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

Saraswathy Chronic heart failure (CHF) is associated with frequent hospitalizations and high mortality. It
Manickavasagam, affects more than 5 million individuals in the USA, and another 660,000 new cases are diagnosed
Ramanna Merla, 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%
Michael M Koerner,
of cases. HF patients are nearly evenly divided between those with reduced left ventricular (LV)
Ken Fujise, Sanjay function or systolic dysfunction and those with preserved LV systolic function or diastolic
Kunapuli, Salvatore dysfunction. The management of HTN in patients with CHF is challenging. Drugs such as
Rosanio and Alejandro E-blockers, angiotensin-converting enzyme inhibitiors, angiotensin receptor blockers, aldosterone
Barbagelata† receptor blockers, hydralazine and nitrates, which have shown mortality benefit in CHF and

Author for correspondence exert antihypertensive effects, should be used as first-line agents to control HTN in CHF. In
University of Texas Medical addition, antihypertensive drugs such as D-receptor blockers that can increase mortality in HF
Branch, 301 University should be avoided. The dihydropyridine group of calcium channel blockers are good
Boulevard 5,106 John Sealy antihypertensive medications with a neutral effect on mortality in patients with CHF. These may
Annex, Galveston, be used in CHF patients with refractory HTN. In patients with HF with reduced ejection fraction,
TX 77555-0553, USA HTN is treated differently in comparison to patients with HF with normal ejection fraction. This
Tel.: +1 409 747 2101 article reviews the treatment of essential HTN in patients at risk for developing HF, in the presence
Fax: +1 409 772 4982 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 African–Americans and the elderly. [5] In these
660,000 new cases are diagnosed each year [1] . patients, HTN may have caused the HF or be
Overall, heart failure (HF) is responsible for an incidental comorbidity if the HF has resulted
12–15 million general practitioner visits and from other diseases, such as coronary athero-
6.5 million hospital-days annually [1] . According sclerosis. Nonetheless, HTN increases afterload,
to a new analysis of 27 years of trend data from making it especially deleterious in HF patients.
the National Hospital-discharge Surveys, HF has Many drugs that have shown mortality ben-
reached epidemic levels in the USA [2] . The pop- efit in CHF also have antihypertensive effects
ulation of HF patients is heterogeneous, ranging and should be used as first-line agents to control
from the asymptomatic to those with chronic HTN in HF. Angiotensin-converting enzyme
decompensation and advanced symptoms. HF (ACE) inhibitors or angiotensin receptor block-
patients are nearly evenly divided between ers (ARBs) have strong evidence to support their
those with reduced left ventricular (LV) systo- use in HTN patients at risk for HF, as well as
lic function (HF with reduced ejection fraction in patients with HFREF [8–16] . Additionally,
[HFREF]) and those with preserved LV systo- ARBs have greater but conflicting evidence
lic function (HF with normal ejection fraction for use in patients with preserved ejection frac-
[HFNEF]). The latter group is associated with tion [17,18] . Thiazides are the first-line drugs in
essential hypertension (HTN) more often [3,4] . patients with HTN at risk for HF [5] . However,
Hypertension is becoming increasingly in patients with established HF, loop diuretics
prevalent, and it is estimated that 50 mil- are prescribed more often and a thiazide may be
lion or more Americans require treatment for added to promote diuresis by sequentially block-
it [5] . Approximately more than two-thirds of ing sodium transport in renal tubules in cases
patients with HF have a past or current history of where volume overload persists, despite loop
HTN [6,7] . HTN increases the risk of HF two- to diuretics [19] . Conflicting data exist in the use

www.expert-reviews.com 10.1586/ERC.09.8 © 2009 Expert Reviews Ltd ISSN 1477-9072 423


Review Manickavasagam, Merla, Koerner et al.

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

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

www.expert-reviews.com 425
Review Manickavasagam, Merla, Koerner et al.

E-receptor blockers are especially appropriate in HF patients to an ACE inhibitor and a loop diuretic, spironolactone signifi-
with HTN. Unlike their performance in patients with HTN cantly reduced mortality at 24 months in patients with class IV HF,
only, E-blockers improve overall and event-free survival in HF and in those with class III HF who had had class IV HF within
patients [56] . Improvement in survival with E-blockade and ACE 6 months [32] . The Epleronone Post-Acute Myocardial Infarction
inhibition appears to be additive and, in seeking their blood pres- Heart Failure Efficacy and Survival Study (EPHESUS) trial
sure goal, hypertensive patients with HF should start E-blocker showed that eplerenone was associated with a 15% reduction in
therapy without waiting to maximize the dose of ACE inhibitor. A overall mortality at 16 months if started within 2 weeks of a myo-
meta-analysis including 22 trials and more than 10,000 patients cardial infarction in patients with a low ejection fraction and evi-
demonstrated the benefit of E-receptor blockade in HF patients dence of HF and/or diabetes [33] . Both spironolactone or epleronone
with HTN [55] . E-blockers significantly reduced mortality at 1 therapy significantly decreased both systolic and diastolic arterial
and 2 years compared with placebo. The study estimated that, pressure compared with placebo and can be of additional aid in the
during the first year, E-blockade saved 3.8 lives per 100 treated management of HTN in these HF population [32,33] .
patients and reduced hospitalizations by four per 100 treated
patients. Since the improvement appears to be dose related, the Diuretics
aim in stable HF patients with HTN is to eventually maximize Although diuretics are the mainstay of treating acutely decom-
both E-blocker therapy and ACE-inhibition (or angiotensin pensated HF, no long-term, randomized clinical trial has shown
receptor blockade). that they reduce morbidity or mortality, despite their relief of
pulmonary and systemic venous congestion. Loop diuretics (e.g.,
Aldosterone antagonists furosemide, bumetenide, torsemide and ethacrynic acid) are used
Aldosterone can adversely affect the heart’s structure and func- most commonly in HF patients, followed by thiazide and thi-
tion [57–59] . Blocking its effects can improve survival of patients azide-like diuretics (e.g., chlorthalidone, hydrochlorothiazide,
with moderate-to-severe HF symptoms with recent decompensa- indapamide and metolazone), which are usually less effective in
tion [60] , and recent myocardial infarction with LV dysfunction [61] . this setting. Treating volume overload with a loop diuretic reduces
Aldosterone-blocking agents may also reduce arrhythmic death intracardiac filling pressure and cardiac output and, in hyper-
in patients with mild-to-moderate HF [62] . The Randomized tensive patients, may decrease systolic and diastolic blood pres-
Aldactone Evaluation Study (RALES) trial found that when added 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 Use in all patients Use in patients Ideal in moderately Ideal in Black people
contraindicated. If patient unless contraindicated with fluid overload severe or severe HF with moderate-to-severe
intolerable to ACE-I recent decompensation HF who were already
secondary to cough or in patients with a recent being treated with
start ARB MI and LVD 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 (ACC), American Heart Association (AHA) and Heart Failure
in blood urea nitrogen (BUN) may represent tissue hypoperfusion Society accept using amlodipine in HF patients with HTN
that warrants a reduction in dose. because it may be safe and well tolerated [19] . Limited trials have
Thiazides can reduce the incidence of HF in patients with reported that reducing central sympathetic outflow (clonidine)
HTN and prevent HTN-related mortality and morbidity but fail and blocking peripheral D-receptors (prazosin) can benefit CHF
to prolong survival if patients already have HF. Recent guidelines patients [29,30] . These agents are not recommended for CHF at this
suggest using thiazide diuretics in hypertensive HF patients with time. Potent vasodilators (minoxidil) are avoided in HF patients
mild fluid retention because of their persistent antihypertensive because they promote sodium retention (TABLE 1) [19] .
action [19] . The Heart Failure Society suggests adding chloro-
thiazide or metolazone to a loop diuretic if the latter is unsuc- HTN in patients with HFNEF
cessful in reduce fluid retention alone [8] . One may fully block the The Organized Program to Initiate Lifesaving Treatment in
distal convoluted tubule by administering a diuretic that affects Hospitalized Patients with Heart Failure (OPTIMIZE–HF)
the distal tubule, followed by a loop diuretic. This may increase Registry confirmed the high prevalence of HFNEF and indi-
the natriuresis in chronic renal failure patients, in whom thiazides cated that their postdischarge mortality and hospitalization rates
alone are much less effective. However, this combination may not are similar to those with HFREF [68] . Nevertheless, we lack reli-
significantly reduce blood pressure. able data on the optimal management of these patients. HTN
frequently coexists, and a recent study cites HTN as the cause
Hydralazine & nitrates of approximately 61% of HFNEF cases. Many patients will have
Combining isosorbide dinitrate and hydralazine with stand- LV hypertrophy and approximately two-thirds will have diastolic
ard therapy is especially effective in prolonging the survival of dysfunction as well [32] .
African–American patients with moderate-to-severe HF [64] , and For these patients, the AHA/ACC recommend a lower tar-
may provide good blood pressure control in those already taking get blood pressure than for uncomplicated HTN (i.e., less than
an ACE inhibitor, E-blocker and, perhaps, also an aldosterone 130/80 mmHg [17,19,69]), since higher blood pressures continue to
antagonist. The African–American Heart Failure Trial (AHeFT) worsen ventricular structure and performance. Increases in systolic
showed that a fixed-dose combination of isosorbide dinitrate and blood pressure slow myocardial relaxation [70] , and hypertrophy
hydralazine improved the survival of African–American patients increases passive chamber stiffness. Fortunately, blood pressure con-
with class III or IV HF by 43% [64,65] . The combination’s reduc- trol will eventually improve diastolic function in these patients [17] .
tion of blood pressure may have helped improve survival. Since However the blood pressure that may be achieved without adversely
this regimen calls for multiple daily doses, is less efficient in reduc- affecting cardiac output will vary widely from patient to patient.
ing mortality and blood pressure and causes more side effects than
ACE inhibition alone and, therefore, it is usually added to ACE Renin–angiotensin inhibitors
inhibitor and E-blocker therapy (FIGURE 2) [14] . Angiotensin receptor blockade has been well studied in patients.
The CHARM-Preserved trial showed that candesartan reduced
Less-ideal agents hospitalizations of patients with class II–IV CHF whose ejection
Some drugs are not recommended for HF patients. Calcium chan- fraction was greater than 40%, although it did not significantly
nel blockade does not improve symptoms and can worsen CHF reduce cardiovascular death. In another study, losartan improved
and the risk of death in these patients. Amlodipine and felodipine exercise tolerance and quality of life [17] . LV hypertrophy may regress
neither improve nor worsen the survival of HF patients [66,67] and, to a greater degree with angiotensin receptor blockade than ACE
generally, would not be chosen before other drugs of known inhibition. A meta-analysis examining the efficacy of antihyper-
survival benefit. However, the American College of Cardiology tensive drugs in reversing LV hypertrophy in patients with HTN

www.expert-reviews.com 427
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 their HTN. Nitrates and hydralazine are good add-on agents and
diastolic blood pressures of those at risk may prevent HF; diuret- preferred if ACE inhibition, angiotensin receptor blockade and
ics do this in a wide range of target populations [36] . ACE inhibi- E-adrenergic blockade are not tolerated (TABLE 2) .
tors also prevent HF, making them good add-on drugs but, when Although HFNEF is increasing rapidly, especially in elderly
used alone, their ability to reduce cardiovascular outcomes is not individuals, we have little evidence-based data to guide our phar-
superior to other antihypertensive drugs [19] . Calcium channel and macologic management of this condition. ARBs, ACE inhibition,
D-blockers are less effective in preventing HF [19] . and E-receptor and calcium channel blockade play an important
When treating HTN in a patient at risk of or already with HF, role in controlling blood pressure, while diuretics are reserved for
factors such as LV function and nature of dysfunction, whether patients with volume overload. There is little doubt that ongoing
systolic or diastolic, should be taken into consideration. A patient trials, such as TOPCAT, will provide information that will help
with stage B HF has structural abnormalities but no symptoms of us treat the HTN that coexists with HFNEF.
failure. Many such patients have had a myocardial infarction with In the next 5 years, we expect newer drugs being approved for
or without evidence of ventricular remodeling, and are at consid- treatment of HTN in HF. Several agents currently under inves-
erable risk of developing HF [80,81] . ACE inhibition is preferred for tigation include nebivolol, a third-generation, highly selective
these patients, followed by E-receptor blockade. Combining these E1-receptor blocker that also promotes endothelial nitric oxide
drugs is especially helpful [82] . Angiotensin receptor blockade is production [83] . HF patients with HTN tolerate this drug well.
used in patients intolerant to ACE inhibitors. In patients with symptomatic HF and reduced systolic function,
Stage C HF patients currently have or have had HF symp- its hemodynamic effects are similar to carvedilol. A large trial
toms. All these patients should take both an ACE inhibitor and showed that nebivolol reduced the composite end point of mortal-
E-receptor blocker at the highest doses tolerated. These agents ity and hospitalization in HF patients [84] . Europe has approved
reduce the mortality and hospitalization rates of these patients. the drug for mild-to-moderate, uncomplicated HTN and mild-
Spironolactone, nitrates and hydralazine are added if HTN to-moderate HF and, in the USA, the drug is now under FDA
remains uncontrolled in advanced HF, and diuretics are reserved review. In the Study of the Effects of Nebivolol Intervention on
for patients with volume overload. Amlodipine may be considered Outcomes and Rehospitalisation in Seniors With Heart Failure
but in general, calcium channel blockade is not indicated for (SENIORS) trial, nebivolol significantly reduced the composite
routine treatment of HTN in HF patients with reduced systo- end point of death and cardiovascular hospitalizations in patients
lic function, unless there is a need after target dose. The other aged at least 70 years whose ejection fractions were reduced or
evidence-based treatments fail to control the blood pressure. preserved [84] .
Stage D patients are end stage when hypotension is more likely Aliskiren, a direct renin inhibitor, is another novel agent whose
than HTN. These patients respond favorably to ACE inhibition dose-dependent reductions in blood pressure are comparable to
and E-adrenergic blockade (similarly to those with mild-to-mod- an ARB, but aliskiren blocks the renin–angiotensin–aldosterone
erate disease) but it is not clear if angiotensin receptor blockade system more completely than other downstream inhibitors and
is as effective as ACE inhibition in this group [19] . Spironolactone prevents the increase in plasma renin that follows diuretic therapy,
prolongs the life and reduces the hospitalization frequency of ACE inhibition, calcium channel and angiotensin receptor block-
NYMA III and IV patients and is another good choice for treating 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 Financial & competing interests disclosure
typically do not respond well to E-receptor blockade. The agent may The authors have no relevant affiliations or financial involvement with
also help HF patients and, although not approved for HF, it appears any organization or entity with a financial interest in or financial conflict
promising. In the Aliskiren Observation of Heart Failure Treatment with the subject matter or materials discussed in the manuscript. This
(ALOFT) study, favorable neurohormonal changes occurred in includes employment, consultancies, honoraria, stock ownership or options,
HF patients after combining aliskiren with ACE inhibition or expert testimony, grants or patents received or pending, or royalties.
angiotensin receptor blockade and a E-receptor blocker [88] . No writing assistance was utilized in the production of this manuscript.

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87 Villamil A, Chrysant SG, Calhoun D et al. Affiliations s Ken Fujise, MD


Renin inhibition with aliskiren provides Division of Cardiology, Department of
s Saraswathy Manickavasagam, MD
additive antihypertensive efficacy when Internal Medicine, Medical School,
University of Texas Medical Branch,
used in combination with University of Texas Health Science Center
301 University Boulevard 5,106 John Sealy
hydrochlorothiazide. J. Hyperten. 25(1), at Houston, Houston, TX, USA
Annex, Galveston, TX 77555-0553, USA
217–226 (2007). s Sanjay Kunapuli, MD
s Ramanna Merla, MD
88 Recio-Mayoral A, Kaski JC, McMurray JJ, University of Texas Medical Branch,
Heart Failure and Heart Transplant Fellow
Horowitz J, van Veldhuisen DJ, Remme 301 University Boulevard 5,106 John Sealy
University of Texas Medical Branch
WJ. Clinical trials update from the Annex, Galveston, TX 77555-0553, USA
301 University Blvd, JSA 5.106G,
European Society of Cardiology Congress s Salvatore Rosanio, MD
Galveston, TX 77555, USA
in Vienna, 2007: PROSPECT, EVEREST, University of Texas Medical Branch,
Tel.: +1 409 772 1533
ARISE, ALOFT, FINESSE, Prague-8, 301 University Boulevard 5,106 John Sealy
CARESS in MI and ACUITY. Cardiovasc. s Michael M Koerner, MD
Annex, Galveston, TX 77555-0553, USA
Drugs Ther. 21(6), 459–465 (2007). University of Texas, John Sealy Hospital,
Division of Cardiology, 301 University s Alejandro Barbagelata, MD
Boulvard, John Sealy Annex, Ste 5.106, University of Texas Medical Branch,
Galveston, TX 77555, USA 301 University Boulevard 5,106 John Sealy
Annex, Galveston, TX 77555-0553, USA
Tel.: +1 409 747 2101
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