Editorial Comment
Antihypertensive treatment escalation: a three-drug
combination and why?
Costas Thomopoulos a, Helena Michalopoulou b, and Thomas Makris a
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I
n the 2018 European Society of Cardiology and Euro-
pean Society of Hypertension (ESC/ESH) guidelines for
the management of arterial hypertension [1], antihy-
pertensive treatment initiation with combination of two
drugs is recommended (step 1) for the majority of hyper-
tensive patients. The exceptions to this general rule are
patients with grade 1 hypertension and low overall cardio-
vascular risk and elderly patients with impaired physical
performance or multiple comorbidities (frailty). Another
important recommendation of the 2018 ESC/ESH guidelines
[1] is that the new blood pressure (BP) target defining
treatment goal is between 120 and 130 mmHg for SBP
and lower than 80 mmHg for DBP, at least for the subgroup
of uncomplicated hypertensive patients aged less than 65
years, whereas a less strict systolic BP target is reserved for
the elderly. When treatment target is not achieved with a
two-drug combination (preferably in a single pill), a three-
drug combination (step 2) should be introduced.
In the present issue of the Journal of Hypertension, Salam
et al. [2] through a systematic review and meta-analysis of
randomized controlled trials comparing double-drug and
triple-drug BP-lowering combinations give further support
to the guideline view that triple-drug combinations reduce
BP levels in a higher extent compared with double-drug
combinations. Indeed, in this analysis [2], triple-drug com-
binations lowered SBP/DBP by 5.4/3.2 mmHg compared
with double-drug combinations. Although the extent of
absolute BP change is strictly associated with baseline BP
levels – because of the Wilder’s principle [3] – the attained
BP difference between double and triple-drug combina-
tions was almost identical for both untreated (with higher
baseline BP) and treated (with lower baseline BP) patients.
Thus, the study by Salam et al. [2], in line with the 2018 ESC/
ESH guidelines, suggests that a double combination treat-
ment may be implemented for treatment initiation (in
Journal of Hypertension 2019, 37:1587–1589
a
Department of Cardiology, Helena Venizelou Hospital and bDepartment of Cardiol-
ogy, Metaxa Cancer Hospital, Piraeus, Greece
Correspondence to Costas Thomopoulos, MD, Department of Cardiology, 2 Helena
Venizelou Square, 11521 Athens, Greece. Tel: +30 210 6402262;
e-mail: thokos@otenet.gr
J Hypertens 37:1587–1589 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights
reserved.
DOI:10.1097/HJH.0000000000002132
Journal of Hypertension
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
previously untreated patients) because the overall observed
SBP/DBP change from baseline was quite large (i.e. 32/
19 mmHg) and this reduction was accomplished mainly
during the first 2 weeks of treatment. However, in case
of failure to achieve individualized BP targets, patients with
on-treatment uncontrolled hypertension will have an at
least further 5/3 mmHg increased BP reduction when a
triple-drug compared with a double combination is admin-
istered. Although Salam et al. [2] stressed-out that BP control
with a triple-drug combination was more frequent by 33%
[95% confidence interval (25%,41%)] compared with a
double one, the different definitions of BP control across
selected studies together with the age-related ‘moving BP
targets’ adopted in the current guidelines [1] make this
finding less important.
According to the 2018 ESC/ESH guidelines [1], adverse
events emerging from incremental BP decrease, should be
closely monitored by attending doctors, because these are
associated with increased rate of discontinuations from the
ongoing treatment and deprivation of treatment-related
benefits [4]. Also, discontinuations because of BP-lowering
have been steadily associated with increased rate of future
cardiovascular events soon after treatment withdrawal [5].
Again, Salam et al. [2] in this analysis, have shown that
incident discontinuations because of adverse events related
to treatment were marginally higher (but not significant)
with triple-drug treatment compared with double-drug
combinations. The marginal lack of statistical significance
of treatment discontinuations for a SBP difference of
5.4 mmHg can be attributed to the short follow-up period
limited to 4–10 weeks only (less time to develop symp-
toms) or alternatively because patients had a limited time to
complain for the ongoing adverse events [2]. It has been
previously shown in a large comprehensive overview of
BP-lowering trials that for 5 mmHg achieved SBP differ-
ence, the discontinuations related to treatment were
increased by 35% over a period of 4 years [4]. However,
we should acknowledge that a trial setting discourages
treatment discontinuations, because patients are volunteers
and doctors are investigators adhering to the trial design,
and consequently treatment discontinuations in standard
medical practice are expected to be higher than in trials.
In order to pursue effective BP-lowering and by acknowl-
edging that BP reduction promotes increasing rate of adverse
events, doctors should escalate treatment when the attained
www.jhypertension.com 1587
Thomopoulos et al.
BP levels are out-of-target, but also elaborate a more straight-
forward patient–doctor relationship to ensure that each
separate patient adheres to be free of adverse event-pre-
scribed treatment. Beyond the remainder of drug adherence,
special attention should be paid to lifestyle changes-related
adherence. It would not be worthwhile to escalate pharma-
cological treatment (step 1, step 2, and so on) without strict
implementation of lifestyle measures. Obesity, increased salt
intake, and physical inactivity represent the main modifiable
triggers of polypharmacy in hypertension management, a
condition that both physicians and patients should recipro-
cally acknowledge in each of their follow-up interactions.
Let us suppose that a patient under a double combination
treatment at low doses (step 1) is out-of-BP target, but his/her
adherence is good, and lifestyle measures are implemented as
prescribed, as well. What comes next? Should we opt imme-
diately for a triple-drug combination (step 2) always at low
doses or increase the dose (up-titrate) of the ongoing double
low-dose combination? Although it is well known that increas-
ing the dose of monotherapy compared with low doses of
double combination treatment is less effective [6], it is largely
unknown whether this observation can be extended to
another scenario that is, increasing the dose of each or both
drugs of a double combination regimen (’step 1-plus’) vs.
adopting low doses of a triple-drug combination. Again, Salam
et al. [2] demonstrated that doubling the dose of one of the
components of a dual-drug combination is four times less
effective in terms of BP-lowering compared with a triple-drug
combination at lower doses, whereas they also suggested (but
based on one study only) that even if full doses of the double
combination are implemented, the triple low-dose combina-
tion still would have succeeded an almost two-fold higher BP-
lowering. Thus, the triple low-doses drug combination (step
2) is associated with more effective BP-lowering compared
with either the single agent or the dual agents dosing up-
titration (’step 1-plus’) of the double-drug combination. It
should be determined whether low-doses triple-drug combi-
nation may control BP within-goal faster and reduce the dose-
related adverse events of the double-drug combination when
administered at higher doses. However, when the attained BP
is very close to the target with a low-dose double-drug
combination, doctors may not use a triple-drug combination
(step 2) to achieve target goal, but to increase the dose of one
of the drugs contained in the double combination (‘step 1-
plus’). A nonprespecified post hoc analysis of the Action in
Diabetes and Vascular Disease: Preterax and Diamicron Con-
trolled Evaluation (ADVANCE) trial [7] preserving randomiza-
tion, showed that when a baseline calcium-channel blocker
(nonstudy drug) was received on top of the randomized
treatments (i.e. perindopril and indapamide vs. placebo),
all-cause death incidence was significantly lower compared
with the effect of the active treatment on the same outcome
when a calcium channel was not present in the baseline active
regimen, whereas permanent discontinuations because of
treatment were not different between randomized arms again
stratified by baseline calcium-channel blocker administration.
This kind of indirect randomized evidence for the favorable
effects of the triple combination treatment on all-cause death
should be taken with caution because it was surprisingly
produced independently of BP-lowering (i.e. the resulted
attained SBP difference was of 1.5 mmHg greater in those
1588 www.jhypertension.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
not receiving a calcium-channel blocker) and because of the
possible imbalance in different confounding factors (e.g. 10-
year fatal cardiovascular risk in those receiving vs. those not
receiving calcium-channel blockers at baseline was 13.9 vs.
9.1%, respectively). Subgroup analyses by baseline character-
istics (e.g. by calcium-channel blocker) should not be seen
as substitutes of currently lacking outcome randomized
trials directly comparing triple to dual-drug combination
treatments.
In the early 2000s, Law et al. [8] based on 354 short-term
randomized efficacy BP-lowering trials estimated the extent
of BP reduction of different drug classes considered alone
and suggested that similar BP changes are expected for all
agents at equivalent doses for the same pretreatment BP
levels. For multiple drug treatment (two, three or more drugs)
at standard or half-standard doses, the expected BP reduction
is calculated by applying general equations to each drug, in
turn, allowing for the effect of the first in lowering pretreat-
ment BP for the second, and the second for the third, and so
on [9]. Thus, the physician according to this methodology can
predict the achieved BP levels following a multiple drug
combination at different doses for each individual combina-
tion drug component. The predicted efficacy according to the
Law et al. [8] prediction model was close to the observed
efficacy shown in the analysis by Salam et al. [2] and most
importantly predicted that all triple-drug combination treat-
ments would be associated with a greater BP reduction
compared with all two-drug combinations. Beyond all of
the above mathematical assumptions to predict BP-lowering
[8] and the important results of the study by Salam et al. [2], the
clinician should always monitor BP levels carefully following
increases of antihypertensive regimen potency as BP
responses may differ across patients and environmental
conditions. Furthermore, the general assumption that all
categories of antihypertensive agents produce similar BP
reductions is not consistently seen in the usual clinical
practice because various pathophysiological pathways are
differently activated in different patients (e.g. volume-depen-
dent vs. stiffness-dependent hypertension) [10].
Triple combinations not only effectively lower BP within
goal, but their role in hypertension management is beyond
BP-lowering. When administered in a single pill, triple-drug
combinations simplify treatment and ameliorate adherence
to treatment, but they have also the ability to treat different
types of inertia. First, they may partially treat the clinical
inertia of doctors to prescribe more effective treatments.
Some doctors do not always adhere to the guideline recom-
mendations, others have a relaxed attitude about BP control,
and a further group of doctors has not enough time to
establish a good relationship with the patient to guarantee
the prompt treatment intensification, the evaluation of adher-
ence and the monitoring of the adverse events. Second, they
may partially treat the patient’s inertia to implement long-
term lifestyle changes. Missing BP reduction because of
patients’ resistance to lifestyle changes is ‘perfectly’ counter-
balanced by potentiated combination treatments, like the
triple-drug combinations. Triple-drug combinations in a
single pill may also ‘treat’ the economic hardship at patient
and health system level, as these are associated with a
beneficial cost–effectiveness ratio. Finally, as triple-drug
combinations in our hands today were developed at least
Volume 37  Number 8  August 2019

10 years ago by the pharmaceutical companies [11], their
market penetrance compared with monotherapies or double
combinations is expected to display an increase especially
after the latest ESC/ESH guidelines release [1].
After single-pill triple-drug combinations, the future of
hypertension treatment by drugs may also include a single-
pill quadruple-drug combination regimen (even at minimal
doses) [12], whereas the use of aldosterone-receptor antag-
onists may be anticipated earlier before the development of
the resistant hypertension phenotype [13]. However, doc-
tors treating hypertensive patients should not only always
consider the available or forthcoming antihypertensive
potentiation but should also reflect on the opposite direc-
tion, that is, on how a pharmacological treatment de-esca-
lation can be achieved in separate patients. Still remains
questionable whether renal sympathetic denervation may
have a role toward treatment de-escalation [14], but as
pointed out in previous sections of the present report,
lifestyle changes should not be disregarded. Educational
interventions at national health system level under the
guidance of internationally relevant medical Societies, like
the European Society of Hypertension, may play an impor-
tant role to increase hypertension awareness and early
diagnosis of the disease. Treatment and control of hyper-
tension before hypertension-related organ damage devel-
opment may reduce antihypertensive polypharmacy and
less than three drugs can effectively control BP within goal.
Until then, triple-drug combination antihypertensive treat-
ments should replace dual-drug combinations whenever
patients remain uncontrolled [1,2].
ACKNOWLEDGEMENTS
Conflicts of interest
C.T. reports grants and personal fees from Sanofi, Servier,
Menarini, MSD, Innovis, Astra Zeneca, and Boehringer-
Ingelheim, all outside the area of work reported here.
H.M. and T.M. declare no competing interests.
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