ARB-Based Single-Pill Platform to Guide a Practical Therapeutic Approach to Hypertensive Patients

Abstract

Hypertension is a major modifiable risk for the development of cardiovascular, cerebrovascular and renal diseases. Thus, effective treatment of high blood pressure is an important strategy for reducing disease burden; however, in spite of the availability of numerous effective therapies only 30-40 % of patients with hypertension achieve the recommended blood pressure goals of <140/90 mmHg. Lack of adherence to therapy and reluctance to intensify therapy are cited frequently to explain the discrepancy between potential and attained outcomes. Adherence is closely related to the tolerability, effectiveness and complexity of therapy. Therapeutic inertia may be influenced by concerns over tolerability, as well as the lack of clear preferences for therapies when managing patients with risk factors and comorbidities. Effective and well-tolerated single pill combination therapies are now available that improve adherence and simplify treatment. The combination of a renin-angiotensin system blocker with a calcium channel blocker and a diuretic improves adherence to therapy. We have devised a practical tool for orienting the application of well-tolerated single pill 2/3 drug fixed dose combination therapies in clinical situations commonly encountered when treating hypertensive patients. This approach employs the angiotensin receptor blocker olmesartan alone or in combinations with amlodipine and/or hydrochlorothiazide. This platform is based on clinical evidence, guidelines, best practice, and clinical experience where none of these is available. We believe it will increase the percentage of hypertensive patients who achieve blood pressure control when applied as part of an integrative approach that includes regular follow-up and instruction on lifestyle changes.

Full text

POSITION PAPER
ARB-Based Single-Pill Platform to Guide a Practical Therapeutic
Approach to Hypertensive Patients
Massimo Volpe •Alejandro de la Sierra •
Reinhold Kreutz •Ste
´phane Laurent •
Athanasios J. Manolis
Received: 10 December 2013 / Accepted: 25 January 2014
ÓSpringer International Publishing Switzerland 2014
Abstract Hypertension is a major modifiable risk for the
development of cardiovascular, cerebrovascular and renal
diseases. Thus, effective treatment of high blood pressure
is an important strategy for reducing disease burden;
however, in spite of the availability of numerous effective
therapies only 30–40 % of patients with hypertension
achieve the recommended blood pressure goals of \140/
90 mmHg. Lack of adherence to therapy and reluctance to
intensify therapy are cited frequently to explain the dis-
crepancy between potential and attained outcomes.
Adherence is closely related to the tolerability, effective-
ness and complexity of therapy. Therapeutic inertia may be
influenced by concerns over tolerability, as well as the lack
of clear preferences for therapies when managing patients
with risk factors and comorbidities. Effective and well-
tolerated single pill combination therapies are now avail-
able that improve adherence and simplify treatment. The
combination of a renin-angiotensin system blocker with a
calcium channel blocker and a diuretic improves adherence
to therapy. We have devised a practical tool for orienting
the application of well-tolerated single pill 2/3 drug fixed
dose combination therapies in clinical situations commonly
encountered when treating hypertensive patients. This
approach employs the angiotensin receptor blocker olme-
sartan alone or in combinations with amlodipine and/or
hydrochlorothiazide. This platform is based on clinical
evidence, guidelines, best practice, and clinical experience
where none of these is available. We believe it will
increase the percentage of hypertensive patients who
achieve blood pressure control when applied as part of an
integrative approach that includes regular follow-up and
instruction on lifestyle changes.
Keywords Hypertension Fixed dose combination 
Amlodipine Hydrochlorothiazide Olmesartan
medoxomil Chronic kidney disease Cardiovascular
disease Cerebrovascular disease Risk factors
1 Introduction
Hypertension is a major modifiable risk factor for the
development of cardiovascular, cerebrovascular and renal
diseases [1–3]. It is unquestionable that controlling blood
pressure (BP) can reduce the risk of cardiovascular diseases
[4]. Thus, effective treatment of high BP is an important
strategy for reducing the burden of cardiovascular disease
M. Volpe (&)
Department of Clinical and Molecular Medicine, School of
Medicine and Psychology, Sapienza University of Rome, Via di
Grottarossa 1035-39, 00189 Rome, Italy
e-mail: massimo.volpe@uniroma1.it
M. Volpe
IRCCS Neuromed, Pozzilli, Italy
A. de la Sierra
Department of Internal Medicine, Hospital Mu
´tua Terrassa,
University of Barcelona, Terrassa, Spain
R. Kreutz
Department of Clinical Pharmacology and Toxicology Charite
´,
Universita
¨tsmedizin Berlin, Charite
´platz 1,
10117 Berlin, Germany
S. Laurent
Department of Pharmacology and INSERM U 970, European
Georges Pompidou Hospital, Universite
´Paris-Descartes and
Assistance Publique Ho
ˆpitaux de Paris, Paris, France
A. J. Manolis
Cardiology Department, Asclepeion General Hospital,
Athens, Greece
High Blood Press Cardiovasc Prev
DOI 10.1007/s40292-014-0043-6

and numerous controlled clinical trials have shown that BP
control rates of 70 % or greater are achievable. However,
in spite of the availability of effective therapies hyperten-
sion remains poorly controlled [5]. A study conducted in 12
European countries revealed that only 38.8 % of 7,060
treated hypertensive patients age 50 and above had
achieved the BP target of \140/90 mmHg [6].
Reasons for this discrepancy include lack of adherence
to therapy [7]. This may result from tolerability issues, the
complexity of multidrug regimens and an under apprecia-
tion of the long-term risks associated with hypertension,
especially on the part of asymptomatic patients. Thera-
peutic inertia towards stepping up dosages of existing
medications or adding new medications is often a con-
tributing factor [8]. This may result from unfamiliarity with
guidelines or to the lack of a clear strategy regarding
application of the five classes of antihypertensive drugs,
itself due to the paucity of comparative studies among drug
classes. Standardised treatment approaches may improve
the application of guidelines to clinical practice [9].
Less than one third of patients achieve control on
monotherapy and most hypertensive patients who do
achieve BP targets require a combination of at least two
antihypertensive drugs. International guidelines recom-
mend that patients at high cardiovascular risk and those
needing a reduction in systolic BP of more than 20 mmHg
(10 mmHg diastolic) to meet BP targets may benefit from
initiating therapy with a two-drug combination. Failure to
achieve control with a two-drug combination at full dosage
may require switching to another two-drug combination, or
adding a third drug [10].
Rational and effective single pill 2/3 drug fixed dose
combination therapy represents an excellent strategy for
improving blood pressure control and is one of the key
elements in a successful large-scale hypertension program
that achieved an 80 % BP control rate in over half a million
patients [11].
Hypertension is a multifactorial disease and combina-
tions targeting different pathophysiological mechanisms
can have additive or synergistic effects on BP and block
contra-regulatory mechanisms [12].
Control can often be achieved with lower doses of
individual components, thus reducing dose-dependent side
effects. Some combinations are inherently better tolerated
[13]. Improved tolerability and simplification of therapy
may contribute to the greater adherence seen with such
combinations [14,15].
We propose a platform approach for orienting single-pill
2/3 drug fixed dose combination therapies that considers
risk factors and organ damage, as well as the grade of
hypertension. It is organised to simplify therapy and
overcome therapeutic inertia. This is an integrative
approach that should be combined with non-pharmacologic
therapy and lifestyle changes including salt restriction and
weight management.
In designing this platform, we considered that the only
possible guideline-preferred combination for triple therapy
includes a RAS-blocker, a calcium antagonist and a
diuretic [10]. We selected a strategy based on angiotensin-
receptor-blocker (ARB) because they have been shown to
provide favourable tolerability, adherence, and protection
against organ damage in randomized controlled clinical
trials. This strategy can be used with any ARB; however,
for practical reasons we demonstrate it with olmesartan
(OM) because it is available in fixed-dose triple combina-
tions with amlodipine (AML) and hydrochlorothiazide
(HCTZ) that provide adequate flexibility for up- or down-
titration of individual components. Moreover, both OM and
AML have relatively long half-lives, which allow once
daily administration.
The platform is a practical tool based on clinical evi-
dence, guidelines, best practice, and clinical experience
where none of these is available. It is a way to apply the
guidelines to clinical practice by matching the appropriate
single pill 2/3 drug fixed dose combinations with the var-
ious situations encountered when treating hypertensive
patients. We believe it will increase the percentage of
hypertensive patients who achieve BP control.
2 Platform Organisation
The platform is neither an algorithm nor a guideline, but an
attempt to apply evidence-based medicine to clinical
practice. This approach does not replace ongoing therapy
for underlying conditions that require treatment with spe-
cific drugs, for example, a beta-blocker for coronary artery
disease with angina, but instead represents add-on therapy
to address uncontrolled hypertension. As such, it is
important to consider compatibility with existing therapy
for underlying conditions. For example, dual RAS block-
ade should be avoided. The physician must determine the
appropriate therapy and dosage for individual patients.
The platform is organised to match a suggested therapy
intensity range with the corresponding level of CV risk. For
example, achieving BP control is more urgent in patients
with higher CV risk and such patients may benefit from
higher dosages and/or combination therapy. Initiating
therapy with a single pill fixed dose combination of anti-
hypertensive drugs is associated with a higher probability
of achieving BP control [16,17].
The platform is organised in two parts. One addresses
patients with only risk factors or subclinical organ damage
(Fig. 1) and the other is concerned with patients who have
clinically overt organ damage (Fig. 2). Risk factors or
organ damage are presented in the left column and
M. Volpe et al.

hypertension grade is indicated in the top row, increasing
from left to right. These represent the entry points to the
platform. After assessing a patient for the presence of risk
factors, clinical or subclinical organ damage and BP, the
appropriate intensity of therapy can be identified from the
table. Therapy intensity, in terms of dosage range and
combination, increases from left to right, in correspon-
dence with increasing hypertension grade. Patients with
additional risk factors such as smoking, family history of
premature cardiovascular disease or age [55 for men ([65
for women) may benefit from more intense therapy, if
appropriate, and a lower threshold for stepping up therapy.
Therapy should be assessed for effectiveness after
2–4 weeks. Follow-up visits should be scheduled
accordingly. If BP control is not achieved after this period,
therapy should be stepped up by increasing dosage or
moving to the right in the table and a new follow-up visit
scheduled.
3 Hypertensive Patients with Cardiovascular Risk
Factors or Subclinical Organ Damage
3.1 Metabolic Disturbances, Dyslipidaemia, Metabolic
Syndrome
Patients with some or all of the components of the meta-
bolic syndrome have higher cardiovascular risk. In
Fig. 1 Platform for treating hypertensive patients who have specific
risk factors or subclinical organ damage. Patients continue to receive
treatment for underlying conditions according to guidelines. Avoid
dual RAS therapy. Change therapy if ineffective or not tolerated.
AML amlodipine, HCTZ hydrochlorothiazide, OM olmesartan.
a
Con-
sider single-pill triple combination if BP is not at target.
b
Use HCTZ
in elderly patients or AML in young patients.
c
In patients [80 years,
consider a systolic BP target of 150 mmHg; continue therapy only if
well-tolerated, monitor for postural hypotension.
d
ESC Guidelines on
the diagnosis and treatment of peripheral artery diseases [18].
e
Calcium channel blockers and ACE-inhibitors are recommended in
the ESH/ESC 2013 Guidelines for the management of arterial
hypertension if carotid atherosclerosis is present [10].
f
European
Renal Best Practice (ERBP) position statement on Kidney Disease:
Improving Global Outcomes (KDIGO) Clinical Practice Guideline for
the Management of Blood Pressure in Non-dialysis-dependent
Chronic Kidney Disease: an endorsement with some caveats for
real-life application [19].
g
Consider the use of loop diuretics,
especially in patients with CKD stage G3b (eGFR \45 ml/min/
1.73 m
2
).
h
Management of hyperglycemia in type 2 diabetes: a
patient-centered approach: position statement of the American
Diabetes Association (ADA) and the European Association for the
Study of Diabetes (EASD) [20]
Platform Approach to Treat Hypertensive Patients

addition, they tend to have fasting hyperglycaemia and
insulin resistance.
It is important to use antihypertensive therapy that does
not worsen these preexisting metabolic conditions. RAS
blockers and calcium antagonists are the preferred therapy
for hypertension in this setting because they do not reduce
insulin sensitivity. Moreover, meta-analyses of randomised
clinical trials have shown that RAS blockers are associated
with less incident diabetes than other antihypertensive
classes, while CCBs appear to have a neutral effect similar
to placebo on the development of diabetes [25–27].
OM is effective and well-tolerated in patients with
metabolic syndrome. A pooled analysis of two randomised
clinical trials comparing OM and the ACE inhibitor ram-
ipril in 1,435 elderly hypertensive patients age 65–89
revealed that OM was more effective at reducing BP. In
addition, there was no difference in response between
patients with or without the metabolic syndrome [28].
Three-year follow-up of the OMEGA prospective cohort
study, which monitored cardiovascular events in 14,721
hypertensive patients treated with OM revealed that CV
events correlated with achieved BP and dietary salt intake.
About one third of the patients (3,059) had the metabolic
syndrome. BP reductions and the incidence of events were
similar between patients with or without the metabolic
syndrome [29].
Hsueh et al. performed a subgroup analysis of obese
patients enrolled in the Blood Pressure Control in All
Subgroups with Hypertension (BP-CRUSH) study, which
had investigated the efficacy of a treatment algorithm
with OM/AML ±HCTZ in patients whose hypertension
was not controlled with monotherapy. Therapy was
effective and well-tolerated in obese patients (n =505)
[30].
Thus for patients with metabolic syndrome, obesity or
dyslipidaemia, the platform envisions therapy with OM for
grade 1 hypertension and dual therapy with OM/AML for
patients with grade 2 or 3 hypertension, and for patients
who do not achieve target BP with monotherapy (Fig. 1).
3.2 Elderly Patients
Isolated systolic hypertension is common in the elderly,
resulting from arterial stiffening and increasing the risk of
CV events and stroke. There is evidence that treating
elderly patients to guideline targets is beneficial. A
Fig. 2 Platform for treating hypertensive patients who have overt
organ damage. Patients continue to receive treatment for underlying
conditions according to the appropriate guidelines. Avoid dual RAS
therapy. Change therapy if ineffective or not tolerated. AML
amlodipine, HCTZ hydrochlorothiazide, LVEF left ventricular ejec-
tion fraction, OM olmesartan medoxomil.
a
Guidelines for the
management of atrial fibrillation: the Task Force for the Management
of Atrial Fibrillation of the European Society of Cardiology (ESC)
[21].
b
A European Renal Best Practice (ERBP) position statement on
the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical
Practice Guideline for the Management of Blood Pressure in Non-
dialysis-dependent Chronic Kidney Disease: an endorsement with
some caveats for real-life application [19].
c
2013 ESC guidelines on
the management of stable coronary artery disease [22].
d
Consider
single-pill triple combination treatment if BP is not at target.
e
ESO
Guidelines for management of ischaemic stroke and transient
ischaemic attack 2008 [23].
f
ESC Guidelines for the diagnosis and
treatment of acute and chronic heart failure 2012 [24].
g
Initiate OM at
low doses (10 mg) and uptitrate only with close monitoring of serum
potassium.
h
Consider adding loop diuretics for volume overload.
i
Consider replacing HCTZ with a loop diuretic for symptoms of
volume overload
M. Volpe et al.

subgroup analysis of the Felodipine Event Reduction
(FEVER) trial revealed significant cardiovascular and
cerebrovascular protection with more intense treatment in
elderly patients [31]. Perhaps even more important are the
results of the Hypertension in the Very Elderly Trial
(HYVET) and a one-year extension thereof, which con-
firmed the benefits of treating hypertension in the elderly
[32]. Extra attention to tolerability is warranted in this
population to ensure that the risk/benefit ratio is favourable.
Low-dose combination therapy may be useful in this
respect. Elderly hypertensive patients with SBP
C160 mmHg can benefit from reduction of SBP to
150–140 mmHg, including those over the age of 80, if they
are physically and mentally fit. A BP target of \140 mmHg
can be considered for fit elderly patients younger than
80 years with SBP C140 mmHg [10,33]. Diastolic pres-
sure should be monitored and it may be appropriate to start
therapy at lower doses while monitoring for postural
hypotension, impaired cognition, and electrolyte abnor-
malities [34].
A number of studies have investigated antihypertensive
therapy in the elderly. The efficacy and tolerability of OM
20 mg/day was compared with the dihydropyridine cal-
cium channel blocker nitrendipine 20 mg twice-daily in a
randomised 24-week clinical trial conducted in elderly
patients with isolated systolic hypertension [35]. During
the trial, dosages of either drug could be doubled and a
diuretic added if necessary. BP control, defined as sitting
systolic BP B135 mmHg, was achieved in 62.5 % of
patients receiving olmesartan (160/256) and 56 % of
patients receiving nitrendipine (71/126). Both therapies
were well-tolerated.
The Study on COgnition and Prognosis in the Elderly
(SCOPE) was a placebo-controlled trial of candesartan in
elderly patients aged 70–89 years with mild to moderate
hypertension that had a primary endpoint of major car-
diovascular events (cardiovascular mortality, non-fatal
stroke or non-fatal myocardial infarction) and a mean fol-
low-up of 3.7 years [36]. Add-on antihypertensive therapy
had been administered to more than 40 % of patients,
including 84 % of the control arm. A subgroup analysis of
the patients who had not receive add-on therapy after
randomisation (1,253 received only candesartan, 845
received only placebo) revealed a 32 % reduction in major
cardiovascular events in patients treated with candesartan
(p =0.013) [37].
The efficacy and safety of OM were compared to those
of the ACE inhibitor ramipril in elderly patients with
essential arterial hypertension in the Antihypertensive
Efficacy and Safety of Olmesartan Medoxomil and Ram-
ipril in Elderly Patients with Mild to Moderate Essential
Hypertension: the ESPORT study [38]. Patients were ran-
domly assigned to receive OM 10 mg (n =542) or
ramipril 2.5 mg (n =539) once-daily for 12 weeks. Dos-
ages could be doubled after 2 weeks if BP targets were not
achieved. Absolute BP reductions and the proportion of
patients achieving BP targets were significantly greater
with OM (P \0.01 and P \0.05, respectively), whereas
the proportion of patients with drug-related adverse events
was similar.
Thus, elderly patients can benefit from antihypertensive
therapy as long as it is well-tolerated and appropriate
precautions are observed. The platform envisions two dif-
ferent courses depending on age (Fig. 1).
3.3 Atherosclerosis, Arteriosclerosis, or PAD
Hypertensive patients with atherosclerosis (carotid intima-
media thickening or carotid plaque), arteriosclerosis
(increased arterial stiffness) or peripheral artery disease are
at risk of cardiovascular complications and can benefit
from blood pressure reduction. RAS blockers and calcium
channel blockers are superior to beta-blockers and diuretics
in several groups of patients with these alterations [39–41],
and may be better tolerated in symptomatic patients with
PAD.
The platform envisions treating these patients to a BP
target of \140/90 mmHg with monotherapy or combina-
tion therapy, depending on the level of BP elevation.
3.4 Left Ventricular Hypertrophy
LVH is a major independent risk factor for cardiovascular
disease and cerebrovascular events that occurs most com-
monly as a result of chronically elevated afterload due to
hypertension. Thus, in most cases it represents a modifiable
risk factor. In fact, a meta-analysis of 75 randomised
comparative studies confirms that lowering BP can reduce
left ventricular mass, and indicates that beta-blockers
induce significantly less regression than other antihyper-
tensive classes, while ARBs may be associated with more
regression [42,43]. However, this apparent superiority of
ARBs may be due to the fact that most of the studies
analysed had compared them to beta-blockers. Part of the
beneficial effect of RAS blockers may be due to effects on
BP-independent angiotensin functions. Post hoc analyses
of the Losartan Intervention For End Point Reduction in
Hypertension (LIFE) study revealed that therapeutic
regression of LVH improves CV outcomes independent of
blood pressure including a reduction in the incidence of
new-onset atrial fibrillation [44,45].
The platform envisions starting therapy in any hyper-
tensive patient with LVH in agreement with guidelines as
indicated in Fig. 1. Because of the high associated CV risk
and the importance of sustained therapy, effective and
tolerable combination therapy should be considered.
Platform Approach to Treat Hypertensive Patients

3.5 Microalbuminuria or Proteinuria (CKD stage B3)
Microalbuminuria and proteinuria are early markers of
diabetic nephropathy and endothelial dysfunction in gen-
eral. Patients with these markers are at high risk for the
development of progressive chronic kidney disease and
cardiovascular disease. Elevated BP is a major factor in
these conditions and controlling BP at an early stage slows
progression to clinical organ damage and prevents the
occurrence of cardiovascular events. Among antihyper-
tensive agents, RAS inhibitors are the most effective
at preventing and reducing albuminuria and proteinuria
[46,47].
The platform envisions administering OM at 20–40 mg/
day for grade 1 hypertension and stepping up therapy
according to Fig. 1if not at target. Two different courses
are suggested depending on kidney function. Patients with
estimated glomerular filtration rates (eGFR) B40 ml/min/
1.73 m
2
should not receive HCTZ. Instead, a loop diuretic
should be considered if they do not achieve BP control with
the single pill combination of OM/AML at the highest
tolerated dosage.
3.6 Diabetes
The prevalence of hypertension in patients with diabetes is
high and patients with both conditions have a [sevenfold
increase in the risk of mortality [48]. Guidelines recom-
mend initiating drug treatment when systolic BP is
[140 mmHg in diabetic patients, and most patients require
more than two antihypertensive drugs to achieve this target
[10]. Diastolic BP should be \85 mmHg. There is strong
evidence supporting the benefit of treating hypertension in
diabetic patients [49]. Meta-analysis of [70,000 patients in
31 randomised trials reveals a 9 % reduction in stroke risk
and an 11 % reduction in the risk of myocardial infarction
among diabetic patients undergoing intensive BP control
[50]. The favourable effect of RAS blockers on insulin
sensitivity makes them suitable therapy for this setting.
Diabetes predisposes patients to endothelial dysfunction
and kidney disease. The randomised ROADMAP study
investigated the effect of OM 40 mg/day on the develop-
ment of microalbuminuria, an early marker for kidney
disease, in 4,000 hypertensive and normotensive diabetic
patients who were at high risk of developing kidney dis-
ease. Subgroup analysis of hypertensive patients revealed
that OM treatment significantly delayed the development
of microalbuminuria independent of the degree of BP
reduction [51].
OM is effective and well tolerated in combination
therapy for diabetic patients. A subgroup analysis of the
Triple Therapy with Olmesartan Medoxomil, Amlodipine,
and Hydrochlorothiazide in Hypertensive Patients Study
(TRINITY) revealed that diabetic patients responded as
well as non-diabetic patients to triple therapy with OM/
AML/HCTZ, with significantly more patients reaching the
target BP (in this study \130/80 mmHg), while the fre-
quency of adverse events was similar in both groups [52].
Step-up treatment algorithms employing fixed-dose
combinations of OM/AML ±HCTZ for treating diabetic
hypertensive patients have been investigated in open label,
non-comparative studies. Ram et al. reported on 207
hypertensive patients with type 2 diabetes who responded
well to therapy that was assessed at 3-weekly intervals and
intensified if needed [53]. A subgroup analysis of the PB-
CRUSH study also assessed the efficacy and safety of step-
up fixed-dose combination therapy with OM/
AML ±HCTZ assessed at 4-weekly intervals and inten-
sified if needed in hypertensive patients with type 2 dia-
betes [54]. Both studies revealed good efficacy and
tolerability after 12 weeks.
In diabetic patients, the platform envisions initiating
therapy with OM 20–40 mg/day for grade 1 hypertension.
Patients with grade 2 or 3 hypertension should start with
dual combination therapy as indicated in Fig. 1. Depending
on total CV risk, it may be appropriate to start with com-
bination therapy for grades 2 and 3 hypertension.
4 Hypertensive Patients with Clinically Overt Organ
Damage
4.1 Atrial Fibrillation
Hypertension and atrial fibrillation (AF) are frequently
found to coexist, and hypertension is the most important
risk factor for the development of atrial fibrillation. Atrial
fibrillation increases the risk of stroke and cardiovascular
complications, especially in the presence of hypertension.
Asymptomatic recurrence of AF is not uncommon and
carries the same risks associated with symptomatic disease
[55]. The most important therapeutic goals in hypertensive
patients with AF are prevention of thromboembolic com-
plications and control of BP [56]. The risk of bleeding
associated with antithrombotic therapy makes control of
BP even more imperative. Beta-blockers or calcium
channel blockers can provide rate control, but may not be
sufficient to control also BP.
Moreover, ARBs inhibit the arrhythmiogenic effects of
angiotensin II and exert antifibrillatory and antifibrotic
actions in various AF models. According to current ESC
AF guidelines [21] and ESH/ESC hypertension guidelines
[10], ARBs should be considered for prevention of new
onset AF in hypertensive patients with structural heart
disease and especially in those with LVH, post myocardial
infarction and with systolic dysfunction.
M. Volpe et al.

The platform envisions starting antihypertensive therapy
with OM, alone or in combination with HCTZ according to
the grade of hypertension, when these are compatible with
ongoing treatment for AF (Fig. 2).
4.2 Nephropathy CKD Stage [3
Hypertensive patients with diabetes and chronic kidney
disease are at high risk for cardiovascular events. Therapy
should be aimed at cardioprevention because most such
patients will die from cardiovascular disease before
reaching end-stage kidney disease. BP control is a key to
reducing both cardiovascular and renal risks. This is sup-
ported by a recent meta-analysis of [9,000 patients in 11
trials that investigated the effect of antihypertensive ther-
apy intensity on renal and cardiovascular outcomes. The
risk of kidney failure was lower with intensive BP con-
trolled to a lower target, however the beneficial effect was
only see in patients with proteinuria [57].
Proteinuria is predictive of adverse renal events and
reduction of microalbuminuria or overt proteinuria is
associated with delayed progression of chronic kidney
disease. A meta-analysis of 49 randomised studies (6,181
patients) that compared antihypertensive therapies in dia-
betic and non-diabetic patients with proteinuria or micro-
albuminuria revealed that RAS blockade is more effective
than other antihypertensive agents at reducing proteinuria
[46].
This effect is dose-dependent, supporting recommen-
dations to carefully titrate RAS blockade to the maximum
tolerated dosage [58]. However, this should be executed
under close and individualized monitoring of renal function
and potassium serum concentrations. Combination therapy
with a RAS blocker and a CCB is also effective. A sub-
group analysis of the Avoiding Cardiovascular events
through COMbination therapy in Patients LIving with
Systolic Hypertension (ACCOMPLISH) study reveals that
the combination of a RAS blocker and a CCB was more
effective than a RAS blocker-diuretic combination at
slowing the progression of nephropathy [59].
Thus, the platform incorporates a RAS blocker (OM) as
initial therapy for patients with grade 1 hypertension and
nephropathy. Therapy is stepped up by switching to an
OM/AML combination. The addition of a diuretic can
improve volume overload frequently found in patients with
CKD, however HCTZ is not indicated in these patients
because of their poor kidney function. If needed and clin-
ically indicated, a loop diuretic may be added (Fig. 2).
4.3 Coronary Artery Disease
Effects on the risk of myocardial infarction appear to be
comparable among antihypertensive drugs [60]. However,
the relationship between BP reduction and the risk of CV
events may be best described by a J-shaped curve, in which
BP reduction below a certain point is associated with poorer
CV outcomes, most likely due to decreased tissue perfusion.
Guidelines suggest a target SBP of\140 mmHg.
Hypertensive patients who have experienced a recent
myocardial infarction or have coronary artery disease
(CAD) with angina should receive therapy with beta-
blockers. In other patients, treatment for hypertension
should be based on efficacy and tolerability of the antihy-
pertensive agent. Controlling hypertension may prevent the
development of heart failure or atrial fibrillation
The platform envisions starting low dose therapy with
OM for grade 1 hypertension and stepping up therapy to an
intermediate intensity by increasing OM dosage or
switching to a fixed dose combination with OM/AML.
Higher intensity therapy may be achieved by increasing
dosages or adding HCTZ (Fig. 2).
4.4 Previous Stroke or Transient Ischaemic Attack
Hypertension is a major modifiable risk factor for the
incidence and recurrence of cerebrovascular events. The
limited treatment options available in this disease make
primary and secondary prevention particularly important.
Hypertensive patients with systolic BP [140 mmHg who
have had a stroke or transient ischemic attack should
receive antihypertensive treatment; this threshold can be
relaxed to 150 mmHg in patients more than 80 years old.
There is abundant evidence that BP control per se reduces
the risk of stroke, thus any effective therapy is useful.
Meta-analyses of data from randomized, controlled trials
have not shown significant differences in total major car-
diovascular events among regimens based on similar blood
pressure reductions [61–63]. Meta-analyses also indicate
that BP reduction can decrease the risk of recurrent stroke
[64]. Patients who have had a stroke or transient ischaemic
attack are likely to be receiving antithrombotic therapy,
which makes BP control very important for the prevention
of bleeding.
Treatment decisions are based on BP-lowering efficacy
and tolerability, as well as the presence of other compelling
indications that may influence the risk of stroke, such as
AF. In stroke, the relationship between BP and risk is
particularly strong and studies have shown that persistence
on hypertensive therapy also correlates well with outcomes
[65]. Thus, interventions that are better tolerated or asso-
ciated with higher adherence, such as fixed-dose combi-
nations, are expected to improve outcomes.
The platform envisions administering OM 10–20 mg/
day for patients with grade 1 hypertension, and intensifying
therapy by switching to a combination of OM/AML 20–40/
5 mg/day (Fig. 2). Patients not responding may have their
Platform Approach to Treat Hypertensive Patients

AML dosage stepped up, or they may benefit from triple
therapy with OM/AML/HCTZ. When managing patients
with grade 2 or 3 hypertension, it may be appropriate to
initiate therapy at an intermediate intensity with a combi-
nation of OM/AML.
4.5 Heart Failure with Reduced LV Function
Hypertension is a risk factor for the development of heart
failure (HF), both through the development of left ven-
tricular remodelling from chronically high after load,
which may lead to HF with preserved ejection fraction, and
because hypertension is a risk factor for coronary artery
disease, which in turn often leads to HF with reduce
ejection fraction (HFREF) [66]. There is strong evidence
supporting the benefit of ACE-inhibitors or ARBs in pre-
venting development of HF [67], and for ACE-inhibitors
and BBs in improving survival and reducing hospitalisa-
tions [68–70]. BBs also reduce the incidence of atrial
fibrillation in patients with HF [71].
The goals of therapy are to alleviate symptoms, prevent
hospital admissions, and improve survival. Controlling BP
is important because many of these patients will be
receiving antithrombotic therapy and hypertension is a risk
factor for bleeding. Hypertensive patients with HF nor-
mally receive a RAS blocker, which would be an ACE-
inhibitor (or an ARB if an ACE-inhibitor is not tolerated), a
beta-blocker, and a diuretic to counteract neurohumeral
changes and correct the hemodynamic derangement that
occurs in heart failure. ARBs are generally well-tolerated
and are useful for providing RAS blockade in patients
intolerant of ACE inhibitors.
The platform envisions that hypertensive patients with
HFREF who do not tolerate ACE-inhibitors and have
uncontrolled BP on existing therapy receive an OM/HCTZ
single pill combination according to Fig. 2. Patients must
be monitored closely for signs of worsening HF, and dos-
ages titrated accordingly. Most of these patients will
require a loop diuretic to treat symptoms of volume over-
load. Combining loop diuretics with HCTZ increases the
risk of hyponatremia. In advanced stage HF, higher BP is
associated with better outcomes, most likely because of
improved perfusion [72]. Thus antihypertensive therapy
should target a systolic BP around 140 mmHg [10].
4.6 Resistant Hypertension
Resistant hypertension is defined as hypertension that is not
controlled to \140/90 mmHg with an adequately dosed
therapy that includes a diuretic and two other drugs from
different antihypertensive classes [73]. Truly resistant
hypertension may be difficult to distinguish from hyper-
tension that is under-treated due to poor adherence. The
reduced pill burden provided by a single-pill triple com-
bination may improve adherence, thereby facilitating
identification of patients with this condition and avoiding
unnecessary examinations to exclude secondary hyperten-
sion. If BP control is not obtained with the full-dose triple
combination of OM/AML/HCTZ, consider adding a beta-
blocker, or a non-first line antihypertensive agent such as a
mineralocorticoid receptor antagonist or alpha-1-blocker.
5 Conclusions
Effective and well-tolerated single pill 2/3 drug fixed dose
combination therapies have the potential to greatly improve
BP control and close the gap between the promising results
from interventional trials and the disappointing signs from
routine clinical practice. Their success depends on how
well they are applied. With this exercise, we have
attempted to match the appropriate therapeutic intensity
range to cardiovascular risk in situations commonly
encountered when treating hypertensive patients. We
believe it will increase the percentage of hypertensive
patients who achieve blood pressure control and ultimately
reduce the burden of cardiovascular, cerebrovascular and
renal diseases when applied as part of a comprehensive
approach that includes regular follow-up and timely ther-
apy intensification as needed.
Acknowledgements M.V. has received honoraria for lectures and
advisory board participation from Daiichi Sankyo, Menarini interna-
tional, Guidotti and Malesci.
A.S. has received honoraria for participation in sponsored lectures
and/or advisory boards from Abbott, Daiichi-Sankyo, MSD, and
Menarini.
R.K. has received honoraria for lectures and advisory board par-
ticipation from Bayer HealthCare, Berlin-Chemie, Bristol-Myers
Squibb, Daiichi Sankyo, and Menarini.
S.L. has received honoraria for lectures, advisory board participa-
tion, and research grants from Daiichi Sankyo, Menarini, Novartis,
Recordati, and Servier.
A.J.M. has received honoraria for lectures and advisory board
participation from Abbott, Menarini, Recordati, Bayer, Ferrer, Berlin
Chemie.
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