Review
Blood pressure control in hypertension. Pros and cons
of available treatment strategies
Giuseppe Mancia a,b, Federico Rea c, Cesare Cuspidi b,d, Guido Grassi d,e, and Giovanni Corrao c
The low rate of blood pressure (BP) control that
characterizes the hypertensive population in real life is
traditionally associated to factors such as low adherence of
patients to the prescribed treatment regimen, physicians’
therapeutic inertia, and deficiencies of the healthcare
systems. This study will focus on a fourth factor that may
also be importantly involved, i.e. reluctance to adopt drug
treatment strategies that more effectively reduce an
elevated BP. The point will be made that, vis-à-vis
strategies based on patients’ persistence in monotherapy,
drug combinations are accompanied by a much more
frequent BP control. In particular, it will be argued that
compared with the administration of additional drugs after
initial monotherapy, use of combination treatment from
the beginning may carry important advantages, such as a
faster BP control, and thus an earlier protection in patients
at a high cardiovascular risk and a better adherence to the
prescribed drugs and thus a more frequent long-term
achievement of target BP values, possibly also with a more
effective cardiovascular protection. This may justify a more
clear support of this treatment strategy by future
guidelines, in the attempt to lessen the contribution of
hypertension to cardiovascular disease and death.
Keywords: blood pressure control, cardiovascular
prevention, combination treatment, hypertension
Abbreviation: BP, blood pressure
INTRODUCTION
A
large number of studies provides evidence that in
medical practice hypertension achieves therapeutic
control, i.e. blood pressure (BP) is reduced below
the target recommended by major guidelines [1,2] in only a
small fraction of the hypertensive population [3]. The pro-
portion of patients in whom BP control is achieved can be
particularly small in developing countries, but control is far
from being satisfactory in industrialized affluent nations as
well [3,4]. In European nations, for example, the percentage
of patients in whom BP is reduced to less than140/90 mmHg
(the target recommended by the European guidelines) [1] is
rarely reported to be greater than 30% of the individuals
diagnosed as having a BP elevation [1]. The BP control rate
is also low if ambulatory BP is selected as the target because
of the difficulty of effectively reducing BP over the day and
night, including the hours farthest from the antihyperten-
sive drug administration [5,6]. BP control sinks to an
Journal of Hypertension
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
extremely low level when more aggressive BP targets are
pursued, such as less than 130/80 mmHg in patients with
diabetes or an otherwise high cardiovascular risk condition.
An example was offered years ago by the data on the
diabetic component of a large Italian hypertensive popu-
lation [7]. The diabetic patients in which BP was reduced to
less than 140/90 mmHg were 14.9%, whereas only 3.0%
reached less than 130/90 mmHg, i.e. the value recom-
mended as the optimal target for individuals with combined
diabetes and high BP at the time the study was performed
[8].
There is a general agreement that absence of BP control
in real life hypertensive patients has an ominous reflection
on public health, representing the main reason for the
persistent position of hypertension as the first cause of
death and burden of disease worldwide [9]. This is because
a noticeable number of ‘uncontrolled’ hypertensive indi-
viduals does not exhibit BP values just above but markedly
above target. Namely, their ineffective treatment keeps
them not in grade I but also in grade II or III hypertension,
the combination of a modestly and badly uncontrolled
high-BP state [10] accounting for the observation that there
is not much difference in survival between these patients
and those who have never been treated [11]. Improving BP
control is thus unquestionably a goal of fundamental
importance for cardiovascular prevention worldwide.
Years of research have clarified that deficiencies of
healthcare systems, physicians’ failure to react with appro-
priate treatment changes to an uncontrolled BP status
(therapeutic inertia) and low adherence to the prescribed
lifestyle and antihypertensive drug prescriptions all heavily
contribute to the low rate of BP control in the hypertensive
population [1,12,13]. This study will focus on a fourth
contributing factor, namely the limited use of treatment
strategies that may better guarantee the highest rate of
successful treatment in the context of routine medical
practice. Because not all guidelines offer detailed advice
Journal of Hypertension 2017, 35:225–233
a
University of Milano-Bicocca, bIRCCS Istituto Auxologico Italiano, Italy, cDivision of
Biostatistics, Epidemiology and Public Health, Department of Statistics and Quanti-
tative Methods, dDepartment of Health Sciences, University of Milano-Bicocca and
e
IRCCS Multimedica, Sesto San Giovanni, Milan, Italy
Correspondence to Professor Giuseppe Mancia, Piazza dei Daini, 4, 20126 Milano,
Italy. Tel: +39 3474327142; e-mail: giuseppe.mancia@unimib.it
Received 7 July 2016 Revised 4 September 2016 Accepted 12 October 2016
J Hypertens 35:225–233 Copyright ß 2017 Wolters Kluwer Health, Inc. All rights
reserved.
DOI:10.1097/HJH.0000000000001181
www.jhypertension.com 225
Mancia et al.
on the advantages and disadvantages of available treatment
options to the practicing physician [1,2,14,15] the topic has
considerable practical interest. This is particularly the case
for the treatment strategy based on initial use of two
antihypertensive drugs on which new favourable evidence
has been recently obtained.
Monotherapy at increasing doses
The guidelines issued decades ago recommended to fully
exploit the antihypertensive potential of an initial mono-
therapy before moving to or adding another drug [16]. In
other words, they advised to try to achieve BP control by
increasing the dose of the initial drug employed until no
greater BP response was obtained. However, it is now well
established that a progressive increase in the dose of the
administered antihypertensive drugs increases their anti-
hypertensive effect at the price of a much greater increase in
the rate of side-effects, particularly when thiazide diuretics,
calcium channel blockers, and b-blockers are used [17].
Because in real life side-effects are the most important cause
of treatment discontinuation [18] and treatment discontinu-
ation is closely associated with an increased risk of events
[19,20], this treatment strategy cannot anymore be recom-
mended and should indeed be regarded as obsolete, except
when therapeutic caution requires initial administration of a
small drug dose to be later increased to the one known to be
more effective. This may be the case in very elderly patients
in whom an impairment of the mechanisms involved in BP
homeostasis increases the risk of hypotensive episodes, a
further increase being possible by an excessive drug-
generated BP-lowering effect. It has recently been shown
that in the very elderly patient this may have serious
consequences, such as an increase of hospitalization for
hip fractures, which at an advanced age carries a high risk of
ending in a fatal event [21].
Sequential monotherapy
Sequential monotherapy refers to a strategy based on
switching from one monotherapy to another in the attempt
to find the single drug, which reduces BP to control values.
This has a therapeutic rationale because the magnitude of
the BP response to one drug class does not bear a significant
relationship with that to another class [22]. That is, patients
unresponsive or responsive to drugs from different classes
are by no means superimposable. It has, in principle, other
advantages such as that expanding the fraction of the
population under monotherapy may limit drug-related
costs as well as side effect-related incidence because si-
de-effects may occur more frequently with multiple drug
administration. However, as emphasized by the European
guidelines [1], sequential monotherapy is a time consuming
strategy because it may take weeks or months to decide
whether a drug is or is not effective. This may lead patients
to develop frustration, reduce their confidence in the phys-
ician, and ultimately favour low adherence to if not dis-
continuation of treatment. Furthermore, even when high
doses are used, monotherapies are known to be unable to
effectively reduce BP in many hypertensive patients and to
only achieve BP control in just a minor fraction of them,
particularly under circumstances in which treatment is
especially difficult, such as in diabetes and isolated systolic
226 www.jhypertension.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
hypertension [23]. In a study on isolated systolic hyperten-
sion, for example, only one third to one fourth of the
patients achieved BP control by monotherapy, no matter
which antihypertensive drug was employed [24]. Thus,
although necessary when no BP reduction at all is seen
or serious side-effects develop, switching from one drug to
another is not a particularly helpful strategy to improve BP
control in the hypertensive population
From initial monotherapy to later combination
treatment
At variance from the recent US guidelines [2] the European
guidelines [1] strongly support an antihypertensive treat-
ment strategy based on an initial monotherapy at an effec-
tive dose followed, if BP control is not achieved, by the
addition of other drugs. This therapeutic strategy has a
strong pathophysiological rationale, because hypertension
is almost invariably due to different pathogenetic factors
and BP is a multiregulated variable, which makes it possible
for the hypotensive influence of one drug to be modified
and even neutralized by influences acting in an opposite
direction. It is also strongly supported by the demonstration
that drug combinations have a much greater BP-lowering
effect than monotherapy in all conditions in which BP is
elevated and whatever initial monotherapy is employed
[25], the number of hypertensive patients in whom BP
control can be achieved increasing from about one third
with one drug to about two thirds of the patients with two
drugs treatment [26]. This can be usually obtained with a
lower number of visits than those required to achieve BP
control by the sequential monotherapy strategy, with a
favourable reflection also on treatment-related costs.
The large number of available antihypertensive drugs
results in many potentially usable combinations of two
antihypertensive agents. According to the European guide-
lines, [1] recommended combinations should fit the follow-
ing criteria. One, the included drugs should lower BP
through different and complementary mechanisms of
action. Two, the BP-lowering effect of the combination
should be significantly greater than that of the combination
components, and ideally similar to or even greater than
their sum [17]. Three, the combination should have a
favourable tolerability profile, i.e. its side-effects should
not be more frequent than those due to the combination
components to avoid treatment discontinuation, which
depends primarily on side-effects [27] and is followed by
a marked increase of cardiovascular and all-cause mortality
[19,28]. Four, there should be evidence that use of the
combination leads to an improvement of hypertension-
related organ damage and a reduction in the risk of car-
diovascular outcomes. Although rarely tested via random-
ized trial designs, the protective effect of various two drug
combinations against cardiovascular outcomes has been
repeatedly documented in trials in which patients were
under the effect of two rather than one drug for most of the
trial duration. This has been the basis for the European
guidelines to define as preferred two drug treatments of
hypertension an angiotensin-converting enzyme (ACE)-
inhibitor or an angiotensin receptor antagonist with a
diuretic (thiazide, thiazide like, or indapamide), an ACE-
inhibitor or an angiotensin receptor antagonist with a
Volume 35  Number 2  February 2017

calcium channel blocker, and a calcium channel blocker
with a diuretic. Guidelines also mention that other combi-
nations can be used, (for example, an ACE-inhibitor and a
b-blocker in hypertensive patients with coronary disease)
whereas discouraging the concomitant administration of
an ACE inhibitor and an angiotensin receptor antagonist
because of the inconveniences exhibited in outcome trials
[29,30]. Despite its successful use in many old trials, the
association of b-blocker and diuretic is not recommended
for priorital use because of its greater risk of causing new
onset diabetes [31], with thus a possible long-term attenu-
ation of the earlier benefit.
The combination treatment strategy does not only con-
sist of adding a second drug to the initial monotherapy, but
also of moving from two to three as well as from three to
four or more antihypertensive agents. Three antihyperten-
sive drugs are regarded as necessary in about one fourth of
hypertensive patients, although clinical trials suggest that
their administration may usefully extend to no less than 30–
40% of individuals with a BP elevation [32–34], their num-
ber showing a progressive increase when treatment is
prolonged for years [35]. If drugs with different mechanisms
of action (a diuretic, a blocker of the renin-angiotensin
system, and a calcium channel blocker) are employed the
antihypertensive effect clearly exceeds that of a two-drug
combination [36] with SBP falls of 30 mmHg or more in
patients with severe hypertension [36]. This makes a three
drug regimen an important treatment option to consider
when BP is markedly above normal or achieving BP control
is particularly difficult such as in diabetes [37]. Recently, a
‘post hoc’ analysis of the data from the Action in Diabetes
and Vascular Disease: PreterAx and Diamicron MI Con-
trolled Evaluation (ADVANCE) trial has shown that in this
condition the combined administration of indapamide,
perindopril, and a calcium channel blocker was accom-
panied by a lower incidence of cardiovascular events
compared with use of one or two combination components
only [38]. There is thus observational evidence that the
greater BP reduction accompanying a three drug treatment
strategy translates into a greater cardiovascular protective
effect.
A BP reduction can be obtained also by administering
further antihypertensive agents to patients in whom BP
remains uncontrolled with a three-drug regimen [39], the so
called resistant hypertensive patients [1]. Unfortunately, no
evidence is yet available that in these individuals the
resulting BP reduction reduces cardiovascular and/or renal
diseases, thereby excluding the possibility that the long-
standing risk elevation characterizing these patients makes
the risk therapeutically irreversible [40].
Two-drug combination as first step
The last two European guidelines [1,41] list a fourth possible
strategy to lower BP in hypertensive patients, namely initial
administration of two drugs with, if BP control is not
achieved, a subsequent uptitration to a greater dose of
one or both combination components followed by the
addition of a third drug. Guidelines acknowledge that an
initial two drugs administration has the disadvantage that
(1) patients who would achieve BP control with one drug
only are unnecessarily exposed to the cost and potential
Journal of Hypertension
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Initial combination treatment
side-effects of a second medication; (2) in patients with only
a modest BP elevation, two drugs may lead to an excessive
BP reduction, with a potential underperfusion of vital
organs and a greater risk of fall-related traumas [21,42],
which has led some guidelines to recommend its use only
when BP is at least 160/100 mmHg [14]; and (3) adminis-
tration of two drugs may adversely affect adherence to
treatment, which is inversely related to the daily number
of prescribed tablets [43]. It should be emphasized, how-
ever, that two antihypertensive drugs can nowadays be
administered in a single tablet. There is also now evidence
that the protective effect of antihypertensive treatment does
not disappear (according to recent trials it may even be
enhanced) when BP is more markedly reduced and its on-
treatment values are less than 130/80 mmHg [44–46].
Furthermore, in the recent Heart Outcomes Prevention
Evaluation trial [47] the initial administration of a blocker
of the renin angiotensin system and a diuretic has been
found to reduce the risk of cardiovascular outcomes in
patients with grade 1 hypertension (SBP values more than
143 mmHg, average 154 mmHg). Finally, the initial admin-
istration of two drugs allows to achieve a clearcut BP
reduction earlier after treatment initiation than with mono-
therapy. This has been shown to occur in randomized
studies with different two drug combinations (ACE-inhibi-
tors plus calcium channel blockers, angiotensin receptor
antagonists plus calcium channel blockers, renin inhibitors
plus calcium channel blockers, and ACE inhibitors plus
diuretics) [48–53], which leaves no doubt that a ‘fast’ anti-
hypertensive effect as well as an earlier BP control after
treatment initiation is a consistent feature of the initial
combination treatment strategy vs. the strategy that makes
use of a second drug only after a time interval under
monotherapy.
As listed in Table 1 a ‘fast’ antihypertensive effect may
have important clinical advantages. First, several random-
ized trials have established that cardiovascular protection
becomes visible shortly after antihypertensive treatment
initiation [54–58], which means that faster BP reductions
may be associated with a more timely and by and large
greater protective effect. This can be clinically relevant in
individuals with a high cardiovascular risk (the condition in
which, according to the European guidelines initial com-
bination treatment should be considered) in whom the
chance of an event may not be negligible also when
projected over short-time periods, which is incidentally
the reason why studying high cardiovascular risk patients
by designs that include placebo treatments are not allowed
by Ethical Committees even when the period under
placebo is short. Indeed, a ‘post hoc’ analysis of a large
trial on high cardiovascular risk hypertensive patients has
TABLE 1. Possible advantages of the ‘faster’ blood pressure
control associated with initial combination treatment
Titration phase shorter and with less visits
Earlier protective effect (important in patients at high cardiovascular risk)
Better long-term adherence to the prescribed treatment
Better long-term BP control
Greater long-term CV protection
BP, blood pressure.
www.jhypertension.com 227
Mancia et al.

Probability of
blood pressure
control International double-blind RVT n = 1757

1.0
100 6.1%
P < 0.001

0.8
80 +27% 59
% Controlled patients

83
+23% 6.0%

0.6
60 P = 0.014
8.9%

0.5
58
P < 0.001 52
6.1%

0.4
40 P = 0.005 43
33 34 –20% time

0.2
20 27
Per/amlo
Val ± amlo
0

0.0
1 Month 2 Month 3 Month 6 Month 30 45 60 74 93 105 120 135 150 165 180
Time (days)

Probability of blood pressure control using perindopril/amlodipine and valartan + amlodipine,

Valsartan ± Amoldipine (stepped-care straegy) Perindopril / amlodipine (combo as 1st step) over a 6-month period

FIGURE 1 The left panel shows the percentage of patients with blood pressure controlled (< 140/90 mmHg) whereas the right panel shows the actual time to control in
patients treated by a strategy based on initial administration of two drugs in a single tablet (perindopril plus amlodipine) vs. a strategy based on initial monotherapy
(valsartan) followed by the addition of amlodipine. Reproduced with permission from [48,60].

shown that failure to control BP for just one month had an of treatment was around 30% greater when treatment
adverse reflection on patient prognosis [59]. Second, started with two drugs than when drug combination fol-
achieving BP control earlier after treatment initiation lowed a single drug administration, or a sequential mono-
reduces the number of visits to be performed to finalize therapy approach was used [61]. In 2104 Canadian
the proper long-term therapy, making the titration phase hypertensive patients the group with first step combination
more effective within a shorter time interval. To quote some treatment with adapted dosages showed, after 6 months,
examples, in a randomized study on patients with moderate greater BP reduction and a better efficacy/tolerability ratio
hypertension the SBP reduction seen after 2 weeks was 35– (absolute difference 5.2 mmHg SBP, P ¼ 0.02) compared
47% greater with an initial administration of an angiotensin with the group starting treatment with monotherapies and
receptor antagonist and a calcium channel blocker than switching to their combination only at a later time [62].
with the corresponding monotherapy-based strategies, the Finally, that initial combination treatment may improve
difference remaining visible (26–39%) after an additional 6- long-term BP has been shown also by studies on patients
week period [49]. The BP reduction was considerably more managed in real-life conditions. In a retrospective analysis
pronounced up to a 16 weeks of treatment in a study in of the data from about 1700 hypertensive patients Gradman
which initial monotherapies were compared with the com- et al. [63] have reported that the median time to BP control
bination of a renin inhibitor and a calcium channel blocker was significantly shorter (9.7 vs. 11.9 months; P ¼ 0.004) in
[50]. The initial combination treatment with adapted doses the group which was treated initially with a drug combi-
for first line use of an ACE-inhibitor and a calcium channel nation than in the one which was switched to a combination
blocker reduced the time needed to achieve BP control by after monotherapy (Fig. 2, left panel), the reduction of the
20% (74 vs. 93 days) compared with first step monothera- time required to reach BP control amounting to 18.5%.
pies [48,60] (Fig. 1). Shortening the titration phase may have Furthermore, using a large database from US hypertensive
favourable psychological consequences for the patient patients (more than 100,000) Egan et al. [64] have found that
(confidence in physician’s expertise, reduction of anxiety, in patients starting treatment with a drug combination the
etc) whereas reduction of the number of visits can reduce chance of achieving BP control after one year was 35%
costs and the ‘therapeutic inertia’ that not infrequently greater. Interestingly, a greater increase (53%) was exhib-
makes physicians reluctant to upgrade treatment when ited by patients in whom fixed dose rather than free
faced with BP values in need of treatment intensification combinations were used (Fig. 3). This is known to be
[13], ultimately contributing to the long-term persistence of because of the favourable effect of treatment simplification
an uncontrolled hypertension. on adherence to the prescribed treatment regimen [43]. It
Third, studies performed in recent years suggest that can additionally be because of the fact that a potential
‘fast’ BP control, as obtained by initial combination treat- disadvantage of having multiple drugs in one tablet, i.e.
ment, may have also advantages that extend to the chronic inability to selectively increase the dose of one combination
antihypertensive treatment phase and potentially include component only, has now been minimized by the avail-
patients belonging to lower cardiovascular risk strata. ability of single-pill combinations with different doses.
Although in some randomized double-blind studies, Some recent evidence has also been obtained on the
patients moving to combination treatment after initial reasons that are likely to explain why starting treatment
monotherapy ultimately achieved BP values and control with a drug combination may improve long-term BP con-
rates similar to those achieved by patients under initial trol. Using a large administrative database from the Lom-
combination treatment [49,50], in others [51,52,60] the ear- bardy Region, Corrao et al. [12] measured treatment
lier BP difference in favour of the initial combination group discontinuation by patients’ failure to renew an antihyper-
was still visible for a long time after treatment initiation. To tensive drug prescription after its expiration. Treatment
mention further examples, in 533 European hypertensive discontinuation was found to be markedly influenced by
patients, the chance of achieving BP control after 9 months several factors, including the type of drugs employed

228 www.jhypertension.com Volume 35  Number 2  February 2017

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

 Initial combination treatment

Incidence rate
(combination T IRR
vs. add-on) (95% CI) P-Value
% of patients reaching target BP

100 Acute myocardial 0.45 vs. 0.99 0.19 <0.0001

infarction (0.10–0.34)
80 Stroke/TIA 2.57 vs. 2.84 0.79 0.1172
(0.59–1.06)
60
Hospitalization for 0.55 vs. 0.78 0.54 0.0311
heart failure (0.31–0.95)
40 Log-Rank P = 0.0040
Overall 3.34 vs. 4.10 0.62 0.0002
(0.48–0.80)
20
Overall 3.58 vs. 4.28 0.66 0.0008
0 (with death) (0.52–0.84)
0 6 12 18 24 30 36
Time in months 0 0.25 0.5 0.75 1.0 1.25
Combination T Add-on
Combination therapy better better
Add-on

FIGURE 2 The left panel shows the cumulative achievement of blood pressure (BP) target (< 140/90 mmHg) in patients starting treatment with drug combination or with
monotherapy with later switching to combination treatment. The right panel shows the incidence rate ratio (IRR) of cardiovascular events in the two groups. Retrospective
analysis of about 1700 patients in which initial combination treatment cases were matched with cases in which combination treatment was used as add-on to an initial
60 days of monotherapy. Reproduced with permission from [62].

[12,65]. In two large cohorts (about half a million patients
each), however, discontinuation was significantly less in
patients initiating antihypertensive treatment with more
than one drug than in those with initial monotherapy, both
when the comparison was made between combinations
including a diuretic vs diuretic monotherapy and, to a lesser
but significant degree, when it was made between combi-
nation therapies without a diuretic and monotherapies
other than a diuretic (Fig. 4) [65,66].
Although no randomized trial has compared the out-
come incidence and risk of treatment strategies based on
initial drug combinations and monotherapies several con-
siderations support the contention that the advantages of
the former approach lead to a greater protective effect. First,
adherence to treatment is known to bear a close relation-
ship with the rate of BP control [67]. Second, multiple
evidence exists that the level of adherence is a powerful
determinant of the protective effect of treatments in real life
[68], including treatments aimed at reducing an elevated BP
[19,20–69,70]. Finally, the protective effect of starting anti-
hypertensive drug treatment with a combination has been
recently observed in two observational studies. In a com-
munity-based, case-controlled study of 209 650 newly
treated hypertensive patients, starting and continuing
antihypertensive therapy with a drug combination was
associated with a 26% significant reduction in cardiovas-
cular risk compared with patients adopting all other treat-
ment options, i.e. starting and continuing treatment with a
single drug, moving to a combination after monotherapy or
returning to monotherapy after an initial use of a combi-
nation (Fig. 5) [71]. Similar conclusions have been reached
by the study in which BP control was found to be delayed in
patients under initial as compared to those under sub-
sequent combination treatment [63]. The risk of cardiovas-
cular events or mortality was 34% lower in the former
group, the time to achieve BP control being significantly
shorter in the event-free patients than that in patients who
experienced a cardiovascular event (10.6 vs. 15.8 months;
P ¼ 0.001) (Fig. 2, right panel)
Combination treatment in medical practice
Clinical trials aimed at reducing BP to less than 140/
90 mmHg or lower values show that at the end of the
on-treatment period patients were on average under two
antihypertensive drugs or more, leaving no doubt as to the
importance of combination treatment to achieve BP control
[72]. Support also comes from real-life data which show
greater use of combination treatment to parallel an increase

Initial TP n Hazard ratio Hazard ratio

(95% CI) (95% CI)

Monotherapy 79099 Ref

Free combination 18329 1.34 (1.31–1.37)

Single pill combination 9194 1.53 (1.47–1.58)

0.5 1 2
BP control worse BP control better
with combination with combination
FIGURE 3 Increased chance of blood pressure (BP) control over 1 year in patients starting treatment with one drug or with free or single pill combinations. CI: confidence
interval. Reproduced with permission from [63].

Journal of Hypertension www.jhypertension.com 229

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Mancia et al.

Combo with D Combo with D Combo with D Combo with D

vs vs vs vs
D mono non-D mono D mono non-D mono
0 0

12-month discontinuation with

9-month discontinuation with
–20 –20

≤ 2 drug treatment

≥ 2 drug treatment
*
–40 –30 –40
*
–41

–60 –60 *
* –57
–62
–80 –80

FIGURE 4 Reduction of treatment discontinuation (failure to renew an antihypertensive drug prescription for  three months) in patients starting treatment with drug
combinations (combo) vs monotherapy. The reduction is shown for combinations including a diuretic vs diuretic monotherapy or for combinations not including a diuretic
vs a monotherapy other than a diuretic. Treatment discontinuation was assessed over a follow-up of 9 or 12 months. Reproduced with permission from [65,66]. D,
diuretic. P < 0.0001 vs monotherapy.

Initial FU OR*
Mono Mono
Mono Combo
Combo Mono
Combo Combo
0.5 1.0
FIGURE 5 Effect of different blood pressure lowering strategies on the adjusted
risk of hospitalization for coronary and cerebrovascular events in 2.009.650
patients from the Lombardy data base. OR: odds ratio; Mono: monotherapy;
Combo: combination treatment; FU: follow-up; Numbers in parentheses refer to
95% confidence intervals. Reproduced with permission from [70]. Adjusted for
age / gender / number of BP lowering drug classes during FU / concomitant use of
drugs for cariovascular diseae and diabetes.
in the BP control rate. Yet, in clinical practice combination
of antihypertensive drugs is by no means the most fre-
quently prescribed treatment type. Taking data from Italy as
an example, in the 8299 patients with an uncontrolled
hypertension of the Studio Italiano sulla Gestione dell’I-
perTensione (DIGIT) study drug combinations were the
most frequent type of treatment (63.2%) [73], this being the
case also in the 2775 patients followed by specialist phys-
icians in the Studio Italiano Longitiudinale sulla Valutazione
della pertensione ARteriosa nel 2000 (SILVIA) study (56.9%)
1.00 (0.91–1.10)
[74]. In the population of the small San Marino Republic
(n ¼ 7036), on the other hand, the hypertensive patients
0.96 (0.86–1.07)
under two or more drugs were only 46.3% [75], even lower
0.74 (0.65–0.85)
proportions being found in the Italian population from the
2.0 Brisighella town, in which the number of patients admin-
istered antihypertensive polytherapy, albeit increasing from
the extremely low values seen in the early 90s (about 15%)
[76], has remained only slightly greater than 40% in 2009
(Borghi C, personal communication). Low rates of antihy-
pertensive polytherapy have similarly been observed in an
analysis of the population of the Lombardy region (about 10
million), i.e 34.5, 35.8 and 46.8%. The total number of
patients receiving antihypertensive drug prescriptions in
1999, 2005 and 2011, respectively (Corrao G et al., unpub-
lished data). It is important to note that a much smaller
fraction of these patients makes use of drugs combination
as the initial treatment strategy. As shown in Fig. 6, in 2005
the Lombardy patients aged 50–70 years who exhibited no
evidence of cardiovascular disease (no hospitalizations or

Monotherapy Combination Therapy

80 75.3
72.9
70

60

50

% 40
30 27.1
24.7
Free
20 22.2 combination
19.8
10 Single pill
combination
0
2005 2010 2005 2010
(n = 46955) (n = 48466) (n = 46955) (n = 48466)
FIGURE 6 Initial antihypertensive treatment strategy in the Lombardy population. Data were obtained from the Lombardy data-base, limited to subjects aged 50 to 70 years
with an antihypertensive drug prescription and a follow-up of 1 year. Patients were selected for analysis if they had no hospitalization for cardiovascular diseases and no
co-treatment with other cardiovascular drugs in the 5 year preceding the initial prescription. Patients were analysed if they had more than one prescription over the
follow-up period to avoid inclusion of patients with occasional prescriptions only.

230 www.jhypertension.com Volume 35  Number 2  February 2017

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


cotreatments with other cardiovascular drugs in the pre-
ceding 5 years), started antihypertensive treatment with a
combination of two or more drugs in only about one-
quarter of the cases, those making use of single-pill com-
binations being the vast majority. Their number showed, if
anything, a slight reduction 5 years later, indicating that
there is a long way to go before making this treatment
strategy common.
In conclusion, the data reviewed herein confirm that
combination treatment has several important advantages
over monotherapy of hypertension. They also show that
initiating treatment with a combination of antihypertensive
drugs is associated with a faster BP reduction, and suggest,
through the evidence obtained in observational studies,
that this may carry both short-term and long-term advan-
tages, that is, a more timely protection of high cardiovas-
cular risk patients, an improved adherence to treatment, a
persistently more frequent BP control, and a greater
reduction of cardiovascular events. Future research will
have to better clarify the factors responsible for these effects
(favourable psychological impact on the patient, improved
doctor–patient relationship, reduction of doctor’s inertia,
etc) whereas randomized outcome-based trials comparing
initial (especially single tablet) with subsequent combi-
nation treatment will have to unequivocally prove the
benefit and give it a more firm quantitative basis. We
suggest, however,that already at this stage the evidence
available supports a larger use of first line combination
treatment in the hypertensive population to improve on the
currently low rate of therapeutic BP control.
ACKNOWLEDGEMENTS
Conflicts of interest
G.M. has received honoraria for participation in inter-
national meetings from Actavis, Amgen, Bayer, Boehringer
Ingelheim, CVRx, Daiichi Sankyo, Medtronic, Memarini,
Merck, Novartis, Recordati, Sanofi, Servier.
G.G. has received fees for lectures from Merck
and Recordati.
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Reviewers’ Summary Evaluations
Referee 1
Strengths and limitations.
This study compares the advantages and disadvantages
of different antihypertensive drug treatment strategies, and
makes a documented case for combination treatment as an
initial treatment option, which is scarcely implemented in
current clinical practice. The study is interesting, since there
still remains uncertainty on best options to address different
patient situations, relevant given the relatively poor degree
of BP control achieved in routine clinical practice, and
timely because not all current guidelines discuss this topic
in detail and offer clear options with a few exceptions.
Journal of Hypertension
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Initial combination treatment
71. Corrao G, Nicotra F, Parodi A, Zambon A, Heiman F, Merlino L, et al.
Cardiovascular protection by initial and subsequent combination of anti-
hypertensive drugs in daily life practice. Hypertension 2011; 58:566–572.
72. Bakris GL. The importance of blood pressure control in the patient with
diabetes. Am J Med 2004; 116 (Suppl 5A):30S–38S.
73. Giannattasio C, Cairo M, Cesana F, Alloni M, Sormani P, Colombo G,
et al. Blood pressure control in Italian essential hypertensives treated
by general practitioners. Am J Hypertens 2012; 25:1182–1187.
74. Mancia G, Pessina AC, Trimarco B, Grassi G, SILVIA (Studio Italiano
Longitudinale sulla Valutazione della Ipertensione Arteriosa nel 2000)
Study Group. Blood pressure control according to new guidelines
targets in low- to high-risk hypertensives managed in specialist prac-
tice. J Hypertens 2004; 22:2387–2396.
75. Mancia G, Parati G, Borghi C, Ghironzi G, Andriani E, Marinelli L, et al.,
SMOOTH investigators. Hypertension prevalence, awareness, control
and association with metabolic abnormalities in the San Marino popu-
lation: the SMOOTH study. J Hypertens 2006; 24:837–843.
76. Borghi C, Dormi A, D’Addato S, Gaddi A, Ambrosioni E, Brisighella
Heart Study Working Party. Trends in blood pressure control and
antihypertensive treatment in clinical practice: the Brisighella Heart
Study. J Hypertens 2004; 22:1707–1716.
However, trial-based evidence is still lacking on the effect of
initial combo (especially single-pill) vs other treatment
options in relation to cardiovascular risk.
Referee 2
The strength of this review, is that it addresses an issue of
great clinical importance - what are the best clinical strat-
egies for reaching blood pressure targets? In the end of the
day, this question is one of the most important issues in
hypertension treatment today. The weakness is the lack of
trials with cardiovascular outcomes in this area, but the
review explores this issue as far as it is possible with
available data.
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