on blood pressure lowering without significantly
coronary artery disease. increasing adverse events. Dual CCB blockade may be useful in
patients with documented angioedema on RAAS inhibitors or in
Renin–angiotensin –aldosterone system inhibitors patients with advanced renal failure at risk for hyperkalaemia.
and diuretics However, no outcome data are available with dual CCB therapy
Numerous factorial design studies have shown that the combi- and long-term safety remains undocumented.
nation of a thiazide diuretic with an ACE-Inhibitor, an ARB, or a
DRI result in fully additive blood pressure reduction. Diuretics, Unacceptable/ineffective combinations
by depleting intravascular volume, activate the RAAS which Dual renin –angiotensin –aldosterone system blockade
causes salt and water retention as well as vasoconstriction. The For the treatment of hypertension per se, dual RAAS blockade, in
addition of a RAAS blocker attenuates this counter regulatory general, is not recommended.36 In the ONTARGET study,37 there
response. Moreover, diuretic induced hypokalaemia as well as were more adverse events with a combination of telmisartan and
glucose intolerance is mitigated by the addition of a RAAS ramipril than with individual agents and cardiovascular endpoints,
blocker. Chlorthalidone has been shown to be more effective despite a small additional blood pressure reduction, were not
than hydrochlorthiazide in reducing blood pressure and should improved compared with monotherapy. Thus, there is little if any

7. To uptitrate, to substitute, or to combine drugs 2505
reason to combine an ARB with an ACE-Inhibitor for the treatment Adverse effects
of hypertension. However, as blockade of the renin–angiotensin
cascade by either an ACE-Inhibitor or an ARB increases plasma The adverse reactions associated with combination treatments are
renin activity, the argument has been put forward that the addition largely predicted from the known side effects of the individual
of a DRI could have additional benefits. Indeed, the combination of components. However, in older combinations of vasodilators
aliskiren with an ARB has been shown to have a small, significant (hydralazine) with beta-blockers and diuretics, the side effects of
additional effect on blood pressure in a double-blind study of 1797 vasodilatation (tachycardia and fluid retention) were mitigated by
patients.38 However, this fall in blood pressure with dual RAAS the additional drugs. There is some evidence that the oedema
blockade was less than one would have expected by the addition commonly associated with dihydropyridine CCBs is partially
of either a thiazide diuretic or a CCB. Of note, in an open label pro- relieved by co-administration of RAAS blockers44,45 and RAAS
spective crossover study in patients with resistant hypertension, the blockers may reduce the incidence of hypokalaemia induced by
aldosterone antagonist spironolactone was shown to lower blood thiazides.46 On the other hand, it seems likely that the increase
pressure more effectively than conventional dual RAAS blockade.39 in incidence of new-onset diabetes commonly associated with
At the present time, no outcome data are available to support beta-blockers is exacerbated when these drugs are given in con-
benefits of the combination of a DRI with either an ACE-Inhibitor junction with thiazide diuretics. A meta-analysis of the increased
or an ARB. Nevertheless, a randomized double-blind trial (ALTI- incidence of new-onset diabetes with beta-blocker and thiazide
TUDE) has been designed to look into this question and is currently treatment, compared with ‘newer’ drugs, is provided by the
in progress. NICE Guidelines.22
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These conclusions assume that there are no differences
between individual drugs within a particular drug class in relation
Renin –angiotensin –aldosterone system blockers
to their effects on long-term morbidity and mortality. Among
and beta-blockers
the CCBs, the best evidence is for amlodipine. Among the
In patients having suffered a myocardial infarction or in those in
ACE-Is and ARBs, several different drugs have been used both
heart failure, these two drug classes are commonly combined
within and without combination trials in hypertensive patients
because both have been shown to reduce reinfarction rates and
and in other cardiovascular patient groups, and no clear benefits
to improve survival. However, their combination produces little
of one drug over another are evident. For thiazide and thiazide-like
additional blood pressure reduction compared with either mono-
diuretics, there persists an opinion that the evidence base for long-
therapy. Thus, for the treatment of blood pressure per se, there is
term benefits is best for moderate doses of chlorthalidone,17,42,47
no reason to combine these two drug classes.
compared with other thiazides in lower doses. Regrettably, there
are unlikely to be future trials comparing drugs within this class.
Beta-blockers and antiadrenergic drugs For the beta-blockers, atenolol has been the drug most often
Little if any antihypertensive efficacy can be gained when beta- used and claims have been made that had other drugs in this
blockers are combined with antiadrenergic drugs such as clonidine. class been used in the trials then perhaps different results would
In fact, an exaggerated rebound in BP has been observed with this have occurred.48 This is unlikely since the adverse effects of ateno-
combination.40 lol, observed in ASCOT, on blood pressure variability,29 and an
increase in central aortic pressures compared with amlodipine 28
Other drug classes in combination therapy: alpha-blockers (both of which were associated with an increase in cardiovascular
and spironolactone risk), would be likely to occur with most other beta-blockers.
Alpha-adrenoceptor antagonists have been widely used as add-on Outcome trials in hypertension with beta-blockers possessing
drugs in combination regimens to achieve target blood pressures. additional pharmacological properties have not been conducted.
The availability of extended release formulations has improved
their tolerability profile. Data from an observational analysis of
the ASCOT trial showed that doxazosin gastrointestinal thera-
peutic system (GITS) used as third-line therapy lowered blood Fixed-dose combinations and
pressure and caused a modest reduction in serum lipids.41 In con-
trast to earlier findings in ALLHAT,42 doxazosin use in ASCOT was
outcome benefits
not associated with an increased incidence of heart failure. In a recent review of the potential advantages of FDC formulations
For subjects with resistant hypertension, defined as failure over their corresponding free drug components given separately, it
to achieve target blood pressure (,140/90 mmHg) despite was shown that the FDCs were associated with significantly better
maximum doses or maximum tolerated doses of three antihyper- compliance and a non-significant improvement in persistence with
tensive drugs including a RAAS blocker, a CCB, and a thiazide treatment.49 Similarly, in a meta-analysis of nine studies comparing
diuretic, quadruple therapy is frequently required. Recent reports the administration of FDCs with their separate components, the
demonstrate that spironolactone added to triple therapy is associ- adherence rate was improved by 26% in patients receiving FDCs.50
ated with substantial further reductions in blood pressure of, In trials in which blood pressure data were reported, use of
on average, 22/9.5 mmHg.43 Spironolactone is therefore rec- FDCs was associated with a non-significant lowering of systolic
ommended as a component of combination therapy in patients and diastolic pressure (4.1 and 3.1 mmHg, respectively) compared
with resistant hypertension. with the corresponding drugs administered separately.49 Such

8. 2506 P.S. Sever and F.H. Messerli
differences in blood pressure if sustained long term would
undoubtedly confer advantages on cardiovascular outcomes. Table 1 Drug combinations in hypertension:
recommendations
Blood pressure control in practice Preferred
ACEInhibitor/diuretic
Worldwide surveys of blood pressure control to targets rec- ARB/diuretic
ommended by national and international guidelines have consist- ACE-Inhibitor/CCB
ently revealed that in clinical practice the conventional goal of a ARB/CCB
blood pressure ,140/90 mmHg is reached by only a minority of ................................................................................
patients.51 Data from several countries are shown in Figure 5. Acceptable
While there are several explanations for physicians failing to Beta-blocker/diuretic
achieve target blood pressures, including poor compliance or con- CCB (dihydropyridine)/beta-blocker
cordance with drug taking by patients, white coat hypertension, CCB/diuretic
undiagnosed secondary causes of hypertension, and true resistant Renin inhibitor/diuretic
hypertension, in the majority of cases therapeutic inertia on the Renin inhibitor/CCB
part of the physician plays a major role. There is good evidence Dihydopyridine CCB/non-dihydropyridine CCB
................................................................................
that when physicians are faced with patients on treatment for Unacceptable
hypertension, but who have not reached goal blood pressures, ACE-Inhibitor/ARB
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they are reluctant to increase drug doses or initiate second- and Renin inhibitor/ARB
third-line combination therapy.52 Renin inhibitor/ACE-Inhibitor
The issues surrounding these observations are complex. Clearly RAS inhibitor/beta-blocker
lack of education and failure to appreciate the importance of CCB (non-dihydropyridine)/beta-blocker
lowering blood pressure to targets to prevent cardiovascular Centrally acting agent/beta-blocker
outcomes associated with uncontrolled blood pressure are impor-
tant issues. The historical focus on diastolic pressure as the basis
for initiation of therapy and as a treatment target is another. In
practice, diastolic targets of ,90 mmHg are far more commonly often the norm rather than the exception. In hypertension, the
attained than systolic targets of ,160 mmHg.53 underlying rationale for combination therapy is somewhat differ-
Lastly, and importantly, true therapeutic inertia—the reluctance ent. Since we do not know the cause of the blood pressure
to change medications when faced with a patient whose blood elevation, therapy is essentially blind and a shotgun approach
pressures remain above goals. Excuses such as the following may be more efficacious than targeted therapy. This is particularly
example—‘It’s a little bit higher today (cold weather, rush to true because monotherapy invariably triggers a variety of counter
clinic, stress at work, domestic problems etc) but we will see regulatory mechanisms which are mitigated by combination
what it’s like in a few weeks/months time’ are all too frequent. therapy. Thus, a strong case can be made for the early introduction
This major problem can be overcome (as we observe in trials) of combination therapy and conceivably, the time will come when
when physicians or nurses are obliged to follow goal directed combination therapy in low doses will be the preferred option for
treatment algorithms dictated by a trial protocol, and when first-line treatment in patients with hypertension.
‘excuses’ cannot be made to avoid changes in medications when
blood pressures are not at target. Take home message and
An alternative scheme, practised in the UK since 2004, has been
recommendations
to remunerate doctors based on the extent to which they achieve
(1) Many, if not most patients, need two or more drugs from
a number of clinical targets, one of which is dictated by the pro-
different classes to achieve blood pressure control.
portion of their hypertensive patients whose blood pressures are
(2) Combination therapy should be initiated if the patient’s blood
lowered to an audit standard of ,150/90 mmHg. This has contrib-
pressure is .20/10 mmHg above target level unless cardiovas-
uted to improvements in the levels of blood pressure control in
cular status is brittle.
the population and has been accompanied by the increasing use
(3) Preferred or acceptable two drug combinations should be
of combination therapies.54
used (Table 1).
Conclusions (4) Whenever convenience and cost outweigh other consider-
ations fixed-dose combinations rather than individual drugs
The use of combinations of drugs in therapeutic practice is
should be used.
common place in contemporary medicine in a wide variety of
disease categories, for example, in infectious disease, to cover mul-
tiple organisms and to overcome drug resistance; in respiratory Conflict of interest: P.S.S. has received grant income and honor-
illness such as chronic bronchitis or asthma to target multiple aria from Pfizer and Servier. F.H.M. is an ad hoc consultant for the
pathophysiological mechanisms of disease and in neurological con- following organizations: Novartis, Daiichi Sankyo, Pfizer, Takeda,
ditions to interfere with different abnormalities of neurotransmit- Abbott. F.H.M. received grant support from Forest, Daiichi
ter function. In fact throughout medicine, combination therapy is Sankyo and Boehringer Ingelheim.

9. To uptitrate, to substitute, or to combine drugs 2506a
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