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Management of hypertension
in chronic heart failure
Expert Rev. Cardiovasc. Ther. 7(4), 423–433 (2009)

Saraswathy
Manickavasagam,
Ramanna Merla,
Michael M Koerner,
Ken Fujise, Sanjay
Kunapuli, Salvatore
Rosanio and Alejandro
Barbagelata†
†
Author for correspondence
University of Texas Medical
Branch, 301 University
Boulevard 5,106 John Sealy
Annex, Galveston,
TX 77555-0553, USA
Tel.: +1 409 747 2101
Fax: +1 409 772 4982
Chronic heart failure (CHF) is associated with frequent hospitalizations and high mortality. It
affects more than 5 million individuals in the USA, and another 660,000 new cases are diagnosed
each year; overall, heart failure (HF) now accounts for 7% of all deaths from cardiovascular
disease. Hypertension (HTN) increases the risk of development of HF and it precedes it in 75%
of cases. HF patients are nearly evenly divided between those with reduced left ventricular (LV)
function or systolic dysfunction and those with preserved LV systolic function or diastolic
dysfunction. The management of HTN in patients with CHF is challenging. Drugs such as
E-blockers, angiotensin-converting enzyme inhibitiors, angiotensin receptor blockers, aldosterone
receptor blockers, hydralazine and nitrates, which have shown mortality benefit in CHF and
exert antihypertensive effects, should be used as first-line agents to control HTN in CHF. In
addition, antihypertensive drugs such as D-receptor blockers that can increase mortality in HF
should be avoided. The dihydropyridine group of calcium channel blockers are good
antihypertensive medications with a neutral effect on mortality in patients with CHF. These may
be used in CHF patients with refractory HTN. In patients with HF with reduced ejection fraction,
HTN is treated differently in comparison to patients with HF with normal ejection fraction. This
article reviews the treatment of essential HTN in patients at risk for developing HF, in the presence
of HF and the latest developments in treatment that might benefit both HTN and HF management.

KEYWORDS :CONGESTIVEsDIASTOLICsDYSFUNCTIONsHEARTFAILUREsHYPERTENSIONsSYSTOLIC

Approximately 5 million people in the USA threefold and is an important cause of HF in

have chronic heart failure (CHF), and another
660,000 new cases are diagnosed each year [1] .
Overall, heart failure (HF) is responsible for
12–15 million general practitioner visits and
6.5 million hospital-days annually [1] . According
to a new analysis of 27 years of trend data from
the National Hospital-discharge Surveys, HF has
reached epidemic levels in the USA [2] . The pop-
ulation of HF patients is heterogeneous, ranging
from the asymptomatic to those with chronic
decompensation and advanced symptoms. HF
patients are nearly evenly divided between
those with reduced left ventricular (LV) systo-
lic function (HF with reduced ejection fraction
[HFREF]) and those with preserved LV systo-
lic function (HF with normal ejection fraction
[HFNEF]). The latter group is associated with
essential hypertension (HTN) more often [3,4] .
Hypertension is becoming increasingly
prevalent, and it is estimated that 50 mil-
lion or more Americans require treatment for
it [5] . Approximately more than two-thirds of
patients with HF have a past or current history of
HTN [6,7] . HTN increases the risk of HF two- to
African–Americans and the elderly. [5] In these
patients, HTN may have caused the HF or be
an incidental comorbidity if the HF has resulted
from other diseases, such as coronary athero-
sclerosis. Nonetheless, HTN increases afterload,
making it especially deleterious in HF patients.
Many drugs that have shown mortality ben-
efit in CHF also have antihypertensive effects
and should be used as first-line agents to control
HTN in HF. Angiotensin-converting enzyme
(ACE) inhibitors or angiotensin receptor block-
ers (ARBs) have strong evidence to support their
use in HTN patients at risk for HF, as well as
in patients with HFREF [8–16] . Additionally,
ARBs have greater but conflicting evidence
for use in patients with preserved ejection frac-
tion [17,18] . Thiazides are the first-line drugs in
patients with HTN at risk for HF [5] . However,
in patients with established HF, loop diuretics
are prescribed more often and a thiazide may be
added to promote diuresis by sequentially block-
ing sodium transport in renal tubules in cases
where volume overload persists, despite loop
diuretics [19] . Conflicting data exist in the use

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 Review Manickavasagam, Merla, Koerner et al.
of E-blockers for patients with HTN without HF and in patients
with HFNEF [20–25] . Extensive data support the use of E-blockers
in patients with HFREF, especially carvedilol and metopro-
lol  [26–28] . Calcium channel blockers are widely used to treat HTN
in patients at risk for HF [5] ; however, they are not considered in
the management of HTN in HFREF [19,29,30] . A dihydropyridine
group of calcium channel blockers could be used to control HTN
only once other medications have failed, since they exert a neutral
effect on mortality in HFREF patients [19,29,30] . Potentially, they
could be beneficial in patients with HFNEF. Aldosterone receptor
blockers significantly decreased blood pressure in patients with
HTN at risk for HF requiring three or more antihypertensive
medications [31] . In patients with HFREF, aldosterone receptor
blockers decrease both HTN and mortality [32,33] . This article
reviews the current treatment of essential HTN with and without
HF and the latest developments in the treatment of HTN in HF.
Management of HTN in patients at risk of HF
Long-term treatment of both systolic and diastolic HTN reduces
the risk of developing HF by 50% [34] . The goal of the Heart
Failure Society of America for patients with renal insufficiency
(>1 g/day of proteinuria) and those with a high risk of developing
HF is 125/75 mmHg, and 130/85 mmHg in patients with less
than 1 g/day of proteinuria [35] .
The The Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC7) recommendations, based on the
Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT) data, recommend that a thiazide
diuretic, such as hydrochlorthiazide or chlorthalidone, should
be first-line therapy for HTN in patients without diabetes,
angina, ischemic heart disease, HF or chronic kidney disease
[5] , which is fortuitous given the low cost of these drugs [36] .
Hydrochlorothiazide can normalize blood pressure in up to 46%
of patients with mild HTN [37] . Thiazides can reduce the inci-
dence of HF in patients with HTN and prevent HTN-related
mortality and morbidity, but fail to prolong survival if patients
already have HF [19] .
In hypertensive patients with diabetes, ACE inhibitors are pre-
ferred as they slow the progression of diabetic renal disease, pre-
vent recurrent events, such as myocardial infarction in vascular
patients, and may prevent the development of HF [38–40] .
E-adrenergic receptor blockers are discouraged for the treat-
ment of HTN as they have been associated with increased
stroke, especially in the elderly, and do not reduce all-cause
mortality or cardiovascular morbidity and mortality [20–23] .
Although these findings were observed in studies predomi-
nantly using atenolol, the European Society of Hypertension,
European Society of Cardiology [41] and NICE discourage
E-blocker use for HTN unless there are compelling reasons
to do otherwise [42] . Nevertheless, E-adrenergic blockade is
preferred in hypertensive patients with previous myocardial
infarction, in whom they reduce cardiovascular mortality and
provide benefits beyond those attributable to blood pressure
lowering alone [43] .
424
Most patients require more than one agent for optimal blood pres-
sure control. Guidelines recommend starting two drugs for blood
pressures 20 mmHg or more above the desired goal [5,44] . Patients
not responding completely to one drug have almost a 50% likeli-
hood of achieving their blood pressure goal on a second one [45] . Not
all two drug regimes have similar benefits. While thiazide diuretics
and calcium channel blockers work well in African–American and
older patients (aged 55 years and above) [46,47] , younger patients
respond more favorably to ACE inhibitors and ARBs [8,9] . In the
Avoiding Cardiovascular Events in Combination Therapy in
Patients Living with Systolic Hypertension (ACCOMPLISH) trial,
a significant decrease in cardiovascular mortality was found in the
benazepril plus amlodipine arm compared with the benazepril
plus hydrochlorothiazide arm [48] . The mean difference in blood
pressure between the two groups was only 0.9 mmHg systolic and
1.1 mmHg diastolic, which was statistically significant [48] . The
cardiovascular end points did not include development of HF.
Nevertheless, it is important to note that there was a significant
decrease in myocardial infarction, which is a major risk factor for
the development of HF. In patients requiring three or more differ-
ent hypertensive medications, adding spironolactone can decrease
the mean systolic blood pressure by more than 25 mmHg and
diastolic blood pressure by more than 10 mmHg [31] . Combination
of ACE inhibitors and ARBs is associated with increased adverse
events and should be avoided [49] .
Treatment of HTN with D-adrenergic blockade is generally
restricted to patients with urinary tract obstruction or benign
prostatic hyperplasia, since these drugs may increase the incidence
of HF. In the ALLHAT study, secondary end points (major car-
diovascular disease events, mostly driven by the occurrence of
HF) were 25% higher in the doxazosin than the chlorthalidone
arm, and hospitalization for HF was twice as likely (FIGURE 1) [36] .
Management of HTN in patients with reduced
ejection fraction
Patients with HF may present either with reduced or normal ejec-
tion fraction. Despite the difference in ejection fraction, both
groups have similar symptoms and signs. HFREF has been well
studied but little is known about the benefits of treating coexisting
HTN because blood pressure usually decreases as cardiac func-
tion declines and many patients do not live to see the benefits of
long-term antihypertensive therapy [19] . HTN further worsens the
loading conditions of the failing ventricle, and small increases in
afterload can produce large decreases in stroke volume. For this
reason, the blood pressure goal is less than 130/80 mmHg in these
patients [19] . Many experts go further and suggest that patients
reach the lowest blood pressure possible without symptoms or
signs of hypoperfusion. Acceptable systolic blood pressures may be
as low as 90 mmHg without symptoms or signs of hypoperfusion.
However, a prospective study of 24-h blood pressure control in
patients with HFREF demonstrated a high prevalence of signifi-
cant daytime and nocturnal hypotension with the use of additional
medical therapy. Over a 2-year follow-up, the group with the great-
est burden of diastolic hypotensive events experienced more HF
admissions, mortality and emergency admissions [50] .
Expert Rev. Cardiovasc. Ther. 7(4), (2009)
 Management of hypertension in chronic heart failure Review

Not at goal blood pressure (<140/90 mmHg)

(<130/80 mmHg for those with diabetes or chronic kidney disease)

Without compelling indications With compelling indications

SBP 140–159 or DBP 90–99 mmHg SBP > 160 or DBP > 100 mmHg

Post-MI: ACE-I, β-blocker or aldosterone antagonist

Diabetes: diuretic, ACE-I, ARB, β-blocker or CCB
Thiazide-type diuretics for most Two-drug combination for most Chronic kidney disease: ACE-I or ARB
may consider ACE-I, ARB, (usually thiazide-type diuretic and High risk of coronary artery disease:
β-blockers, CCB or combination ACE-I, ARB, β-blocker or CCB) diuretic, β-blockers, ACE-I or CCB

Not at goal blood pressure

Optimize dosages/add additional drugs

Figure 1. Algorithm for treatment of hypertension without heart failure (adapted from JNC-7 guidelines).
ACE-I: Angiotensin-converting enzyme; ARB: Angiotensin receptor blocker; CCB: Calcium channel blocker; DBP: Diastolic blood
pressure; MI: Myocardial infaction; SBP: Systolic blood pressure.

Renin–angiotensin inhibitors
Renin–angiotensin inhibitors include drugs that inhibit conver-
sion of angiotensin I to angiotensin II (ACE inhibitors), block the
angiotensin receptor (ARB) or block aldosterone receptors. A large
body of data indicates that ACE inhibitors decrease the morbidity
of patients with LV dysfunction, reduce hospitalization rates and
reduce the risk of death by 1–4 years in patients at any stage of HF,
including those who are asymptomatic and those who develop HF
early after a myocardial infarction, making these agents first-line
therapy for all categories of HF [10–14] . ACE inhibition also allevi-
ates symptoms, improves clinical status and enhances the sense
of wellbeing in patients with HF [10] . Mechanisms responsible for
these beneficial effects include limitation of cardiac hypertrophy
and fibrosis, reduction of ventricular wall stress and decreased
efferent sympathetic traffic from the brain [51] .
Fortunately, although ACE inhibitors remain first choice, ARBs
are an acceptable alternative, as shown in the Valsartan Heart
Failure Trial (VAL-HeFT) and Candesartan in Heart Failure:
Assessment of Reduction in Mortality and Morbidity (CHARM)
Alternative trials [15,16] .
The CHARM-Added and Val-HeFT trials also demonstrated
that combining an ARB with ACE inhibitor reduces hospitaliza-
tions [52,53] but a more recent meta-analysis suggested that, when
used together, these drugs may markedly increase adverse effects,
such as renal dysfunction, hyperkalemia and symptomatic hypo-
tension [49,54] . Thus, such combination therapy is not recommended
at this time except in rare circumstances of refractory HTN.
E-adrenergic receptor blockade
Owing to their favorable effects on survival and disease progres-
sion, the Heart Failure Society highly recommends the use of
E-adrenergic receptor blockers for patients whose ejection frac-
tion is less than 40%, unless there is a contraindication (FIGURE 1)
or intolerance to the drug [8,55] . The administration of E-blockers
should be started as soon as possible after the diagnosis systo-
lic dysfunction and may be used in patients with compensated
class II, III or IV HF. Carvedilol, sustained-release metoprolol
and bisoprolol have been shown to improve overall and event-
free survival of patients with mild-to-advanced HF and, thus,
are approved for treating HF in the USA [26–28] . Carvedilol is
distinguished by its blocking of E2- and D1-adrenergic recep-
tors, in addition to E1-receptors, and by its antioxidant proper-
ties. The administration of E-receptor blockers with intrinsic
sympathomimetic activity, such as pindolol and acebutolol,
should be avoided.

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 Review Manickavasagam, Merla, Koerner et al.

E-receptor blockers are especially appropriate in HF patients
with HTN. Unlike their performance in patients with HTN
only, E-blockers improve overall and event-free survival in HF
patients [56] . Improvement in survival with E-blockade and ACE
inhibition appears to be additive and, in seeking their blood pres-
sure goal, hypertensive patients with HF should start E-blocker
therapy without waiting to maximize the dose of ACE inhibitor. A
meta-analysis including 22 trials and more than 10,000 patients
demonstrated the benefit of E-receptor blockade in HF patients
with HTN [55] . E-blockers significantly reduced mortality at 1
and 2 years compared with placebo. The study estimated that,
during the first year, E-blockade saved 3.8 lives per 100 treated
patients and reduced hospitalizations by four per 100 treated
patients. Since the improvement appears to be dose related, the
aim in stable HF patients with HTN is to eventually maximize
both E-blocker therapy and ACE-inhibition (or angiotensin
receptor blockade).
Aldosterone antagonists
Aldosterone can adversely affect the heart’s structure and func-
tion [57–59] . Blocking its effects can improve survival of patients
with moderate-to-severe HF symptoms with recent decompensa-
tion [60] , and recent myocardial infarction with LV dysfunction [61] .
Aldosterone-blocking agents may also reduce arrhythmic death
in patients with mild-to-moderate HF [62] . The Randomized
Aldactone Evaluation Study (RALES) trial found that when added
to an ACE inhibitor and a loop diuretic, spironolactone signifi-
cantly reduced mortality at 24 months in patients with class IV HF,
and in those with class III HF who had had class IV HF within
6 months [32] . The Epleronone Post-Acute Myocardial Infarction
Heart Failure Efficacy and Survival Study (EPHESUS) trial
showed that eplerenone was associated with a 15% reduction in
overall mortality at 16 months if started within 2 weeks of a myo-
cardial infarction in patients with a low ejection fraction and evi-
dence of HF and/or diabetes [33] . Both spironolactone or epleronone
therapy significantly decreased both systolic and diastolic arterial
pressure compared with placebo and can be of additional aid in the
management of HTN in these HF population [32,33] .
Diuretics
Although diuretics are the mainstay of treating acutely decom-
pensated HF, no long-term, randomized clinical trial has shown
that they reduce morbidity or mortality, despite their relief of
pulmonary and systemic venous congestion. Loop diuretics (e.g.,
furosemide, bumetenide, torsemide and ethacrynic acid) are used
most commonly in HF patients, followed by thiazide and thi-
azide-like diuretics (e.g., chlorthalidone, hydrochlorothiazide,
indapamide and metolazone), which are usually less effective in
this setting. Treating volume overload with a loop diuretic reduces
intracardiac filling pressure and cardiac output and, in hyper-
tensive patients, may decrease systolic and diastolic blood pres-
sures by as much as 15.8 and 8.2 mmHg, respectively [63] . Even if

Hypertension + HF with low ejection fraction

Not a goal blood pressure < 130/80 mmHg or

lowest achievable blood pressure without symptoms

ACE-I β-blockers Diuretics Spironlactone I/H

Use in all patients unless
contraindicated. If patient
intolerable to ACE-I
secondary to cough
start ARB
Use in all patients Use in patients Ideal in moderately
unless contraindicated with fluid overload severe or severe HF
recent decompensation
or in patients with a recent
MI and LVD
Ideal in Black people
with moderate-to-severe
HF who were already
being treated with
standard therapies

Initiate I/H when ACE-I/ARB

therapy is limited by
hypotension or renal
insufficiency

Figure 2. Choice of agents in treatment of hypertension in patients with low ejection fraction.
ACE-I: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; HF: Heart failure; I/H: Isosorbide dinitrate and
hydrazine; LVD: Left ventricular dysfunction; MI: Myocardial infarction.

426 Expert Rev. Cardiovasc. Ther. 7(4), (2009)

 Management of hypertension in chronic heart failure Review

Table 1. Contraindications to use of major antihypertensive drugs used in heart failure.

Drug Contraindications to use
ACE-I/ARB Contraindicated if life-threatening adverse reactions (e.g., angioedema or anuric renal failure ) on previous exposures
Pregnancy: use with caution if markedly increased serum levels of creatinine (>3 mg/dl), bilateral renal artery stenosis or
elevated levels of serum potassium (>5.5 mmol/l)
E-blocker Caution should be used if E-blockers are initiated in patients with marked bradycardia (<55 beats/min), diabetes with
recurrent hypoglycemia, asthma or resting limb ischemia
Not recommended in patients with asthma with active bronchospasm
Do not initiate in patients hospitalized in an intensive-care unit or those who have required recent treatment with an
intravenous positive inotropic agent
Spironolactone Not recommended when creatinine is >2.5 mg/dl (or creatinine clearance < 30 ml/min) or serum potassium is
>5.0 mmol/l
ACE-I: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker.

this fall in output is tolerated symptomatically, a consequent rise
in blood urea nitrogen (BUN) may represent tissue hypoperfusion
that warrants a reduction in dose.
Thiazides can reduce the incidence of HF in patients with
HTN and prevent HTN-related mortality and morbidity but fail
to prolong survival if patients already have HF. Recent guidelines
suggest using thiazide diuretics in hypertensive HF patients with
mild fluid retention because of their persistent antihypertensive
action [19] . The Heart Failure Society suggests adding chloro-
thiazide or metolazone to a loop diuretic if the latter is unsuc-
cessful in reduce fluid retention alone [8] . One may fully block the
distal convoluted tubule by administering a diuretic that affects
the distal tubule, followed by a loop diuretic. This may increase
the natriuresis in chronic renal failure patients, in whom thiazides
alone are much less effective. However, this combination may not
significantly reduce blood pressure.
Hydralazine & nitrates
Combining isosorbide dinitrate and hydralazine with stand-
ard therapy is especially effective in prolonging the survival of
African–American patients with moderate-to-severe HF [64] , and
may provide good blood pressure control in those already taking
an ACE inhibitor, E-blocker and, perhaps, also an aldosterone
antagonist. The African–American Heart Failure Trial (AHeFT)
showed that a fixed-dose combination of isosorbide dinitrate and
hydralazine improved the survival of African–American patients
with class III or IV HF by 43% [64,65] . The combination’s reduc-
tion of blood pressure may have helped improve survival. Since
this regimen calls for multiple daily doses, is less efficient in reduc-
ing mortality and blood pressure and causes more side effects than
ACE inhibition alone and, therefore, it is usually added to ACE
inhibitor and E-blocker therapy (FIGURE 2) [14] .
Less-ideal agents
Some drugs are not recommended for HF patients. Calcium chan-
nel blockade does not improve symptoms and can worsen CHF
and the risk of death in these patients. Amlodipine and felodipine
neither improve nor worsen the survival of HF patients [66,67] and,
generally, would not be chosen before other drugs of known
survival benefit. However, the American College of Cardiology
(ACC), American Heart Association (AHA) and Heart Failure
Society accept using amlodipine in HF patients with HTN
because it may be safe and well tolerated [19] . Limited trials have
reported that reducing central sympathetic outflow (clonidine)
and blocking peripheral D-receptors (prazosin) can benefit CHF
patients [29,30] . These agents are not recommended for CHF at this
time. Potent vasodilators (minoxidil) are avoided in HF patients
because they promote sodium retention (TABLE 1) [19] .
HTN in patients with HFNEF
The Organized Program to Initiate Lifesaving Treatment in
Hospitalized Patients with Heart Failure (OPTIMIZE–HF)
Registry confirmed the high prevalence of HFNEF and indi-
cated that their postdischarge mortality and hospitalization rates
are similar to those with HFREF [68] . Nevertheless, we lack reli-
able data on the optimal management of these patients. HTN
frequently coexists, and a recent study cites HTN as the cause
of approximately 61% of HFNEF cases. Many patients will have
LV hypertrophy and approximately two-thirds will have diastolic
dysfunction as well [32] .
For these patients, the AHA/ACC recommend a lower tar-
get blood pressure than for uncomplicated HTN (i.e., less than
130/80 mmHg [17,19,69]), since higher blood pressures continue to
worsen ventricular structure and performance. Increases in systolic
blood pressure slow myocardial relaxation [70] , and hypertrophy
increases passive chamber stiffness. Fortunately, blood pressure con-
trol will eventually improve diastolic function in these patients [17] .
However the blood pressure that may be achieved without adversely
affecting cardiac output will vary widely from patient to patient.
Renin–angiotensin inhibitors
Angiotensin receptor blockade has been well studied in patients.
The CHARM-Preserved trial showed that candesartan reduced
hospitalizations of patients with class II–IV CHF whose ejection
fraction was greater than 40%, although it did not significantly
reduce cardiovascular death. In another study, losartan improved
exercise tolerance and quality of life [17] . LV hypertrophy may regress
to a greater degree with angiotensin receptor blockade than ACE
inhibition. A meta-analysis examining the efficacy of antihyper-
tensive drugs in reversing LV hypertrophy in patients with HTN

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 Review Manickavasagam, Merla, Koerner et al.

illustrated that angiotensin receptor blockade and ACE inhibition E-adrenergic receptor blockade
decreased LV mass index by 13 and 10%, respectively [71] . Such Patients with HFNEF respond well to E-adrenergic receptor block-
regression may improve diastolic function; however, another large ade, and the Heart Failure Society recommends these medications
randomized trial showed that valsartan had no such effect [72,73] . for treating HTN with HF [24] . In addition to lowering blood
The Irbesartan in Heart Failure with Preserved Systolic Function pressure, these agents increase diastolic filling time and, thus,
(I-PRESERVE) trial showed no significant decrease in cardiovascu- enhance ventricular filling and coronary perfusion. They also
lar mortality or morbidity measured by death, hospitalization and decrease the ventricular rate response to atrial arrhythmias and
quality of life in patients with HFNEF who were randomly treated induce regression of hypertrophy [24,78] . Carvedilol may reduce
with an ARB–irbesartan or placebo. There was a significant increase the symptoms and repeat hospitalizations of these patients [79] .
in serum creatinine and hyperkalemia in the ARB arm though these In a large study of over 4000 patients, initiation of E-blockers
did not translate to significant clinically adverse events [18] . at discharge in patients with HFNEF was not associated with a
The AHA/ACC guidelines recommend ACE inhibition, but no significant decrease in 1-year mortality or rehospitalization [25] .
studies have clearly demonstrated these medicines benefit patients Many of these patients with HF have other conditions that
with HFNEF. In the OPTIMIZE-HF Registry, ACE inhibi- E-blockade is very likely to benefit, such as a prior myocardial
tion did not improve the mortality or readmission rates of these infarction and atrial fibrillation and, hence, should be included
patients [74] . However, it should be considered for HFNEF patients for HTN management in these scenarios.
who have symptomatic coronary disease, or diabetes and another
risk factor. It can reduce symptoms, ventricular mass, and myocar- Calcium channel blockade
dial stiffness [24,75] . These drugs should be titrated carefully to avoid
Unlike HF patients with reduced systolic function, HFNEF
hypotension, since the poor diastolic function of these patients may
patients are likely to benefit from calcium channel blockade.
make them very preload dependent. Amlodipine may be especially helpful in HFNEF patients with
HTN and limiting angina, in whom the drug may decrease both
Aldosterone antagonist blood pressure and the number of ischemic episodes [19] . Again,
Aldosterone promotes hypertrophy and fibrosis and may be partly as with any agent that suddenly reduces preload in patients with
responsible for the diastolic dysfunction that occurs with age and diastolic dysfunction, dose titration must proceed carefully. The
HTN [76] . Small studies have suggested benefits of aldosterone Heart Failure Society highly recommends nondihydropyrid-
blockade [77] and prompted the larger Treatment of Preserved ine agents (e.g., verapamil and diltiazem) for HFNEF patients
Cardiac Function Heart Failure with an Aldosterone Antagonist with atrial fibrillation that cannot tolerate E-receptor blockade
(TOPCAT) NIH trial, which is now enrolling subjects. or whose heart rates do not decrease sufficiently in response to
it [19] . Verapamil may be particularly help-
Table 2. Treatment of hypertension according to the severity of ful because it can improve myocardial
heart failure. relaxation and compliance
Stage of HF Choice of drugs
Diuretics
A Diuretic-based therapy (thiazide) is the drug of choice No major study has shown that diuretics
ACE-I/BB/ARB are good choices as add-on drugs. D-blockers and CCBs benefit HFNEF patients and, in HFNEF
are less preferred
Treat hypertension according to JNC-7 guidelines
patients with HTN, diuretics are recom-
mended only if the patients are also volume
B ACE-Is are the drug of choice overloaded. In these cases, one may begin
BBs are preferred add-on drugs
Combination of ACE-I and BB is preferred in post-MI patients
with either a thiazide or loop diuretic, or
Aldosterone antagonist is a good add-on agent in post-MI patients advance from a thiazide to a loop diuretic if
ARB can be used in patients intolerant to ACE-I the former proves inadequate [19] . As before,
one must avoid excess preload reduction.
C Combination of ACE-Is and BBs should be administered to all patients
who can tolerate them
Diuretics reduce BP in volume-overloaded patients Nitrates & hydralazine
Spironolactone and I/H are good add-on drugs Excess preload reduction and sudden blood
Amlodipine can be used in resistant patients pressure declines are especially likely when
ARBs are used in patients intolerant to ACE-I treating HFNEF patients with these agents,
D ACE-Is and BBs are used as tolerated and they should be used with caution.
I/H is the treatment of choice in patients who do not tolerate ACEI/BB
ARB can be used in patients intolerant to ACEI, but the benefit is unclear Expert commentary & five-year view
Spironolactone is also an ideal add-on agent In clinical practice we encounter a spectrum
American College of Cardiology/American Heart Association classification of heart failure. of hypertensive patients, ranging from those
ACE-I: Angiotensin converting enzyme inhibitor; ARB: Angiotensin receptor blocker; BB: E-blocker;
BP: Blood pressure; HF: Heart failure; I/H: Isosorbide dinitrate/hydralazine; JNC: Joint National Committee at risk of developing HF, to those with end-
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; MI: Myocardial infarction. stage HF. We recommend treatment of

428 Expert Rev. Cardiovasc. Ther. 7(4), (2009)

 Management of hypertension in chronic heart failure Review

HTN according to the stage of HF. Reducing the systolic and
diastolic blood pressures of those at risk may prevent HF; diuret-
ics do this in a wide range of target populations [36] . ACE inhibi-
tors also prevent HF, making them good add-on drugs but, when
used alone, their ability to reduce cardiovascular outcomes is not
superior to other antihypertensive drugs [19] . Calcium channel and
D-blockers are less effective in preventing HF [19] .
When treating HTN in a patient at risk of or already with HF,
factors such as LV function and nature of dysfunction, whether
systolic or diastolic, should be taken into consideration. A patient
with stage B HF has structural abnormalities but no symptoms of
failure. Many such patients have had a myocardial infarction with
or without evidence of ventricular remodeling, and are at consid-
erable risk of developing HF [80,81] . ACE inhibition is preferred for
these patients, followed by E-receptor blockade. Combining these
drugs is especially helpful [82] . Angiotensin receptor blockade is
used in patients intolerant to ACE inhibitors.
Stage C HF patients currently have or have had HF symp-
toms. All these patients should take both an ACE inhibitor and
E-receptor blocker at the highest doses tolerated. These agents
reduce the mortality and hospitalization rates of these patients.
Spironolactone, nitrates and hydralazine are added if HTN
remains uncontrolled in advanced HF, and diuretics are reserved
for patients with volume overload. Amlodipine may be considered
but in general, calcium channel blockade is not indicated for
routine treatment of HTN in HF patients with reduced systo-
lic function, unless there is a need after target dose. The other
evidence-based treatments fail to control the blood pressure.
Stage D patients are end stage when hypotension is more likely
than HTN. These patients respond favorably to ACE inhibition
and E-adrenergic blockade (similarly to those with mild-to-mod-
erate disease) but it is not clear if angiotensin receptor blockade
is as effective as ACE inhibition in this group [19] . Spironolactone
prolongs the life and reduces the hospitalization frequency of
NYMA III and IV patients and is another good choice for treating
their HTN. Nitrates and hydralazine are good add-on agents and
preferred if ACE inhibition, angiotensin receptor blockade and
E-adrenergic blockade are not tolerated (TABLE 2) .
Although HFNEF is increasing rapidly, especially in elderly
individuals, we have little evidence-based data to guide our phar-
macologic management of this condition. ARBs, ACE inhibition,
and E-receptor and calcium channel blockade play an important
role in controlling blood pressure, while diuretics are reserved for
patients with volume overload. There is little doubt that ongoing
trials, such as TOPCAT, will provide information that will help
us treat the HTN that coexists with HFNEF.
In the next 5 years, we expect newer drugs being approved for
treatment of HTN in HF. Several agents currently under inves-
tigation include nebivolol, a third-generation, highly selective
E1-receptor blocker that also promotes endothelial nitric oxide
production [83] . HF patients with HTN tolerate this drug well.
In patients with symptomatic HF and reduced systolic function,
its hemodynamic effects are similar to carvedilol. A large trial
showed that nebivolol reduced the composite end point of mortal-
ity and hospitalization in HF patients [84] . Europe has approved
the drug for mild-to-moderate, uncomplicated HTN and mild-
to-moderate HF and, in the USA, the drug is now under FDA
review. In the Study of the Effects of Nebivolol Intervention on
Outcomes and Rehospitalisation in Seniors With Heart Failure
(SENIORS) trial, nebivolol significantly reduced the composite
end point of death and cardiovascular hospitalizations in patients
aged at least 70 years whose ejection fractions were reduced or
preserved [84] .
Aliskiren, a direct renin inhibitor, is another novel agent whose
dose-dependent reductions in blood pressure are comparable to
an ARB, but aliskiren blocks the renin–angiotensin–aldosterone
system more completely than other downstream inhibitors and
prevents the increase in plasma renin that follows diuretic therapy,
ACE inhibition, calcium channel and angiotensin receptor block-
ade. The US FDA-approved aliskiren for HTN in 2007 [85–87] . It

Key issues
s Treatment of hypertension (HTN) in the general population is quite different from those with heart failure (HF).
s A wide range of E-blockers have traditionally been used to control blood pressure. Recent evidence suggests that E-blockers may
increase cardiovascular mortality and morbidity when used to treat essential hypertension; however, in HF patients, the use of
E-blockers decreases mortality. The three well-studied and recommended E-blockers in HF are sustained-release metoprolol, carvedilol
and bisoprolol.
s Nondihyropyridine calcium channel blockers (diltiazem and verapamil) are contraindicated in patients with HF (except in HFNEF) because
of their negative inotropic effects. Although dihydropyridine calcium blockers and hydralazine are direct arterial dilators, only
hydralazine in combination with nitrates has been shown to decrease mortality in patients with HF.
s Thiazides are widely used as first-line therapy for hypertension. In patients with HF, the more potent loop diuretics are preferred.
Furthermore, in HF patients with volume overload not responding to single diuretic agents the combination of a thiazide and loop
diuretic is recommended to improve natriuresis through sequential block in the nephrons. This can also help in HTN management on
top of volume overload.
s Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are indicated for the treatment of HTN
in patients with and without HF. The combination of ACE inhibitors and ARBs is not recommended because of the added adverse effects.
s Aldosterone antagonists (spironolactone and epleronone) have additional antihypertensive effects, especially at doses used for HF. They
are indicated for patients with stage C and stage D HF.
s Newer agents, such as nebivolol (a third-generation, highly selective E1-receptor blocker that also promotes endothelial nitric oxide
production) and aliskiren (a direct renin inhibitor), show promising outcomes in the treatment of HTN in HF patients.

www.expert-reviews.com 429
 Review Manickavasagam, Merla, Koerner et al.
can effectively treat hypertensive African–American patients who
typically do not respond well to E-receptor blockade. The agent may
also help HF patients and, although not approved for HF, it appears
promising. In the Aliskiren Observation of Heart Failure Treatment
(ALOFT) study, favorable neurohormonal changes occurred in
HF patients after combining aliskiren with ACE inhibition or
angiotensin receptor blockade and a E-receptor blocker [88] .
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includes employment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or royalties.
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Management of hypertension in chronic heart failure
Affiliations
s Saraswathy Manickavasagam, MD
University of Texas Medical Branch,
301 University Boulevard 5,106 John Sealy
Annex, Galveston, TX 77555-0553, USA
s Ramanna Merla, MD
Heart Failure and Heart Transplant Fellow
University of Texas Medical Branch
301 University Blvd, JSA 5.106G,
Galveston, TX 77555, USA
Tel.: +1 409 772 1533
s Michael M Koerner, MD
University of Texas, John Sealy Hospital,
Division of Cardiology, 301 University
Boulvard, John Sealy Annex, Ste 5.106,
Galveston, TX 77555, USA
Review
s Ken Fujise, MD
Division of Cardiology, Department of
Internal Medicine, Medical School,
University of Texas Health Science Center
at Houston, Houston, TX, USA
s Sanjay Kunapuli, MD
University of Texas Medical Branch,
301 University Boulevard 5,106 John Sealy
Annex, Galveston, TX 77555-0553, USA
s Salvatore Rosanio, MD
University of Texas Medical Branch,
301 University Boulevard 5,106 John Sealy
Annex, Galveston, TX 77555-0553, USA
s Alejandro Barbagelata, MD
University of Texas Medical Branch,
301 University Boulevard 5,106 John Sealy
Annex, Galveston, TX 77555-0553, USA
Tel.: +1 409 747 2101
Fax: +1 409 772 4982
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