PERSONAL REVIEW

Combination of antihypertensive drugs from a historical perspective

PETER A. VAN ZWIETEN1 & CSABA FARSANG2

1Departments of Pharmacotherapy, Cardiology and Cardio-Thoracic Surgery, Academic Medical Center (G4-230),

Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands, and 21st Department of Medicine, Semmelweis University,

Koranyi S.u. 2/a. H-1083 Budapest, Hungary

Introduction

Like many of our colleagues who have been actively

involved in the drug treatment of hypertensive

disease for several decades, we experienced the

development and maturation of drug treatment over

the years. There is no doubt that the older drugs,

such as ganglionic blockers and post-ganglionic

sympathetic neuron-blocker Rauwolfia alkaloids,

were effective in lowering elevated blood pressure

(BP), but their poor tolerability made them obsolete

after the introduction of low-dose diuretics, beta-

blockers, calcium antagonists, angiotensin-convert-

ing enzyme (ACE) inhibitors and angiotensin II-

receptor antagonists (AT1-blockers, ARBs), which

are also effective but usually well tolerated.

Antihypertensive drug development is a medical

success story and there has been a substantial

improvement in drug therapy over the years. As

scientists, we are also grateful for the important

scientific spin-offs offered by the various available

antihypertensive drugs, which has greatly enhanced

our detailed knowledge of the autonomic nervous

system, the central nervous regulation of the

cardiovascular system, kidney function, the renin–

angiotensin–aldosterone system (RAAS) and cal-

cium homeostasis. We both feel that the beneficial

influence of this success story of pharmacological

research is not sufficiently recognized by the medical

profession. Until approximately a decade ago,

monotherapy with one particular drug was the gold

standard of treatment. However, our own experi-

ence, and also that of many others, rather pointed

towards the preferential use of two or even three

drugs simultaneously in order to obtain a satisfactory

control of BP in most patients. Indeed, antihyper-

tensive drugs, which are usually applied for the

remaining years of life, are now rarely administered

alone and in most cases combined with other

therapeutic agents. Firstly, monotherapy of hyper-

tension is shifting more and more towards combina-

tion with two or three antihypertensive drugs.

Furthermore, rising age and frequent comorbidity

of hypertensives will lead to the simultaneous

administration of other therapeutic agents.

Consequently, ‘‘polypharmacy’’ of the average

hypertensive patient is rather the rule than the

exception.

We have briefly discussed these two subjects by

means of two newsletters published in this journal

(1,2). The present survey deals with these issues in

more detail, addressing in particular the combina-

tion of two or more antihypertensive drugs in the

management of hypertension. Relevant interactions

between antihypertensive drugs and other therapeu-

tic agents prescribed simultaneously have been

discussed in detail in one of the two aforementioned

newsletters (1).

How to combine antihypertensive drugs

The rationale for combining two or three antihypertensive

drugs

As demonstrated by numerous small- and large-scale

intervention studies, approximately half of the

patients with essential hypertension can be satisfac-

torily controlled by a single drug (monotherapy).

Correspondence: P. A. van Zwieten, Departments of Pharmacotherapy, Cardiology and Cardio-Thoracic Surgery, Academic Medical Center (G4-230),

Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands. E-mail: hunghyp@axelero.hu

Blood Pressure. 2005; 14: 72–79

ISSN 0803-7051 print/ISSN 1651-1999 online # 2005 Taylor & Francis Group Ltd

DOI: 10.1080/08037050510008922

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This observation implies that the other half of the

patients requires a different approach in order to

achieve appropriate control of BP. To overcome this

problem, there are two potential approaches:

(i) Applying a higher dosage of the drug initially

used as monotherapy;

(ii) Addition of one (or even two) antihypertensive

drugs from a different category.

Wide clinical experience has taught us that the

second approach appears to be the better one. Until

a decade ago, the need for combination drug therapy

had long been neglected, criticized and dismissed in

academic medicine. Criticism particularly addressed

pharmaceutical preparations containing two or even

three different agents, with the argument that the

fixed-dose ratios in such tablets would exclude the

possibility of performing differential titration of

each of the components in individual patients.

However, this view has been substantially reverted

towards an appreciation and even preference of

combined treatment, as expressed in recently issued

guidelines for the management of hypertensive

disease, such as the WHO-ISH 1999 (3), ESH-

ESC 2003 (4), JNC VI (5) and JNC VII (6)

guidelines, respectively.

In most of these guidelines, combination therapy

is advocated more explicitly for certain types of

hypertensive disease such as:

N Isolated systolic hypertension (ISH);

N Accelerated hypertension;

N In patients where BP values lower than 140/

90 mmHg are required in order to prevent

(further) target organ damage (e.g. in diabetes

mellitus: v130/85 mmHg; in chronic parenchy-

matous nephropathy with proteinuria: 125/

75 mmHg), and possibly those with metabolic

syndrome;

N In those where components of the combination

exert synergistic effects not only on BP but also on

associated clinical conditions or on target organ

damage, such as left ventricular hypertrophy

(LVH), congestive heart failure (CHF), post-

stroke or coronary heart disease (CHD).

The advantages of combination therapy are obvious.

This approach allows the combination of low or even

very low doses of two drugs, thus lowering the

incidence and severity of adverse reactions. It can

also be expected that in particular drug combina-

tions the side-effects of two different drugs will

attenuate or neutralize each other. An example is the

combination of an ACE inhibitor (or AT1-blocker)

and a thiazide diuretic: one drug (the ACE inhibitor

or AT1-blocker) will raise plasma potassium levels,

whereas the other one (the diuretic) may cause lower

K+ levels.

Furthermore, the use of fixed combinations in a

single tablet is more and more appreciated, since

it significantly reduces the number of tablets

to be taken daily, thus improving patient compli-

ance, a most relevant source of insufficient ther-

apeutic efficacy in hypertensive patients. In fact,

poor patient compliance appears to be the most

frequent background of what is called ‘‘resistant

hypertension’’. Fixed-dose combinations have

recently been enriched by very-low-dose combina-

tions, which may now be considered first-line

therapy. It should be recognized, however, that

fixed-dose combinations continue to be subject to

the formerly expressed criticism that titration of

the individual antihypertensive drug cannot be

carried out. In spite of this, the aforementioned

advantages of fixed combinations largely outweigh

this criticism.

Over a period of approximately 40 years, several

combinations of antihypertensive drugs have been

studied and shown to be effective in lowering

elevated BP. In most cases, the evidence supporting

the favourable effect of such combinations is based

upon relatively small and not always randomized

studies. So far, large intervention studies have not

frequently addressed the use of combination therapy

by means of special branches. However, it should be

realized that in several large intervention studies one

or two more drugs had to be added to the original

study agent, in order to achieve appropriate BP

control in the majority of patients. For instance in

the much debated ALLHAT study, in the last year

of treatment 60% of the patients required on average

2.1 drugs to control their BP (7). Also, in somewhat

older large studies, originally designed to study the

value of monotherapy with a diuretic or a beta-

blocker, several other types of antihypertensive

agents had to be added in order to achieve

satisfactory control of BP (8). Finally, the results of

the recently published INVEST study show that the

combination of verapamil-SR+trandolapril was as

effective as that of atenolol+diuretic in patients with

hypertension and CHD (9).

Choice of drug combinations

Much of the choice of combinations of two or even

three antihypertensive drugs is based on empiricism,

modest clinical experience and theoretical argu-

ments derived from pharmacological mechanisms.

Combination of antihypertensive drugs from a historical perspective 73

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In this section, we shall discuss a series of drug

combinations, which are used or have been used in

clinical practice. Before doing so, we mention a more

rational approach, proposed by Brown et al. (10),

which is derived from the Cambridge AB/CD rule.

This approach is based upon the influence of well-

known antihypertensive drugs on the RAAS in

different groups of older versus younger patients.

Accordingly, the following categories of drugs

should be distinguished:

A. ACE inhibitor/AT1 blocker: Block or suppress

RAAS activity;

B. Beta-blocker;

C. Calcium antagonist: May stimulate RAAS

activity (short acting dihydropiridines);

D. Diuretic (thiazide): Stimulate RAAS activity.

Young Caucasian patients usually have renin-

dependent hypertension that responds well to

blockade or suppression of the RAAS activities by

angiotensin I-converting enzyme inhibition, AT1-

receptor blockade (A) or a beta-blocker (B). Most

other patients who have low-renin hypertension that

responds better to calcium-channel blockade (C) or

diuretics (D), drugs that activate the RAAS and

thus render patients responsive to the addition of

renin suppressive activity by means of A/B-type

drugs. This approach may be summarized as follows

(10):

1. Younger (v55 years) non-black patients:

Stepwise treatment schedule:

A or B

A (or B)+C or D

A+C+D

A+C+D; add either alpha-blocker,

spironolactone, or a different diuretic.

2. Older (w55 years) or African-American

patients:

Stepwise treatment schedule:

C or D

A (or B)+C or D

A+C+D

A+C+D; add either alpha-blocker,

spironolactone or other type of diuretic

We now enumerate a series of drug combinations

and discuss some of their pros and cons. Although

on pathophysiological, pharmacological and haemo-

dynamic grounds these combination schedules make

a great deal of sense, the evidence underlying these

drug associations is rather limited but partially

substantiated by epidemiological studies.

A. Thiazide diuretic+beta-blocker

These two categories of drugs, applied on a very

large scale for at least 30 years, are considered the

well proven but older approaches in the treatment of

hypertension. Their combination has long been

favoured by guidelines for patients with uncompli-

cated hypertension without target organ damage. In

the early 1990s, the use of these two types of drugs

and their combination was the subject of the well-

known meta-analysis by Collins and collaborators

(11), which continues to be quoted frequently. Later

on, this combination has been included in several

large-scale intervention studies such as STOP-1,

MRC, ALLHAT etc. (7,8). Thiazides, beta-blockers

and their combinations have long been widely

considered the evidence-based gold standard of

hypertension management, although this opinion

may now be challenged by more recent trials with

calcium antagonists, ACE inhibitors or AT1-recep-

tor blockers. A disadvantage of this combination is

the unfavourable effects on lipid metabolism and

insulin sensitivity. The latter may be the reason why

newly developed diabetes mellitus is more frequent

in patients treated by this combination, than in those

with no treatment or other combinations

(ALLHAT, ANBP-2, ARIC, ALLHAT, CAPPP,

CHARM, COMET, HOPE, INVEST, INSIGHT,

LIFE, SCOPE, ALPINE, PEACE studies).

B. Thiazide diuretic+ACE inhibitor

This combination is considered a very potent

antihypertensive medication, based upon a solid

rationale. In the previously discussed Cambridge

schedule, the ACE inhibitor blocks RAAS activity,

which is stimulated by the diuretic (10). Because of

the potent antihypertensive action of this combina-

tion, the addition of an ACE inhibitor to a diuretic

(or vice versa) should be carried out cautiously, in

order to prevent a too rapid decrease in BP. ISH,

frequently occurring in the elderly, is considered a

suitable target for the combination ACE inhibitor+-diuretic. Furthermore it should be considered that

ACE inhibitors are first-choice treatment (frequently

combined with a diuretic) in CHF. Consequently,

hypertensive patients with simultaneous CHF are

logical candidates for the treatment with the

combination ACE inhibitor+diuretic.

C. Thiazide diuretic+AT1-blocker (ARB)

On theoretical grounds, this combination resembles

the aforementioned association diuretic+ACE

inhibitor. Without any doubt, this is a potent

74 P. A. van Zwieten & C. Farsang

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BP-lowering drug combination, although the evi-

dence substantiating its beneficial actions is less

extensive than that supporting ACE inhibitor+diure-

tic. This is understandable, since the ACE inhibitors

have been used much longer than the AT1-blockers.

In the LIFE Study (12), the combination AT1-

blockers+diuretic has been proved more protective

in patients with hypertension with LVH from stroke

and from development of new diabetes mellitus than

the combination diuretic+beta-blocker. In high-risk

hypertensive patients involved in the VALUE Trial

(13), this combination was more effective in

preventing patients from having CHF or new

diabetes mellitus than the combination of a calcium

antagonist+diuretic. ISH is also a condition where

this combination should be applied and it may also

be beneficial for patients with hypertension and

CHF. Finally, it should be realized that several solid

studies have substantiated the renoprotective action

of AT1-blockers (RENAAL, IDNT, IRMA-2

Studies) in patients with hypertension and type 2

diabetes mellitus (14–16). The patients included in

these studies usually received a combination of an

AT1-blocker and a diuretic.

D. ACE inhibitor +AT1-blocker (ARB)

On theoretical grounds, this would be an attractive

combination for the more complete suppression of

the RAAS activity, attacking the system at two

different targets. The ACE inhibitor inhibits the

formation of angiotensin II, the main and noxious

effector agent of the RAAS, whereas the AT1-

blocker inhibits the various effects of angiotensin II

at the level of the AT1-receptor. However, the

intervention trials so far completed have yielded

somewhat conflicting results for this combination, at

least for the treatment of hypertension.

More convincing beneficial results have obtained

in studies concerning CHF, in particular the

CHARM investigations (17,18) and in ValHeFT

patients not receiving beta-blockers (19). Finally,

this combination can be thought of in hypertensive

patients with diabetic nephropathy (CALM Study)

as well as with glomerulonephritis (COOPERATE

study), since the combination of both types of drugs

have been shown to decrease proteinuria more than

the individual components. Accordingly, this com-

bination may display renoprotective activity.

E. Diuretic+imidazoline (11) receptor antagonist

This combination, which has not been studied on

any larger scale, can be thought of if a beta-blocker is

not indicated or cannot be added to a diuretic agent

because of contraindications.

F. Diuretic+calcium antagonist (dihydropyridine)

Both diuretics and calcium antagonists have been

demonstrated to be efficacious and beneficial in the

SHEP, SYST-EUR and Syst-China studies, respec-

tively, in patients with ISH who are mostly elderly

(20–21a). The combination of both types of drugs

therefore appears to be a logical one in ISH patients,

although appropriate epidemiological studies should

be performed for this purpose. In the recently

published VALUE trial (13), this combination was

more effective in preventing hypertensive patients

from having acute myocardial infarction (MI) than

the combination of ARB+diuretic, possibly because

of its greater antihypertensive effect during the first

6 months of the study.

G. Alpha-blocker+beta-blocker

There exists little evidence for the efficacy of this

combination. Bbeta-blockers with additional alpha-

blocking activity, such as labetalol, have been

studied for this purpose, but the alpha-component

of labetalol is very weak (22) and therefore an

inconclusive basis for studying this combination.

Carvedilol, a non-cardioselective beta-blocker with

alpha-1 adrenoceptor blocking properties, was

extensively studied in patients with CHF (NYHA I

through IV), but no conclusive evidence has

emerged for its use in hypertension. In the

COMET Trial, carvedilol was more effective in

preventing patients with CHF from having new

diabetes mellitus than the cardioselecive metoprolol.

H. Betablocker+ACE inhibitor

Although the antihypertensive effect of this combi-

nation is less than that of diuretics+beta-blockers

(7,23), it should be used in hypertensive patients

after MI, in those with CHD or with CHF. There is

hardly an argument defending this combination in

hypertensive patients without target organ damage.

I. Calcium antagonist (dihydropyridine type)+beta-

blocker

Hypertensive patients with CHD can be treated by

this combination. Both types of drugs are known to

be efficacious antihypertensive agents, but they also

display beneficial activity with respect to CHD. In a

small study, the fixed combination of the two types

Combination of antihypertensive drugs from a historical perspective 75

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of drugs (felodipine+metoprolol) was shown to

improve a patient’s therapeutic compliance (24).

J. Calcium antagonist+ACE inhibitor

This combination can be suggested for the treatment

of hypertensive patients with nephropathy, CHD

or established artherosclerosis. The combination

displays pronounced antihypertensive activity.

Ca-antagonists are known to have anti-ischaemic

activity in CHD. ACE inhibitors are proved reno-

protective, particularly in patients with diabetic

nephropathy.

Calcium antagonists, as shown for lacidipine in

the ELSA study (25), amlodipine in PREVENT

study (26), nifedipine-GITS in the INSIGHT study

(27), and verapamil in the VHAS study (27a) are

proved to display anti-atherogenic activity. For ACE

inhibitors, this effect has also been revealed

(SECURE study) (28).

A fixed combination of the calcium antagonist

verapamil and the ACE inhibitor trandolapril has

been registered in various countries (29), and

successfully used in the INVEST study, being so

far the unique experience with a fixed combination

in a large-scale, hard-endpoint investigation

involving patients with hypertension and CHD (9).

The ASCOT Study was recently stopped because

the combination of amlodipine+perindopril was

more effective in preventing patients from having

hard cardiovascular outcomes than the combi-

nation of a beta-blocker+diuretic (results not yet

published).

K. Calcium antagonist+AT1-blocker (ARB)

This combination globally resembles that of an

ACE inhibitor and a calcium antagonist, and the

beneficial effects may be expected to be similar, as an

additive synergism appears between the two compo-

nents in hypertensive patients (30). The renopro-

tective activity of ARB in type 2 diabetic patients

appears to be well established (14–16). Losartan

displays uricosuric activity (not a class effect of the

ARB), which may be advantageous in patients with

gout (31).

L. ACE inhibitor+imidazoline I1 receptor agonist

(moxonidine, rilmenidine)

Theoretically, this combination could be thought of

if it would be desirable to suppress simultaneously

the activities of both the RAAS and the sympathetic

nervous system (SNS). The antihypertensive effect

of rilmenidine was potentiated by addition of

perindopril in a long-term (2 years) VERITAS

study (32,33). The metabolic syndrome has been

proposed as a target for SNS-suppressant drugs

such as moxonidine or rilmenidine, since the

syndrome is believed to be partly the result of SNS

hyperactivity.

Figures 1 and 2, taken from the ESH-ESC

guidelines (4) demonstrate the schedule of decision

making concerning the choice of drugs, as well as a

schematic schedule visualizing the established and

less clearly applied drug combinations in the

treatment of hypertension.

Triple combinations

A few suggestions have been put forward for triple

combinations involving different antihypertensive

drugs. These combinations are put together on

merely theoretical grounds, virtually without formal

clinical evidence. Arguments in favour of the use

Figure 1. Choice between monotherapy and combination therapy.

76 P. A. van Zwieten & C. Farsang

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of one particular category of drugs are the same

as those discussed above for the components of

combinations of two different drugs. The following

drug combinations are conceivable:

M. Diuretic+beta-blockers+calcium antagonist: a very

potent combination, which could be used in treat-

ment of accelerated hypertension.

N. Diuretics +, calcium antagonists+ACE inhibitors:

potentially beneficial in the treatment of diabetic

hypertensive patients, of those with accelerated

hypertension or ISH.

O. AT1-antagonists+calcium antagonists+diuretics: this

triple combination may help reaching the target BP

(v130/85 mmHg) in hypertensive patients with

type 2 diabetes mellitus or ISH.

P. ACE inhibitors+alpha1-adrenoreceptor antagonists+i-

midazoline I1 agonists: potentially beneficial in the

treatment of diabetic hypertensive patients or for

those with metabolic syndrome, particularly when

beta-blockers are contraindicated or not well toler-

ated.

Q. ACE inhibitors+calcium antagonists+beta-blockers:

potentially beneficial in hypertensive patients with

CHD.

R. ACE inhibitors+diuretics+beta-blockers: all com-

pounds are indicated in patients with hypertension

and CHF.

The various combinations of two or three drugs and

their potential use in the management of hyperten-

sion have been listed in Table I.

Conclusions and perspectives

Our views concerning the validity of combination

therapy in the management of hypertension have

altered significantly during the past decade. The

former tendency for monotherapy as the preferred

approach is shifting more and more towards

combination therapy, and newer guidelines already

support the use of two drugs to start treatment. This

is particularly true for the very-low-dose combina-

tions such as indapamide (0.625 mg)+perindopril

(2 mg). The advantages of this combination are that

it is practically devoid of side-effects, and that a

combination of the same components with higher

doses (1.25+4 mg) is also available for continuation

of therapy when BP is not controlled with the very

low dose. The former damnation of tablets contain-

ing two or three drugs by academic medicine is

increasingly being abandoned and such preparations

are now recognized to be useful because they will

facilitate the therapeutic schedule and thus improve

patient compliance. In addition, it should be realized

that hypertensive patients, in particular the elderly,

are frequently subject to substantial comorbidity,

which usually leads to ‘‘polypharmacy’’ and rather

complex pharmacotherapeutic schedules. Any

attempts to simplify such schedules, in particular in

the elderly, should be appreciated. Furthermore, we

should seriously consider the proposition to develop

the ‘‘polypill’’ a preparation that should contain

antihypertensives, acetylsalicylic acid (ASA,

AspirinH) and a statin. Such a preparation, to be

used by subjects with significant cardiovascular risk

factors (hypertension, diabetes mellitus, smoking,

etc.), would greatly facilitate compliance with

respect to a complex pharmacotherapeutic regimen.

Figure 2. Possible combinations of different classes of antihypertensive agents.

Combination of antihypertensive drugs from a historical perspective 77

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So far, our choice of drug combination is mainly

based upon haemodynamic, metabolic and pharma-

cological criteria. It would be desirable to gather

more normal evidence for the validity of combina-

tion therapy by means of appropriate branches

within clinical trials.

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Table I. Potential use of antihypertensive combinations.

Drugs Potential use

Diuretics +beta-blockers Uncomplicated hypertension without target organ damage

Diuretics+ACE inhibitors Hypertension+CHF

Diuretics+AT1-blockers ISH+CHF; possibly ISH

Diuretics+imidazoline (I1)-receptor agonists To be used when a beta-blocker (contra-indications) cannot be

added to a diuretic

Diuretics+calcium-antagonists (dihydropyridines) ISH (usually elderly patients)

Beta-blockers+alpha-blockers Accelerated hypertension

Beta-blockers+ACE inhibitors Hypertensives: post-MI (sec. prevention), CHD, CHF

Ca-antagonist+beta-blockers Hypertension+CHD

Ca-antagonist+ACE inhibitors Hypertension+nephropathy, CHD or atherosclerosis

Ca-antagonists+AT1-blockers Hypertension+nephropathy, CHD or atherosclerosis (?)

ACE inhibitors+AT1-blockers Hypertension+nephropathy

ACE inhibitors+imidazoline (I1)-receptor agonists Patients with activated RAAS and SNS

Diuretics+beta-blockers+calcium antagonists Accelerated hypertension

Diuretics+calcium antagonists+ACE inhibitors Accelerated hypertension ISH, hypertension+diabetes mellitus

Diuretics+calcium antagonists+AT1-antagonists Accelerated hypertension ISH, hypertension+diabetes mellitus

ACE inhibitors+alpha1-blockers+imidazoline (I1)-receptor agonists Hypertension+diabetes mellitus; metabolic syndrome

ACE inhibitors+Ca-antagonists+beta-blockers Hypertension+CHD

ACE, angiotensin-converting enzyme; CHF, congestive heart failure; ISH, isolated systolic hypertension; MI, myocardial infarction; CHD,

coronary heart disease, RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system.

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